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Sample records for placebo-controlled dose-escalation proof-of-concept

  1. Efficacy and safety of celgosivir in patients with dengue fever (CELADEN): a phase 1b, randomised, double-blind, placebo-controlled, proof-of-concept trial.

    Science.gov (United States)

    Low, Jenny G; Sung, Cynthia; Wijaya, Limin; Wei, Yuan; Rathore, Abhay P S; Watanabe, Satoru; Tan, Boon Hian; Toh, Liying; Chua, Lian Tee; Hou, Yan'an; Chow, Angelia; Howe, Shiqin; Chan, Wing Ki; Tan, Kah Hin; Chung, Jasmine S; Cherng, Benjamin P; Lye, David C; Tambayah, Paul A; Ng, Lee Ching; Connolly, John; Hibberd, Martin L; Leo, Yee Sin; Cheung, Yin Bun; Ooi, Eng Eong; Vasudevan, Subhash G

    2014-08-01

    Dengue infection is the most common mosquito-borne viral disease worldwide, but no suitable antiviral drugs are available. We tested the α-glucosidase inhibitor celgosivir as a treatment for acute dengue fever. To establish eligibility for inclusion in a phase 1b, randomised, double-blind, placebo-controlled, proof-of-concept trial, individuals aged 21-65 years who had had a fever (≥38°C) for less than 48 h, met at least two criteria indicating probable dengue infection, and had a positive result on a dengue point-of-care test kit or PCR assay were referred for screening at a centre in Singapore between July 30, 2012, and March 4, 2013. Using a web-based system, we randomly assigned patients who met full inclusion criteria after screening (1:1; random permuted block length four) to celgosivir (initial 400 mg loading dose within 6 h of randomisation, followed by 200 mg every 12 h for a total of nine doses) or matched placebo. Patients and the entire study team were masked to group assignment. The primary endpoints were mean virological log reduction (VLR) from baseline for days 2, 3, and 4, and area under the fever curve (AUC) for a temperature above 37°C from 0 h to 96 h. Efficacy analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01619969. We screened 69 patients and randomly assigned 50 (24 to celgosivir, 26 to placebo). Mean VLR was greater in the celgosivir group (-1·86, SD 1·07) than in the placebo group (-1·64, 0·75), but the difference was non-significant (-0·22, 90% CI -0·65 to 0·22; one-sided p=0·203). The mean AUC was also higher in the celgosivir group (54·92, SD 31·04) than in the placebo group (40·72, 18·69), but again the difference was non-significant (14·20, 90% CI 2·16-26·25; one-sided p=0·973). We noted similar incidences of adverse events between groups. Although generally safe and well tolerated, celgosivir does not seem to reduce viral load or fever burden in patients with

  2. Effects of voluntary dose escalation in a placebo-controlled, flexible-dose trial of fesoterodine in subjects with overactive bladder.

    Science.gov (United States)

    Staskin, David; Khullar, Vik; Michel, Martin C; Morrow, Jon D; Sun, Franklin; Guan, Zhonghong; Dmochowski, Roger

    2011-11-01

    To characterize the response to fesoterodine treatment for overactive bladder (OAB) in subjects who did or did not choose to dose escalate in a flexible-dose study. Subjects were randomized to fesoterodine 4  mg or placebo. At week 2, subjects could remain on 4  mg (non-escalators) or choose to increase to 8  mg (escalators) for the remaining 10 weeks (sham escalation for placebo). Subjects completed 3-day bladder diaries at baseline, week 2 and week 12 noting micturitions, urgency episodes, and urgency urinary incontinence (UUI) episodes. Sixty-three per cent of 438 subjects randomized to fesoterodine and 73% of 445 randomized to placebo dose escalated. At baseline, fesoterodine escalators had significantly more micturitions and urgency episodes than fesoterodine non-escalators (P fesoterodine non-escalators versus escalators (P fesoterodine non-escalators and escalators (P > 0.05). The placebo escalator group did not demonstrate a similar response over placebo non-escalators following the dose escalation decision point. A rapid and robust response to fesoterodine 4  mg was demonstrated in non-escalators. Subjects who chose to dose escalate to fesoterodine 8  mg at week 2 showed significant improvement by week 12 versus baseline and week 2 (prior to escalation), as well as versus placebo. Dose escalation to 8  mg fesoterodine provided subjects with efficacy and tolerability similar to those who were satisfied with the 4-mg dose. Copyright © 2011 Wiley Periodicals, Inc.

  3. Recombinant T-Cell Receptor Ligand (RTL for Treatment of Multiple Sclerosis: A Double-Blind, Placebo-Controlled, Phase 1, Dose-Escalation Study

    Directory of Open Access Journals (Sweden)

    Vijayshree Yadav

    2012-01-01

    Full Text Available Background. Recombinant T-cell receptor ligand 1000 (RTL1000 is a single-chain protein construct containing the outer two domains of HLA-DR2 linked to myelin-oligodendrocyte-glycoprotein- (MOG- 35–55 peptide. Analogues of RTL1000 induce T-cell tolerance, reverse clinical and histological disease, and promote repair in experimental autoimmune encephalomyelitis (EAE in DR2 transgenic, C57BL/6, and SJL/J mice. Objective. Determining the maximum tolerated dose, safety, and tolerability of RTL1000 in multiple sclerosis (MS subjects. Methods. This was a multicenter, Phase I dose-escalation study in HLA-DR2+ MS subjects. Consecutive cohorts received RTL1000 doses of 2, 6, 20, 60, 200, and 100 mg, respectively. Subjects within each cohort randomly received a single intravenous infusion of RTL1000 or placebo at a 4 : 2 ratio. Safety monitoring included clinical, laboratory, and brain magnetic resonance imaging (MRI evaluations. Results. Thirty-four subjects completed the protocol. All subjects tolerated the 2–60 mg doses of RTL1000. Doses ≥100 mg caused hypotension and diarrhea in 3 of 4 subjects, leading to discontinuation of further enrollment. Conclusions. The maximum tolerated dose of RTL1000 in MS subjects is 60 mg, comparable to effective RTL doses in EAE. RTL1000 is a novel approach for MS treatment that may induce immunoregulation without immunosuppression and promote neural repair.

  4. Acute beetroot juice supplementation on sympathetic nerve activity: a randomized, double-blind, placebo-controlled proof-of-concept study.

    Science.gov (United States)

    Notay, Karambir; Incognito, Anthony V; Millar, Philip J

    2017-07-01

    exaggerated sympathetic outflow in clinical populations.NEW & NOTEWORTHY The hemodynamic benefits of dietary nitrate supplementation have been attributed to nitric oxide-mediated peripheral vasodilation. Here, we provide proof of concept that acute dietary nitrate supplementation using beetroot juice can decrease muscle sympathetic outflow at rest and during exercise in a normotensive population. These results have applications for targeting central sympathetic overactivation in disease. Copyright © 2017 the American Physiological Society.

  5. No effect on QT intervals of mipomersen, a 2'-O-methoxyethyl modified antisense oligonucleotide targeting ApoB-100 mRNA, in a phase I dose escalation placebo-controlled study, and confirmed by a thorough QT (tQT) study, in healthy subjects.

    Science.gov (United States)

    Yu, Rosie Z; Gunawan, Rudy; Li, Zhaoyang; Mittleman, Robert S; Mahmood, Asif; Grundy, John S; Singleton, Walter; Geary, Richard; Wang, Yanfeng

    2016-03-01

    The aim of this study to evaluate the effect of mipomersen on QT intervals in a phase I dose escalation, placebo-controlled study, and a thorough QT (tQT) study in healthy subjects. In the initial phase I study, 29 healthy subjects received either single or multiple (for 4 weeks) ascending doses of mipomersen (50-400 mg) administered subcutaneously (SC) or via a 2-h intravenous (IV) infusion, and 7 subjects received placebo. In the confirmative tQT study, 58 healthy subjects received placebo, 400 mg IV moxifloxacin, 200 mg SC, or 200 mg IV of mipomersen in a double-blind, 4-way crossover design with a minimum 5-day washout between treatments. ECG measurements were performed at baseline and selected time points (including Tmax). The correlation between QTcF intervals corrected for baseline and time-matched placebo when available with PK plasma exposure was evaluated by linear regression analysis. In the phase I study, no positive correlation between the PK exposure and ∆QTcF or ∆∆QTcF was observed within the wide dose or exposure range tested. Similar results were observed in the tQT study, where the predicted ΔΔQTcF and its upper bound of the 90% CI at Cmax of therapeutic and supratherapeutic dose were approximately -1.7 and 2.9 ms, respectively. Mipomersen showed no effect on QT intervals in both the phase I dose escalation study and the tQT study. These results support the proposal that QT assessment can be made in a phase I dose escalation study, and no tQT study may be necessary if the phase I dose escalation study showed a negative QT effect.

  6. Efficacy and safety of guaifenesin for upper back, neck, and shoulder pain: a Phase II proof-of-concept, multicenter, placebo-controlled, repeat-dose, parallel-group study

    OpenAIRE

    Collaku A; Yue Y.; Reed K

    2017-01-01

    Agron Collaku, Yong Yue, Kenneth Reed GlaxoSmithKline Consumer Healthcare, Parsippany, NJ, USA Background/objective: Guaifenesin, an over-the-counter (OTC) expectorant, has exhibited muscle relaxant effects preclinically and clinically. This proof-of-principle study explored whether OTC doses of guaifenesin can provide relief from acute upper back, neck, or shoulder muscle spasm and pain. Methods: This multicenter, placebo-controlled, repeat-dose, parallel study randomly ass...

  7. Efficacy and safety of guaifenesin for upper back, neck, and shoulder pain: a Phase II proof-of-concept, multicenter, placebo-controlled, repeat-dose, parallel-group study.

    Science.gov (United States)

    Collaku, Agron; Yue, Yong; Reed, Kenneth

    2017-01-01

    Guaifenesin, an over-the-counter (OTC) expectorant, has exhibited muscle relaxant effects preclinically and clinically. This proof-of-principle study explored whether OTC doses of guaifenesin can provide relief from acute upper back, neck, or shoulder muscle spasm and pain. This multicenter, placebo-controlled, repeat-dose, parallel study randomly assigned adults experiencing acute pain and muscle spasm in their upper back, neck, or shoulder to guaifenesin 600 or 1200 mg or matched placebo twice daily (BID) in a 2:2:1:1 ratio for 7 days. The primary end point was the change from baseline in muscle spasm relief, measured using an 11-point numeric rating scale (0=not present to 10=unbearable) recorded twice daily and averaged over the 7-day treatment period. Analyses were performed using a linear mixed model that included treatment as a fixed effect and site as a random effect. A total of 77 subjects were included in the 4 treatment groups. Least squares mean muscle spasm score over 7 days was 1.77 with guaifenesin 1200 mg, 1.42 with its matched placebo, 1.53 with guaifenesin 600 mg, and 1.74 with its matched placebo. Treatment with guaifenesin 1200 mg BID provided 25% greater reduction in mean muscle spasm over its matched placebo and 16% greater reduction than guaifenesin 600 mg BID. These differences were not statistically significant. Based on comparisons of absolute mean values, a consistent directional change in effect was observed, suggesting some benefit from placebo to lower-to-upper doses of guaifenesin with regard to muscle spasm, tension, pain, discomfort, and relaxation. No severe or serious adverse events were reported. Results suggest the potential for OTC dose of guaifenesin 1200 mg BID to provide symptomatic relief of upper back musculoskeletal pain and spasm. Confirmation of this preliminary result in a larger, adequately powered study is needed.

  8. Efficacy and safety of guaifenesin for upper back, neck, and shoulder pain: a Phase II proof-of-concept, multicenter, placebo-controlled, repeat-dose, parallel-group study

    Science.gov (United States)

    Collaku, Agron; Yue, Yong; Reed, Kenneth

    2017-01-01

    Background/objective Guaifenesin, an over-the-counter (OTC) expectorant, has exhibited muscle relaxant effects preclinically and clinically. This proof-of-principle study explored whether OTC doses of guaifenesin can provide relief from acute upper back, neck, or shoulder muscle spasm and pain. Methods This multicenter, placebo-controlled, repeat-dose, parallel study randomly assigned adults experiencing acute pain and muscle spasm in their upper back, neck, or shoulder to guaifenesin 600 or 1200 mg or matched placebo twice daily (BID) in a 2:2:1:1 ratio for 7 days. The primary end point was the change from baseline in muscle spasm relief, measured using an 11-point numeric rating scale (0=not present to 10=unbearable) recorded twice daily and averaged over the 7-day treatment period. Analyses were performed using a linear mixed model that included treatment as a fixed effect and site as a random effect. Results A total of 77 subjects were included in the 4 treatment groups. Least squares mean muscle spasm score over 7 days was 1.77 with guaifenesin 1200 mg, 1.42 with its matched placebo, 1.53 with guaifenesin 600 mg, and 1.74 with its matched placebo. Treatment with guaifenesin 1200 mg BID provided 25% greater reduction in mean muscle spasm over its matched placebo and 16% greater reduction than guaifenesin 600 mg BID. These differences were not statistically significant. Based on comparisons of absolute mean values, a consistent directional change in effect was observed, suggesting some benefit from placebo to lower-to-upper doses of guaifenesin with regard to muscle spasm, tension, pain, discomfort, and relaxation. No severe or serious adverse events were reported. Conclusion Results suggest the potential for OTC dose of guaifenesin 1200 mg BID to provide symptomatic relief of upper back musculoskeletal pain and spasm. Confirmation of this preliminary result in a larger, adequately powered study is needed. PMID:28356767

  9. Efficacy and safety of guaifenesin for upper back, neck, and shoulder pain: a Phase II proof-of-concept, multicenter, placebo-controlled, repeat-dose, parallel-group study

    Directory of Open Access Journals (Sweden)

    Collaku A

    2017-03-01

    Full Text Available Agron Collaku, Yong Yue, Kenneth Reed GlaxoSmithKline Consumer Healthcare, Parsippany, NJ, USA Background/objective: Guaifenesin, an over-the-counter (OTC expectorant, has exhibited muscle relaxant effects preclinically and clinically. This proof-of-principle study explored whether OTC doses of guaifenesin can provide relief from acute upper back, neck, or shoulder muscle spasm and pain. Methods: This multicenter, placebo-controlled, repeat-dose, parallel study randomly assigned adults experiencing acute pain and muscle spasm in their upper back, neck, or shoulder to guaifenesin 600 or 1200 mg or matched placebo twice daily (BID in a 2:2:1:1 ratio for 7 days. The primary end point was the change from baseline in muscle spasm relief, measured using an 11-point numeric rating scale (0= not present to 10= unbearable recorded twice daily and averaged over the 7-day treatment period. Analyses were performed using a linear mixed model that included treatment as a fixed effect and site as a random effect. Results: A total of 77 subjects were included in the 4 treatment groups. Least squares mean muscle spasm score over 7 days was 1.77 with guaifenesin 1200 mg, 1.42 with its matched placebo, 1.53 with guaifenesin 600 mg, and 1.74 with its matched placebo. Treatment with guaifenesin 1200 mg BID provided 25% greater reduction in mean muscle spasm over its matched placebo and 16% greater reduction than guaifenesin 600 mg BID. These differences were not statistically significant. Based on comparisons of absolute mean values, a consistent directional change in effect was observed, suggesting some benefit from placebo to lower-to-upper doses of guaifenesin with regard to muscle spasm, tension, pain, discomfort, and relaxation. No severe or serious adverse events were reported. Conclusion: Results suggest the potential for OTC dose of guaifenesin 1200 mg BID to provide symptomatic relief of upper back musculoskeletal pain and spasm. Confirmation of

  10. MOR103, a human monoclonal antibody to granulocyte–macrophage colony-stimulating factor, in the treatment of patients with moderate rheumatoid arthritis: results of a phase Ib/IIa randomised, double-blind, placebo-controlled, dose-escalation trial

    Science.gov (United States)

    Behrens, Frank; Tak, Paul P; Østergaard, Mikkel; Stoilov, Rumen; Wiland, Piotr; Huizinga, Thomas W; Berenfus, Vadym Y; Vladeva, Stoyanka; Rech, Juergen; Rubbert-Roth, Andrea; Korkosz, Mariusz; Rekalov, Dmitriy; Zupanets, Igor A; Ejbjerg, Bo J; Geiseler, Jens; Fresenius, Julia; Korolkiewicz, Roman P; Schottelius, Arndt J; Burkhardt, Harald

    2015-01-01

    Objectives To determine the safety, tolerability and signs of efficacy of MOR103, a human monoclonal antibody to granulocyte–macrophage colony-stimulating factor (GM-CSF), in patients with rheumatoid arthritis (RA). Methods Patients with active, moderate RA were enrolled in a randomised, multicentre, double-blind, placebo-controlled, dose-escalation trial of intravenous MOR103 (0.3, 1.0 or 1.5 mg/kg) once a week for 4 weeks, with follow-up to 16 weeks. The primary outcome was safety. Results Of the 96 randomised and treated subjects, 85 completed the trial (n=27, 24, 22 and 23 for pooled placebo and MOR103 0.3, 1.0 and 1.5 mg/kg, respectively). Treatment emergent adverse events (AEs) in the MOR103 groups were mild or moderate in intensity and generally reported at frequencies similar to those in the placebo group. The most common AE was nasopharyngitis. In two cases, AEs were classified as serious because of hospitalisation: paronychia in a placebo subject and pleurisy in a MOR103 0.3 mg/kg subject. Both patients recovered fully. In exploratory efficacy analyses, subjects in the MOR103 1.0 and 1.5 mg/kg groups showed significant improvements in Disease Activity Score-28 scores and joint counts and significantly higher European League Against Rheumatism response rates than subjects receiving placebo. MOR103 1.0 mg/kg was associated with the largest reductions in disease activity parameters. Conclusions MOR103 was well tolerated and showed preliminary evidence of efficacy in patients with active RA. The data support further investigation of this monoclonal antibody to GM-CSF in RA patients and potentially in those with other immune-mediated inflammatory diseases. Trial registration number NCT01023256 PMID:24534756

  11. MOR103, a human monoclonal antibody to granulocyte-macrophage colony-stimulating factor, in the treatment of patients with moderate rheumatoid arthritis: results of a phase Ib/IIa randomised, double-blind, placebo-controlled, dose-escalation trial.

    Science.gov (United States)

    Behrens, Frank; Tak, Paul P; Østergaard, Mikkel; Stoilov, Rumen; Wiland, Piotr; Huizinga, Thomas W; Berenfus, Vadym Y; Vladeva, Stoyanka; Rech, Juergen; Rubbert-Roth, Andrea; Korkosz, Mariusz; Rekalov, Dmitriy; Zupanets, Igor A; Ejbjerg, Bo J; Geiseler, Jens; Fresenius, Julia; Korolkiewicz, Roman P; Schottelius, Arndt J; Burkhardt, Harald

    2015-06-01

    To determine the safety, tolerability and signs of efficacy of MOR103, a human monoclonal antibody to granulocyte-macrophage colony-stimulating factor (GM-CSF), in patients with rheumatoid arthritis (RA). Patients with active, moderate RA were enrolled in a randomised, multicentre, double-blind, placebo-controlled, dose-escalation trial of intravenous MOR103 (0.3, 1.0 or 1.5 mg/kg) once a week for 4 weeks, with follow-up to 16 weeks. The primary outcome was safety. Of the 96 randomised and treated subjects, 85 completed the trial (n=27, 24, 22 and 23 for pooled placebo and MOR103 0.3, 1.0 and 1.5 mg/kg, respectively). Treatment emergent adverse events (AEs) in the MOR103 groups were mild or moderate in intensity and generally reported at frequencies similar to those in the placebo group. The most common AE was nasopharyngitis. In two cases, AEs were classified as serious because of hospitalisation: paronychia in a placebo subject and pleurisy in a MOR103 0.3 mg/kg subject. Both patients recovered fully. In exploratory efficacy analyses, subjects in the MOR103 1.0 and 1.5 mg/kg groups showed significant improvements in Disease Activity Score-28 scores and joint counts and significantly higher European League Against Rheumatism response rates than subjects receiving placebo. MOR103 1.0 mg/kg was associated with the largest reductions in disease activity parameters. MOR103 was well tolerated and showed preliminary evidence of efficacy in patients with active RA. The data support further investigation of this monoclonal antibody to GM-CSF in RA patients and potentially in those with other immune-mediated inflammatory diseases. NCT01023256. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  12. Bistatic SAR: Proof of Concept.

    Energy Technology Data Exchange (ETDEWEB)

    Yocky, David A.; Doren, Neall E.; Bacon, Terry A.; Wahl, Daniel E.; Eichel, Paul H.; Jakowatz, Charles V,; Delaplain, Gilbert G.; Dubbert, Dale F.; Tise, Bertice L.; White, Kyle R.

    2014-10-01

    Typical synthetic aperture RADAR (SAR) imaging employs a co-located RADAR transmitter and receiver. Bistatic SAR imaging separates the transmitter and receiver locations. A bistatic SAR configuration allows for the transmitter and receiver(s) to be in a variety of geometric alignments. Sandia National Laboratories (SNL) / New Mexico proposed the deployment of a ground-based RADAR receiver. This RADAR receiver was coupled with the capability of digitizing and recording the signal collected. SNL proposed the possibility of creating an image of targets the illuminating SAR observes. This document describes the developed hardware, software, bistatic SAR configuration, and its deployment to test the concept of a ground-based bistatic SAR. In the proof-of-concept experiments herein, the RADAR transmitter will be a commercial SAR satellite and the RADAR receiver will be deployed at ground level, observing and capturing RADAR ground/targets illuminated by the satellite system.

  13. ATAC Process Proof of Concept Final Report

    Energy Technology Data Exchange (ETDEWEB)

    Bri Rolston; Sarah Freeman

    2014-03-01

    Researchers at INL with funding from the Department of Energy’s Office of Electricity Delivery and Energy Reliability (DOE-OE) evaluated a novel approach for near real-time consumption of threat intelligence. Demonstration testing in an industry environment supported the development of this new process to assist the electric sector in securing their critical networks. This report provides the reader with an understanding of the methods used during this proof of concept project. The processes and templates were further advanced with an industry partner during an onsite assessment. This report concludes with lessons learned and a roadmap for final development of these materials for use by industry.

  14. The Versatile Transceiver Proof of Concept

    CERN Document Server

    Troska, J; Papadopoulos, S; Papakonstantinou, I; Rui Silva, S; Seif el Nasr, S; Sigaud, C; Stejskal,; Soos, C; Vasey, F

    2009-01-01

    SLHC experiment upgrades will make substantial use of optical links to enable high-speed data readout and control. The Versatile Link project will develop and assess optical link architectures and components suitable for deployment at SLHC. The on-detector element will be bidirectional optoelectronic module: the Versatile Transceiver that will be based on a commercially available module type minimally customized to meet the constraints of the SLHC on-detector environment in terms of mass, volume, power consumption, operational temperature and radiation environment. We report on the first proof of concept phase of the development, showing the steps towards customization and first results of the radiation resistance of candidate optoelectronic components.

  15. Group online mindfulness training: proof of concept.

    Science.gov (United States)

    Kemper, Kathi J; Yun, Jonathan

    2015-01-01

    Mindfulness-based stress reduction training is attractive, but training with an expert teacher is often inconvenient and costly. This proof-of-concept project assessed the feasibility of providing a hybrid of free online mindfulness-based stress reduction training with small group peer facilitation. Six medical students asked a family medicine resident with 5 years of meditation experience but no formal training as a teacher to facilitate 8 weekly group sessions using a free online mindfulness-based stress reduction course. They completed pre- and posttraining questionnaires online. Six of the 7 trainees completed at least half the sessions. Completers and noncompleters had similar age (29 years), gender (about half male), and health status. Changes in the expected direction were observed for perceived stress, mindfulness, resilience, and confidence in providing calm, compassionate care. The hybrid of online mindfulness-based stress reduction training with peer support is feasible. Additional research is warranted to formally evaluate the impact of this approach.

  16. Scada Malware, a Proof of Concept

    Science.gov (United States)

    Carcano, Andrea; Fovino, Igor Nai; Masera, Marcelo; Trombetta, Alberto

    Critical Infrastructures are nowadays exposed to new kind of threats. The cause of such threats is related to the large number of new vulnerabilities and architectural weaknesses introduced by the extensive use of ICT and Network technologies into such complex critical systems. Of particular interest are the set of vulnerabilities related to the class of communication protocols normally known as “SCADA” protocols, under which fall all the communication protocols used to remotely control the RTU devices of an industrial system. In this paper we present a proof of concept of the potential effects of a set of computer malware specifically designed and created in order to impact, by taking advantage of some vulnerabilities of the ModBUS protocol, on a typical Supervisory Control and Data Acquisition system.

  17. Quantifying reliability uncertainty : a proof of concept.

    Energy Technology Data Exchange (ETDEWEB)

    Diegert, Kathleen V.; Dvorack, Michael A.; Ringland, James T.; Mundt, Michael Joseph; Huzurbazar, Aparna (Los Alamos National Laboratory, Los Alamos, NM); Lorio, John F.; Fatherley, Quinn (Los Alamos National Laboratory, Los Alamos, NM); Anderson-Cook, Christine (Los Alamos National Laboratory, Los Alamos, NM); Wilson, Alyson G. (Los Alamos National Laboratory, Los Alamos, NM); Zurn, Rena M.

    2009-10-01

    This paper develops Classical and Bayesian methods for quantifying the uncertainty in reliability for a system of mixed series and parallel components for which both go/no-go and variables data are available. Classical methods focus on uncertainty due to sampling error. Bayesian methods can explore both sampling error and other knowledge-based uncertainties. To date, the reliability community has focused on qualitative statements about uncertainty because there was no consensus on how to quantify them. This paper provides a proof of concept that workable, meaningful quantification methods can be constructed. In addition, the application of the methods demonstrated that the results from the two fundamentally different approaches can be quite comparable. In both approaches, results are sensitive to the details of how one handles components for which no failures have been seen in relatively few tests.

  18. The direct liquefaction proof of concept program

    Energy Technology Data Exchange (ETDEWEB)

    Comolli, A.G.; Lee, L.K.; Pradhan, V.R.; Stalzer, R.H. [New York & Puritan Avenues, Lawrenceville, NJ (United States)

    1995-12-31

    The goal of the Proof of Concept (POC) Program is to develop Direct Coal Liquefaction and associated transitional technologies towards commercial readiness for economically producing premium liquid fuels from coal in an environmentally acceptable manner. The program focuses on developing the two-stage liquefaction (TSL) process by utilizing geographically strategic feedstocks, commercially feasible catalysts, new prototype equipment, and testing co-processing or alternate feedstocks and improved process configurations. Other high priority objectives include dispersed catalyst studies, demonstrating low rank coal liquefaction without solids deposition, improving distillate yields on a unit reactor volume basis, demonstrating ebullated bed operations while obtaining scale-up data, demonstrating optimum catalyst consumption using new concepts (e.g. regeneration, cascading), producing premium products through on-line hydrotreating, demonstrating improved hydrogen utilization for low rank coals using novel heteroatom removal methods, defining and demonstrating two-stage product properties for upgrading; demonstrating efficient and economic solid separation methods, examining the merits of integrated coal cleaning, demonstrating co-processing, studying interactions between the preheater and first and second-stage reactors, improving process operability by testing and incorporating advanced equipment and instrumentation, and demonstrating operation with alternate coal feedstocks. During the past two years major PDU Proof of Concept runs were completed. POC-1 with Illinois No. 6 coal and POC-2 with Black Thunder sub-bituminous coal. Results from these operations are continuing under review and the products are being further refined and upgraded. This paper will update the results from these operations and discuss future plans for the POC program.

  19. Dose escalation of a curcuminoid formulation

    Directory of Open Access Journals (Sweden)

    Crowell James

    2006-03-01

    Full Text Available Abstract Background Curcumin is the major yellow pigment extracted from turmeric, a commonly-used spice in India and Southeast Asia that has broad anticarcinogenic and cancer chemopreventive potential. However, few systematic studies of curcumin's pharmacology and toxicology in humans have been performed. Methods A dose escalation study was conducted to determine the maximum tolerated dose and safety of a single dose of standardized powder extract, uniformly milled curcumin (C3 Complex™, Sabinsa Corporation. Healthy volunteers were administered escalating doses from 500 to 12,000 mg. Results Seven of twenty-four subjects (30% experienced only minimal toxicity that did not appear to be dose-related. No curcumin was detected in the serum of subjects administered 500, 1,000, 2,000, 4,000, 6,000 or 8,000 mg. Low levels of curcumin were detected in two subjects administered 10,000 or 12,000 mg. Conclusion The tolerance of curcumin in high single oral doses appears to be excellent. Given that achieving systemic bioavailability of curcumin or its metabolites may not be essential for colorectal cancer chemoprevention, these findings warrant further investigation for its utility as a long-term chemopreventive agent.

  20. Natural Tuning: Towards A Proof of Concept

    CERN Document Server

    Dubovsky, Sergei; Mirbabayi, Mehrdad

    2013-01-01

    The cosmological constant problem and the absence of new natural physics at the electroweak scale, if confirmed by the LHC, may either indicate that the nature is fine-tuned or that a refined notion of naturalness is required. We construct a family of toy UV complete quantum theories providing a proof of concept for the second possibility. Low energy physics is described by a tuned effective field theory, which exhibits relevant interactions not protected by any symmetries and separated by an arbitrary large mass gap from the new "gravitational" physics, represented by a set of irrelevant operators. Nevertheless, the only available language to describe dynamics at all energy scales does not require any fine-tuning. The interesting novel feature of this construction is that UV physics is not described by a fixed point, but rather exhibits asymptotic fragility. Observation of additional unprotected scalars at the LHC would be a smoking gun for this scenario. Natural tuning also favors TeV scale unification.

  1. Acute toxicity evaluation of proliferol: a dose-escalating, placebo-controlled study in rats.

    Science.gov (United States)

    Dagenais, Simon; Mayer, John; Wooley, James R; Haldeman, Scott; Hite, Mark

    2007-01-01

    Proliferol is an investigational new drug containing lidocaine hydrochloride 0.25%, dextrose 12.5%, glycerin 12.5%, and phenol 1.0% in aqueous solution. Despite extensive human experience with similar drugs administered by intraligamentous injection for chronic musculoskeletal disorders, little is known concerning preclinical toxicity. The purpose of this study was to assess the acute toxicity of intramuscular Proliferol in 96 (48 male, 48 female) Charles River strain rats, which were randomly assigned to low- (1x), medium- (5x), or high- (10x) dose Proliferol (derived from a human dose of 20 ml on a volume per bodyweight basis), or high-dose saline placebo. Observations included clinical observations, biochemistry, hematology, urinalysis, and full histopathology after 24 h or 14 days. There were no signs of ill health or reaction to treatment, and gait and body temperature were within normal limits. Biochemistry findings at 24 h included elevated aspartate aminotransferase, alanine aminotransferase, and haptoglobin; at 14 days all values were within normal ranges. Urinalysis findings at 24 h included increased urobilinogen and blood in all dose groups compared with placebo. Urine concentrations of phenol and lidocaine were greatest at 2 h and absent at 24 h. Histopathology findings included localized acute inflammatory soft tissue changes at the injection sites at 24 h and skeletal muscle regeneration at 14 days, which were consistent with the anticipated mechanism of action of Proliferol. There was no evidence of systemic toxicity from intramuscular injection of Proliferol in rats at up to 10x the human dose.

  2. CIRCULATING MOVING BED COMBUSTION PROOF OF CONCEPT

    Energy Technology Data Exchange (ETDEWEB)

    Jukkola, Glen

    2010-06-30

    Circulating Moving Bed (CMB) combustion technology has its roots in traditional circulating fluidized bed technology and involves a novel method of solid fuel combustion and heat transfer. CMB technology represents a step change in improved performance and cost relative to conventional PC and FBC boilers. The CMB heat exchanger preheats the energy cycle working fluid, steam or air, to the high temperature levels required in systems for advanced power generation. Unique features of the CMB are the reduction of the heat transfer surfaces by about 60% as a result of the enhanced heat transfer rates, flexibility of operation, and about 30% lower cost over existing technology. The CMB Phase I project ran from July 2001 through March 2003. Its objective was to continue development of the CMB technology with a series of proof of concept tests. The tests were conducted at a scale that provided design data for scale up to a demonstration plant. These objectives were met by conducting a series of experiments in ALSTOM Power’s Multi-use Test Facility (MTF). The MTF was modified to operate under CMB conditions of commercial interest. The objective of the tests were to evaluate gas-to-solids heat transfer in the upper furnace, assess agglomeration in the high temperature CMB bubbling bed, and evaluate solids-to-tube heat transfer in the moving bed heat exchanger. The Phase I program results showed that there are still some significant technical uncertainties that needed to be resolved before the technology can be confidently scaled up for a successful demonstration plant design. Work remained in three primary areas: • scale up of gas to solid heat transfer • high temperature finned surface design • the overall requirements of mechanical and process design. The CMB Phase II workscope built upon the results of Phase I and specifically addressed the remaining technical uncertainties. It included a scaled MTF heat transfer test to provide the necessary data to scale up gas

  3. Factors associated with dose escalation of fesoterodine for treatment of overactive bladder in people >65 years of age: A post hoc analysis of data from the SOFIA study.

    Science.gov (United States)

    Wagg, Adrian; Darekar, Amanda; Arumi, Daniel; Khullar, Vik; Oelke, Matthias

    2015-06-01

    To investigate factors which may influence dose escalation of antimuscarinics for overactive bladder (OAB) in older patients and how dose escalation affects treatment efficacy. A post hoc analysis of data from the 12-week randomized, placebo controlled phase of the SOFIA study investigating treatment with fesoterodine in older people with OAB. Predictors and outcomes in patients aged ≥65 years with OAB who did or did not choose to escalate from fesoterodine 4 to 8 mg before the first dose-escalation choice point (week 4) and at the end of the study (week 12) were assessed. Variables which significantly increased likelihood of dose escalation were, at baseline, body mass index (OR: 1.06, 95% CI 1.01, 1.12; P = 0.0222), and male gender (OR: 2.06, 95% CI 1.28, 3.32; P = 0.0028) and at week 4, change from baseline in urgency episodes (OR: 1.12, 95% CI 1.05, 1.20; P = 0.0008), patient perception of bladder control (PPBC) (OR: 1.44, 95% CI 1.12, 1.84; P = 0.004). At week 12, dose escalation was associated with slightly reduced treatment outcomes compared to week 4 non-escalators. No baseline disease related factor associated with dose escalation was identified. Magnitude of change in urgency episodes and reduction in PPBC at 4 weeks were associated with dose escalation. These data may be of use to healthcare providers as they allow judgement to be made in individual patients, allowing treatment decisions to be made. At end of treatment, improvements in efficacy and quality of life were achieved in both escalators and non-escalators. © 2014 Wiley Periodicals, Inc.

  4. US NDC Modernization: Service Oriented Architecture Proof of Concept

    Energy Technology Data Exchange (ETDEWEB)

    Hamlet, Benjamin R. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Encarnacao, Andre Villanova [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Jackson, Keilan R. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Hays, Ian A. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Barron, Nathan E. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Simon, Luke B. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Harris, James M. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Young, Christopher J. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)

    2014-12-01

    This report is a progress update on the US NDC Modernization Service Oriented Architecture (SOA) study describing results from a proof of concept project completed from May through September 2013. Goals for this proof of concept are 1) gain experience configuring, using, and running an Enterprise Service Bus (ESB), 2) understand the implications of wrapping existing software in standardized interfaces for use as web services, and 3) gather performance metrics for a notional seismic event monitoring pipeline implemented using services with various data access and communication patterns. The proof of concept is a follow on to a previous SOA performance study. Work was performed by four undergraduate summer student interns under the guidance of Sandia staff.

  5. Electronic Vehicle Identification Architecture and Proof of Concept

    NARCIS (Netherlands)

    Passchier, I.; Chevrollier, N.G.; Mulder,A.; Vliet,A.O.T.van

    2009-01-01

    An architecture and a proof of concept for Electronic Vehicle Identification have beendeveloped. The system has been successfully tested in a pilot with 23 participants over a period of three months and a total distance of 75.000 km travelled. The architecture consists of a functional definition, a

  6. Evaluation of TENCompetence proof of concept assessment tools

    NARCIS (Netherlands)

    Petrov, Milen; Aleksieva-Petrova, Adelina; Stefanov, Krassen; Schoonenboom, Judith; Miao, Yongwu

    2008-01-01

    Petrov, M., Aleksieva-Petrova, A., Stefanov, K., Schoonenboom, J., & Miao, Y. (2008). Evaluation of TENCompetence proof of concept assessment tools. In H. W. Sligte & R. Koper (Eds.). Proceedings of the 4th TENCompetence Open Workshop. Empowering Learners for Lifelong Competence Development: pedagog

  7. Electronic Vehicle Identification Architecture and Proof of Concept

    NARCIS (Netherlands)

    Passchier, I.; Chevrollier, N.G.; Mulder,A.; Vliet,A.O.T.van

    2009-01-01

    An architecture and a proof of concept for Electronic Vehicle Identification have beendeveloped. The system has been successfully tested in a pilot with 23 participants over a period of three months and a total distance of 75.000 km travelled. The architecture consists of a functional definition, a

  8. Evaluation of TENCompetence proof of concept assessment tools

    NARCIS (Netherlands)

    Petrov, Milen; Aleksieva-Petrova, Adelina; Stefanov, Krassen; Schoonenboom, Judith; Miao, Yongwu

    2008-01-01

    Petrov, M., Aleksieva-Petrova, A., Stefanov, K., Schoonenboom, J., & Miao, Y. (2008). Evaluation of TENCompetence proof of concept assessment tools. In H. W. Sligte & R. Koper (Eds.). Proceedings of the 4th TENCompetence Open Workshop. Empowering Learners for Lifelong Competence Development: pedagog

  9. A Proof-of-Concept Randomized Controlled Study of Gabapentin: Effects on Cannabis Use, Withdrawal and Executive Function Deficits in Cannabis-Dependent Adults

    OpenAIRE

    Mason, Barbara J.; Crean, Rebecca; Goodell, Vivian; Light, John M.; Quello, Susan; Shadan, Farhad; Buffkins, Kimberly; Kyle, Mark; Adusumalli, Murali; Begovic, Adnan; Rao, Santosh

    2012-01-01

    There are no FDA-approved pharmacotherapies for cannabis dependence. Cannabis is the most widely used illicit drug in the world, and patients seeking treatment for primary cannabis dependence represent 25% of all substance use admissions. We conducted a phase IIa proof-of-concept pilot study to examine the safety and efficacy of a calcium channel/GABA modulating drug, gabapentin, for the treatment of cannabis dependence. A 12-week, randomized, double-blind, placebo-controlled clinical trial w...

  10. Visualizing Digital Forensic Datasets: A Proof of Concept.

    Science.gov (United States)

    Tassone, Christopher F R; Martini, Ben; Choo, Kim-Kwang Raymond

    2017-02-01

    Digital forensic visualization is an understudied area despite its potential to achieve significant improvements in the efficiency of an investigation, criminal or civil. In this study, a three-stage forensic data storage and visualization life cycle is presented. The first stage is the decoding of data, which involves preparing both structured and unstructured data for storage. In the storage stage, data are stored within our proposed database schema designed for ensuring data integrity and speed of storage and retrieval. The final stage is the visualization of stored data in a manner that facilitates user interaction. These functionalities are implemented in a proof of concept to demonstrate the utility of the proposed life cycle. The proof of concept demonstrates the utility of the proposed approach for the storage and visualization of digital forensic data. © 2017 American Academy of Forensic Sciences.

  11. High Altitude Venus Operational Concept (HAVOC): Proofs of Concept

    Science.gov (United States)

    Jones, Christopher A.; Arney, Dale C.; Bassett, George Z.; Clark, James R.; Hennig, Anthony I.; Snyder, Jessica C.

    2015-01-01

    The atmosphere of Venus is an exciting destination for both further scientific study and future human exploration. A recent internal NASA study of a High Altitude Venus Operational Concept (HAVOC) led to the development of an evolutionary program for the exploration of Venus, with focus on the mission architecture and vehicle concept for a 30-day crewed mission into Venus's atmosphere at 50 kilometers. Key technical challenges for the mission include performing the aerocapture maneuvers at Venus and Earth, inserting and inflating the airship at Venus during the entry sequence, and protecting the solar panels and structure from the sulfuric acid in the atmosphere. Two proofs of concept were identified that would aid in addressing some of the key technical challenges. To mitigate the threat posed by the sulfuric acid ambient in the atmosphere of Venus, a material was needed that could protect the systems while being lightweight and not inhibiting the performance of the solar panels. The first proof of concept identified candidate materials and evaluated them, finding FEP-Teflon (Fluorinated Ethylene Propylene-Teflon) to maintain 90 percent transmittance to relevant spectra even after 30 days of immersion in concentrated sulfuric acid. The second proof of concept developed and verified a packaging algorithm for the airship envelope to inform the entry, descent, and inflation analysis.

  12. VAMP in Stellarium/VirGO: A Proof of Concept

    Science.gov (United States)

    Kapadia, Amit; Chéreau, Fabien; Christensen, Lars Lindberg; Nielsen, Lars Holm; Gauthier, Adrienne; Hurt, Robert; Wyatt, Ryan

    2008-06-01

    The Virtual Astronomy Multimedia Project (VAMP) and the Astronomy Visualization Metadata (AVM) standard will give observatories and astronomers an easy way to distribute their astronomical visualisation products. The CAP2007 demonstration which is described here is an early, although fully functioning, proof-of-concept for the VAMP project showing the capabilities and functionalities of the AVM. Our hope is to encourage people to begin applying the AVM standard to their Education and Public Outreach (EPO) images as they witness the spectacular end results that applications like Stellarium, World Wide Telescope, and Sky in Google Earth can bring to the future.

  13. ReACT Methodology Proof of Concept Final Report

    Energy Technology Data Exchange (ETDEWEB)

    Bri Rolston; Sarah Freeman

    2014-03-01

    The Department of Energy’s Office of Electricity Delivery and Energy Reliability (DOE-OE) funded INL Researchers to evaluate a novel process for assessing and mitigating cyber security risks. The proof of concept level of the method was tested in an industry environment. This case study, plus additional case studies will support the further development of the method into a tool to assist industry in securing their critical networks. This report provides an understanding of the process developed in the Response Analysis and Characterization Tool (ReACT) project. This report concludes with lessons learned and a roadmap for final development of these tools for use by industry.

  14. SSFF Health Management Analysis Report. Part 2: Proof of Concept

    Science.gov (United States)

    Wilson, L.; Spruill, J.; Hong, Y.

    1995-01-01

    In this Proof of Concept analysis on SSFF Health Management the following area was described: the Gas Distribution Subsystem (GDS) was studied and evaluated utilizing the PDR Configuration and with respect to the design features encompassing Health Management (HM) aspects outlined in the Generic Handbook. From the results of this study, it was found that there is a definite need for coordinating measurements within and between the subsystems that will ensure that Functional Failures are properly revealed and substantiated as valid by other measurements, even those from other interfacing subsystems.

  15. Dose escalation studies with caspofungin against Candida glabrata.

    Science.gov (United States)

    Domán, Marianna; Kovács, Renátó; Perlin, David S; Kardos, Gábor; Gesztelyi, Rudolf; Juhász, Béla; Bozó, Aliz; Majoros, László

    2015-09-01

    Echinocandins are recommended as first-line agents against invasive fungal infections caused by Candida glabrata, which still carry a high mortality rate. Dose escalation of echinocandins has been suggested to improve the clinical outcome against C. glabrata. To address this possibility, we performed in vitro and in vivo experiments with caspofungin against four WT C. glabrata clinical isolates, a drug-susceptible ATCC 90030 reference strain and two echinocandin-resistant strains with known FKS mutations. MIC values for the clinical isolates in RPMI 1640 were ≤ 0.03 mg l(-1 ) but increased to 0.125-0.25 mg l(-1 )in RPMI 1640+50% serum. In RPMI 1640+50% serum, the replication of C. glabrata was weaker than in RPMI 1640.Caspofungin in RPMI 1640 at 1 and 4 mg l(-1) showed a fungicidal effect within 7 h against three of the four clinical isolates but was only fungistatic at 16 and 32 mg l(-1) (paradoxically decreased killing activity). In RPMI 1640+50% serum, caspofungin at ≥ 1 mg l(-1) was rapidly fungicidal (within 3.31 h) against three of the four isolates. In a profoundly neutropenic murine model, all caspofungin doses (1, 2, 3, 5 and 20 mg kg(-1) daily) decreased the fungal tissue burdens significantly (P caspofungin dose escalation does not improve efficacy.

  16. Dose escalation study of rhenium-186 hydroxyethylidene diphosphonate in patients with metastatic prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Klerk, J.M.H. de (Dept. of Nuclear Medicine, Univ. Hospital, Utrecht (Netherlands)); Zonnenberg, B.A. (Oncology Section, Dept. of Internal Medicine, Univ. Hospital, Utrecht (Netherlands)); Schip, A.D. van het (Dept. of Nuclear Medicine, Univ. Hospital, Utrecht (Netherlands)); Dijk, A. van (Center for Hospital Pharmacy, Univ. Hospital, Utrecht (Netherlands)); Han, S.H. (Dept. of Nuclear Medicine, Univ. Hospital, Utrecht (Netherlands)); Quirijnen, J.M.S.P. (Dept. of Nuclear Medicine, Univ. Hospital, Utrecht (Netherlands)); Blijham, G.H. (Oncology Section, Dept. of Internal Medicine, Univ. Hospital, Utrecht (Netherlands)); Rijk, P.P. van (Dept. of Nuclear Medicine, Univ. Hospital, Utrecht (Netherlands))

    1994-10-01

    Rhenium-186 hydroxyethylidene diphosphonate ([sup 186]Re-HEDP) has been used for the palliative treatment of metastatic bone pain. A phase 1 dose escalation study was performed using [sup 186]Re-HEDP. Twenty-four patients with hormone-resistant prostate cancer entered the study. Each patient had at least four bone metastases and adequate haematological function. Groups of at least three consecutive patients were treated with doses starting at 1295 MBq and increasing to 3515 MBq (escalated in increments of 555 MBq). Thrombocytopenia proved to be the dose-limiting toxicity, while leucopenia played a minor role. Early death occurred in one patient (10 days after administration) without clear relationship to the [sup 186]Re-HEDP therapy. Transient neurological dysfunction was seen in two cases. Two patients who received 3515 MBq [sup 186]Re-HEDP showed grade 3 toxicity (thrombocytes 25-50 x 10[sup 9]/l), defined as unacceptable toxicity. After treatment alkaline phosphatase levels showed a transient decrease in all patients (mean: 26% [+-] 10% IU/l; range: 11%-44%). Prostate-specific antigen values showed a decline in eight patients, preceded by a temporary increase in three patients. From this study we conclude that the maximally tolerated dose of [sup 186]Re-HEDP is 2960 MBq. A placebo-controlled comparative study on the efficacy of [sup 186]Re-HEDP has been initiated. (orig.)

  17. Phonetic compliance: a proof-of-concept study

    Directory of Open Access Journals (Sweden)

    Véronique eDelvaux

    2014-12-01

    Full Text Available In this paper, we introduce the concept of phonetic compliance, which is defined as the intrinsic individual ability to produce speech sounds that are unusual in the native language, and constitutes a part of the ability to acquire L2 phonetics and phonology. We argue that phonetic compliance represents a systematic source of variance that needs to be accounted for if one wants to improve the control over the independent variables manipulated in SLA experimental studies. We then present the results of a two-fold proof-of-concept study aimed at testing the feasibility of assessing phonetic compliance in terms of gradient. In study 1, a pilot data collection paradigm is implemented on an occasional sample of 10 native French speakers engaged in two reproduction tasks involving respectively vowels and aspirated stops, and data are analysed using descriptive statistics. In study 2, complementary data including L1-typical realizations are collected, resulting in the development of a first set of indicators that may be useful to appropriately assess, and further refine the concept of, phonetic compliance. Based on a critical analysis of the contributions and limitations of the proof-of-concept study, general discussion formulates the guidelines for the following stages of development of a reliable and valid test of phonetic compliance.

  18. A Numerical Proof of Concept for Thermal Flow Control

    Directory of Open Access Journals (Sweden)

    V. Dragan

    2017-02-01

    Full Text Available In this paper computational fluid dynamics is used to provide a proof of concept for controlled flow separation using thermal wall interactions with the velocity boundary layer. A 3D case study is presented, using a transition modeling Shear Stress Transport turbulence model. The highly loaded single slot flap airfoil was chosen to be representative for a light aircraft and the flow conditions were modeled after a typical landing speed. In the baseline case, adiabatic walls were considered while in the separation control case, the top surface of the flaps was heated to 500 K. This heating lead to flow separation on the flaps and a significant alteration of the flow pattern across all the elements of the wing. The findings indicate that this control method has potential, with implications in both aeronautical as well as sports and civil engineering applications.

  19. Integrated Workforce Planning Model: A Proof of Concept

    Science.gov (United States)

    Guruvadoo, Eranna K.

    2001-01-01

    Recently, the Workforce and Diversity Management Office at KSC have launched a major initiative to develop and implement a competency/skill approach to Human Resource management. As the competency/skill dictionary is being elaborated, the need for a competency-based workforce-planning model is recognized. A proof of concept for such a model is presented using a multidimensional data model that can provide the data infrastructure necessary to drive intelligent decision support systems for workforce planing. The components of competency-driven workforce planning model are explained. The data model is presented and several schemes that would support the workforce-planning model are presented. Some directions and recommendations for future work are given.

  20. A proof-of-concept study with the tyrosine kinase inhibitor nilotinib in spondyloarthritis.

    Science.gov (United States)

    Paramarta, Jacqueline E; Turina, Maureen C; Noordenbos, Troy; Heijda, Tanja F; Blijdorp, Iris C; Yeremenko, Nataliya; Baeten, Dominique

    2016-10-27

    To evaluate the immunomodulating and clinical effects of nilotinib, a tyrosine kinase inhibitor, in a proof-of-concept study in spondyloarthritis (SpA) assessing the mast cell as potential novel therapeutic target in this disease. Twenty eight patients with active peripheral (pSpA) and/or axial SpA (axSpA) were included in a randomized, double-blind, placebo-controlled clinical trial (Trial registration: Trialregister.nl NTR2834). Patients were treated 1:1 with nilotinib or placebo for 12 weeks, followed by an open label extension for another 12 weeks. Paired synovial tissue biopsies, serum sampling and assessment of clinical symptoms were performed serially. In pSpA (n = 13) synovial inflammation appeared to diminish after 12 weeks of nilotinib treatment as evidenced by histopathology (decrease in number of infiltrating CD68+ and CD163+ macrophages and mast cells). Compared to placebo mRNA expression of c-Kit as mast cell marker (p = 0.037) and of pro-inflammatory cytokines such as IL-6 (p = 0.024) were reduced. The reduction of synovial inflammation was paralleled by a decrease in serum biomarkers of inflammation such as C-reactive protein (p = 0.024) and calprotectin (p = 0.055). Also clinical parameters such as patient's global assessment of disease activity (p = 0.031) and ankylosing spondylitis disease activity score (p = 0.031) showed improvement upon 12 weeks of nilotinib but not placebo treatment. This improvement was further augmented at week 24. In contrast to pSpA, neither serum biomarkers of inflammation nor clinical parameters improved upon nilotinib treatment in axSpA. During the trial one serious adverse event occurred, which was considered unrelated to the study drug. This small proof-of-concept study suggests that nilotinib treatment modulates inflammation and clinical symptoms in pSpA. A similar effect was not seen in axSpA. trialregister.nl registration code NTR2834 registered 31 March 2011.

  1. PET-guided dose escalation tomotherapy in malignant pleural mesothelioma

    Energy Technology Data Exchange (ETDEWEB)

    Fodor, Andrei; Dell' Oca, Italo; Pasetti, Marcella; Di Muzio, Nadia Gisella [San Raffaele Scientific Institute, Milan (Italy). Dept. of Radiotherapy; Fiorino, Claudio; Broggi, Sara; Cattaneo, Giovanni Mauro; Calandrino, Riccardo [San Raffaele Scientific Institute, Milan (Italy). Medical Physics; Gianolli, Luigi [San Raffaele Scientific Institute, Milan (Italy). Dept. of Nuclear Medicine

    2011-11-15

    To test the feasibility of salvage radiotherapy using PET-guided helical tomotherapy in patients with progressive malignant pleural mesothelioma (MPM). A group of 12 consecutive MPM patients was treated with 56 Gy/25 fractions to the planning target volume (PTV); FDG-PET/CT simulation was always performed to include all positive lymph nodes and MPM infiltrations. Subsequently, a second group of 12 consecutive patients was treated with the same dose to the whole pleura adding a simultaneous integrated boost of 62.5 Gy to the FDG-PET/CT positive areas (BTV). Good dosimetric results were obtained in both groups. No grade 3 (RTOG/EORTC) acute or late toxicities were reported in the first group, while 3 cases of grade 3 late pneumonitis were registered in the second group: the duration of symptoms was 2-10 weeks. Median overall survival was 8 months (1.2-50.5 months) and 20 months (4.3-33.8 months) from the beginning of radiotherapy, for groups I and II, respectively (p = 0.19). A significant impact on local relapse from radiotherapy was seen (median time to local relapse: 8 vs 17 months; 1-year local relapse-free rate: 16% vs 81%, p = 0.003). The results of this pilot study support the planning of a phase III study of combined sequential chemoradiotherapy with dose escalation to BTV in patients not able to undergo resection. (orig.)

  2. SPARCLE: Electrostatic Dust Control Tool Proof of Concept

    Science.gov (United States)

    Clark, P. E.; Curtis, S. A.; Minetto, F.; Marshall, J.; Nuth, J.; Calle, C.

    2010-01-01

    Successful exploration of most planetary surfaces, with their impact-generated dusty regoliths, will depend on the capabilities to keep surfaces free of the performance-compromising dust. Once in contact with surfaces, whether set in motion by natural or mechanical means, regolith fines, or dust, behave like abrasive Velcro, coating surfaces, clogging mechanisms, making movement progressively more difticult, and being almost impossible to remove by mechanical mcans (brushing). The successful dust removal strategy will deal with dust dynamics resulting from interaction between Van der Waals and Coulombic forces. Here, proof of concept for an electrostatically-based concept for dust control tool is described and demonstrated. A low power focused electron beam is used in the presence of a small electrical field to increase the negative charge to mass ratio of a dusty surface until dust repulsion and attraction to a lower potential surface, acting as a dust collector, occurred. Our goal is a compact device of less than 5 kg mass and using less than 5 watts of power to be operational in less than 5 years with heritage from ionic sweepers for active spacecraft potential control (e.g ., on POLAR). Rovers could be fitted with devices that could hamess the removal of dust for sampling as part of the extended exploration process on Mercury, Mars, asteroids or outer solar system satellites, as well as the Moon.

  3. The paperless labeling initiative: a proof-of-concept study.

    Science.gov (United States)

    Ruchalski, Charles

    2004-01-01

    Traditional paper professional package inserts (PPIs) are used on a daily basis by a variety of healthcare providers to locate and disseminate drug information. Unfortunately, paper PPIs are sometimes not accessible to the healthcare provider, appear unreadable due to varied font sizes, and are often considered not to be user-friendly. In December 2000, the Food and Drug Administration proposed regulations that would revise the format of PPIs. To determine whether electronic delivery of PPI information is achievable in community pharmacy practice settings. Electronic PPIs are an alternative means of delivering this information. This 12-week proof-of-concept study evaluated the Health Information Designs/Thomson Healthcare and Etreby Computer Company for electronic delivery of PPIs in 6 chain and 4 independent community pharmacies, with 5 pharmacies evaluating each system. Participating pharmacists were asked 9 questions designed to determine the feasibility of implementing electronic PPI delivery, as well as pharmacist satisfaction with each system. Pharmacists deemed both systems to be accessible and user-friendly. Pharmacists from both groups felt that the electronic PPIs were challenging to read and that printing took too long. Future studies in a more diverse selection of dispensing sites, including pharmacies (community and hospital based), clinics, and physician practices, need to be performed to maximize the use of electronic PPIs.

  4. SPARCLE: Electrostatic Dust Control Tool Proof of Concept

    Science.gov (United States)

    Clark, P. E.; Curtis, S. A.; Minetto, F.; Marshall, J.; Nuth, J.; Calle, C.

    2010-01-01

    Successful exploration of most planetary surfaces, with their impact-generated dusty regoliths, will depend on the capabilities to keep surfaces free of the performance-compromising dust. Once in contact with surfaces, whether set in motion by natural or mechanical means, regolith fines, or dust, behave like abrasive Velcro, coating surfaces, clogging mechanisms, making movement progressively more difticult, and being almost impossible to remove by mechanical mcans (brushing). The successful dust removal strategy will deal with dust dynamics resulting from interaction between Van der Waals and Coulombic forces. Here, proof of concept for an electrostatically-based concept for dust control tool is described and demonstrated. A low power focused electron beam is used in the presence of a small electrical field to increase the negative charge to mass ratio of a dusty surface until dust repulsion and attraction to a lower potential surface, acting as a dust collector, occurred. Our goal is a compact device of less than 5 kg mass and using less than 5 watts of power to be operational in less than 5 years with heritage from ionic sweepers for active spacecraft potential control (e.g ., on POLAR). Rovers could be fitted with devices that could hamess the removal of dust for sampling as part of the extended exploration process on Mercury, Mars, asteroids or outer solar system satellites, as well as the Moon.

  5. 76 FR 36919 - Proof of Concept Demonstration for Electronic Reporting of Clean Water Act Compliance Monitoring...

    Science.gov (United States)

    2011-06-23

    ... commercial products or services of any third-party software providers. Proof of Concept Demonstration for... software provider selected for participating in the technical proof of concept demonstration by EPA must... concept by the software provider are: Ability of the software provider's electronic reporting software...

  6. Proton-minibeam radiation therapy: A proof of concept

    Energy Technology Data Exchange (ETDEWEB)

    Prezado, Y. [IMNC-UMR 8165, CNRS, Paris 7 and Paris 11 Universities, 15 rue Georges Clemenceau, 91406 Orsay Cedex (France); Fois, G. R. [Dipartimento di Fisica, Universita degli Studi di Cagliari, Strada provinciale Monserrato Sestu km 0.700, Monserrato, Cagliari 09042 (Italy)

    2013-03-15

    Purpose: This Monte Carlo simulation work aims at studying a new radiotherapy approach called proton-minibeam radiation therapy (pMBRT). The main objective of this proof of concept was the evaluation of the possible gain in tissue sparing, thanks to the spatial fractionation of the dose, which could be used to deposit higher and potentially curative doses in clinical cases where tissue tolerances are a limit for conventional methods. Methods: Monte Carlo simulations (GATE v.6) have been used as a method to calculate the ratio of the peak-to-valley doses (PVDR) for arrays of proton minibeams of 0.7 mm width and several center-to-center distances, at different depths in a water phantom. The beam penumbras were also evaluated as an important parameter for tissue sparing, for example, in the treatment of non-cancer diseases like epilepsy. Two proton energies were considered in this study: a clinically relevant energy (105 MeV) and a very high energy (1 GeV), to benefit from a reduced lateral scattering. For the latter case, an interlaced geometry was also evaluated. Results: Higher or similar PVDR than the ones obtained in x-rays minibeam radiation therapy were achieved in several pMBRT configurations. In addition, for the two energies studied, the beam penumbras are smaller than in the case of Gamma Knife radiosurgery. Conclusions: The high PVDR obtained for some configurations and the small penumbras in comparison with existing radiosurgery techniques, suggest a potential gain in healthy tissue sparing in this new technique. Biological studies are warranted to assess the effects of pMBRT on both normal and tumoral tissues.

  7. Wireless Roadside Inspection Proof of Concept Test Final Report

    Energy Technology Data Exchange (ETDEWEB)

    Capps, Gary J [ORNL; Franzese, Oscar [ORNL; Knee, Helmut E [ORNL; Plate, Randall S [ORNL; Lascurain, Mary Beth [ORNL

    2009-03-01

    The U.S. Department of Transportation (DOT) FMCSA commissioned the Wireless Roadside Inspection (WRI) Program to validate technologies and methodologies that can improve safety through inspections using wireless technologies that convey real-time identification of commercial vehicles, drivers, and carriers, as well as information about the condition of the vehicles and their drivers. It is hypothesized that these inspections will: -- Increase safety -- Decrease the number of unsafe commercial vehicles on the road; -- Increase efficiency -- Speed up the inspection process, enabling more inspections to occur, at least on par with the number of weight inspections; -- Improve effectiveness -- Reduce the probability of drivers bypassing CMV inspection stations and increase the likelihood that fleets will attempt to meet the safety regulations; and -- Benefit industry -- Reduce fleet costs, provide good return-on-investment, minimize wait times, and level the playing field. The WRI Program is defined in three phases which are: Phase 1: Proof of Concept Test (POC) Testing of commercially available off-the-shelf (COTS) or near-COTS technology to validate the wireless inspection concept. Phase 2: Pilot Test Safety technology maturation and back office system integration Phase 3: Field Operational Test Multi-vehicle testing over a multi-state instrumented corridor This report focuses on Phase 1 efforts that were initiated in March, 2006. Technical efforts dealt with the ability of a Universal Wireless Inspection System (UWIS) to collect driver, vehicle, and carrier information; format a Safety Data Message Set from this information; and wirelessly transmit a Safety Data Message Set to a roadside receiver unit or mobile enforcement vehicle.

  8. Efficacy of imatinib dose escalation in Chinese gastrointestinal stromal tumor patients

    Institute of Scientific and Technical Information of China (English)

    Jian Li; Ji-Fang Gong; Jie Li; Jing Gao; Nai-Ping Sun; Lin Shen

    2012-01-01

    AIM:To investigate the efficacy and safety of imatinib dose escalation in Chinese patients with advanced gastrointestinal stromal tumor (GIST).METHODS:Advanced GIST patients previously failing 400 mg imatinib treatment were enrolled in this study.Patients received imatinib with dose escalation to 600mg/d,and further dose escalation to 800 mg/d if imatinib 600 mg/d failed.Progression-free survival,overall survival,clinical efficacy,c-kit/PDGFRA genotype and safety were evaluated.RESULTS:52 patients were enrolled in this study.For the 47 evaluable patients receiving imatinib (600 mg/d),the disease control rate was 40.4%,and the median progression-free survival for all patients was 17 wk (95% CI:3.9-30.1).The median overall survival after dose escalation was 81 wk (95% CI:36.2-125.8).Adverse events,mainly edema,fatigue,granulocytopenia and skin rash were tolerable.However,further dose escalation (800 mg/d) in 14 cases was ineffective,with disease progression and severe adverse events.Among 30 cases examined for gene mutations,patients with exon 9 mutations experienced a better progression-free survival of 47 wk.CONCLUSION:Imatinib dose escalation to 600 mg/d is more appropriate for Chinese patients and may achieve further survival benefit.

  9. Automation of strategy using IDEF0 — A proof of concept

    National Research Council Canada - National Science Library

    Waissi, Gary R; Demir, Mustafa; Humble, Jane E; Lev, Benjamin

    2015-01-01

    ... to a model- and software-based approach. A sequence of examples, as a proof-of-concept, is shown to demonstrate the use of IDEF0 to translate document-based strategic plans to model-based plans...

  10. IκB kinase inhibition as a potential treatment of osteoarthritis - results of a clinical proof-of-concept study.

    Science.gov (United States)

    Grothe, K; Flechsenhar, K; Paehler, T; Ritzeler, O; Beninga, J; Saas, J; Herrmann, M; Rudolphi, K

    2017-01-01

    This publication summarizes the clinical development of the compound SAR113945, an IκB kinase inhibitor injected intra-articularly in a slow-release formulation to treat patients with symptomatic osteoarthritis (OA) of the knee. In vitro experiments demonstrated a specific inhibition of the IκB kinase complex. Profiling of SAR113945 on kinases, enzymes and ion channels supported the initiation of a clinical development. Cellular assay systems also revealed an inhibition in the synthesis of interleukin 1β, tumor necrosis factor α (TNFα) and the prostaglandin E2 (PGE2). In vivo studies demonstrated positive effects of SAR113945 on thermal and mechanical hyperalgesia and even showed superiority in comparison with triamcinolone. Pharmacokinetic measurements showed a sustained release of dissolved SAR113945 locally supporting a comparably high exposure in the knee joint combined with a low systemic exposure. Three phase 1 studies with a dose-escalating design confirmed safety and tolerability of SAR113945. In those studies SAR113945 showed a positive trend on the WOMAC scores. The proof-of-concept or phase 2a study failed to show any effect in the overall group of recruited study participants for the primary endpoint, the WOMAC pain subscore at day 56, but showed a statistically significant difference in a subgroup of patients who had presented with effusion at baseline. Inhibiting the NFκB signaling pathway is an attractive method to treat patients with signs and symptoms of OA. The preclinical work and the results of the phase 1 studies appeared promising for a full clinical development, however, the proof-of-concept study failed to show efficacy in a larger patient sample size. Copyright © 2016 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

  11. Dose escalation for unresectable locally advanced non-small cell lung cancer: end of the line?

    Science.gov (United States)

    Hong, Julian C; Salama, Joseph K

    2016-02-01

    Radiation Therapy Oncology Group (RTOG) 0617 was a randomized trial that investigated both the impact of radiation dose-escalation and the addition of cetuximab on the treatment of non-small cell lung cancer (NSCLC). The results of RTOG 0617 were surprising, with the dose escalation randomization being closed prematurely due to futility stopping rules, and cetuximab ultimately showing no overall survival benefit. Locally advanced unresectable NSCLC has conventionally been treated with concurrent chemoradiation. Though advances in treatment technology have improved the ability to deliver adequate treatment dose, the foundation for radiotherapy (RT) has remained the same since the 1980s. Since then, progressive studies have sought to establish the safety and efficacy of escalating radiation dose to loco-regional disease. Though RTOG 0617 did not produce the anticipated result, much interest remains in dose escalation and establishing an explanation for the findings of this study. Cetuximab was also not found to provide a survival benefit when applied to an unselected population. However, planned retrospective analysis suggests that those patients with high epidermal growth factor receptor (EGFR) expression may benefit, suggesting that cetuximab should be applied in a targeted fashion. We discuss the results of RTOG 0617 and additional findings from post-hoc analysis that suggest that dose escalation may be limited by normal tissue toxicity. We also present ongoing studies that aim to address potential causes for mortality in the dose escalation arm through adaptive or proton therapy, and are also leveraging additional concurrent systemic agents such as tyrosine kinase inhibitors (TKIs) for EGFR-activating mutations or EML4-ALK rearrangements, and poly (ADP-ribose) polymerase (PARP) inhibitors.

  12. Proof of Concept for an Approach to a Finer Resolution Inventory

    Science.gov (United States)

    Chris J. Cieszewski; Kim Iles; Roger C. Lowe; Michal Zasada

    2005-01-01

    This report presents a proof of concept for a statistical framework to develop a timely, accurate, and unbiased fiber supply assessment in the State of Georgia, U.S.A. The proposed approach is based on using various data sources and modeling techniques to calibrate satellite image-based statewide stand lists, which provide initial estimates for a State inventory on a...

  13. A Real-Time Open Access Platform Towards Proof of Concept for Smart Grid Applications

    DEFF Research Database (Denmark)

    Kemal, Mohammed Seifu; Petersen, Lennart; Iov, Florin

    2017-01-01

    This paper presents development of real time open access platform towards proof of concept of smart grid applications deployed at Smart Energy System Laboratory of Aalborg University. Discussed on the paper is the architecture and set-up of the platform by elaborating the three main layers...

  14. Reducing antimicrobial therapy for asymptomatic bacteriuria among noncatheterized inpatients: a proof-of-concept study.

    Science.gov (United States)

    Leis, Jerome A; Rebick, Gabriel W; Daneman, Nick; Gold, Wayne L; Poutanen, Susan M; Lo, Pauline; Larocque, Michael; Shojania, Kaveh G; McGeer, Allison

    2014-04-01

    This proof-of-concept study demonstrates that no longer routinely reporting urine culture results from noncatheterized medical and surgical inpatients can greatly reduce unnecessary antimicrobial therapy for asymptomatic bacteriuria without significant additional laboratory workload. Larger studies are needed to confirm the generalizability, safety, and sustainability of this model of care.

  15. Frameworks for Proof-of-Concept Clinical Trials of Interventions That Target Fundamental Aging Processes.

    Science.gov (United States)

    Justice, Jamie; Miller, Jordan D; Newman, John C; Hashmi, Shahrukh K; Halter, Jeffrey; Austad, Steve N; Barzilai, Nir; Kirkland, James L

    2016-11-01

    Therapies targeted at fundamental processes of aging may hold great promise for enhancing the health of a wide population by delaying or preventing a range of age-related diseases and conditions-a concept dubbed the "geroscience hypothesis." Early, proof-of-concept clinical trials will be a key step in the translation of therapies emerging from model organism and preclinical studies into clinical practice. This article summarizes the outcomes of an international meeting partly funded through the NIH R24 Geroscience Network, whose purpose was to generate concepts and frameworks for early, proof-of-concept clinical trials for therapeutic interventions that target fundamental processes of aging. The goals of proof-of-concept trials include generating preliminary signals of efficacy in an aging-related disease or outcome that will reduce the risk of conducting larger trials, contributing data and biological samples to support larger-scale research by strategic networks, and furthering a dialogue with regulatory agencies on appropriate registration indications. We describe three frameworks for proof-of-concept trials that target age-related chronic diseases, geriatric syndromes, or resilience to stressors. We propose strategic infrastructure and shared resources that could accelerate development of therapies that target fundamental aging processes. © The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America.

  16. Density and Flow-Velocity Measurement Technology for Dredging Applications - Proof of Concept Study

    Energy Technology Data Exchange (ETDEWEB)

    Greenwood, Margaret S.; Tucker, Brian J.; Diaz, Aaron A.

    2004-10-01

    This technical letter report provides the results of all PNNL managed activities on this project, and contains a description of the data acquisition configuration and testing protocols, results and conclusions from this work. This technical letter report constitutes the final deliverable to be submitted to the client for this proof-of-concept study.

  17. Dose-Escalated Robotic SBRT for Stage I–II Prostate Cancer

    OpenAIRE

    Meier, Robert

    2015-01-01

    Stereotactic body radiotherapy (SBRT) is the precise external delivery of very high-dose radiotherapy to targets in the body, with treatment completed in one to five fractions. SBRT should be an ideal approach for organ-confined prostate cancer because (I) dose-escalation should yield improved rates of cancer control; (II) the unique radiobiology of prostate cancer favors hypofractionation; and (III) the conformal nature of SBRT minimizes high-dose radiation delivery to immediately adjacent o...

  18. Dose-Escalated Robotic SBRT for Stage I-II Prostate Cancer

    OpenAIRE

    Robert eMeier

    2015-01-01

    Abstract: Stereotactic body radiotherapy (SBRT) is the precise external delivery of very high-dose radiotherapy to targets in the body, with treatment completed in one to five fractions. SBRT should be an ideal approach for organ-confined prostate cancer because (I) dose escalation should yield improved rates of cancer control; (II) the unique radiobiology of prostate cancer favors hypofractionation and (III) the conformal nature of SBRT minimizes high-dose radiation delivery to immediately a...

  19. Targeting interleukin-15 in patients with rheumatoid arthritis: a proof-of-concept study

    DEFF Research Database (Denmark)

    Baslund, Bo; Tvede, Niels; Danneskiold-Samsoe, Bente;

    2005-01-01

    Interleukin-15 (IL-15) is a proinflammatory, innate response cytokine that mediates pleiotropic effector function in rheumatoid arthritis (RA) inflammatory synovitis. Our objective was to study the ability of HuMax-IL15, a human IgG1 anti-IL-15 monoclonal antibody, to neutralize exogenous and end...... and endogenous IL-15 activity in vitro and to perform a phase I-II dose-escalation trial with HuMax-IL15 in patients with active RA....

  20. Toward proof of concept of a one health approach to disease prediction and control.

    Science.gov (United States)

    Rabinowitz, Peter M; Kock, Richard; Kachani, Malika; Kunkel, Rebekah; Thomas, Jason; Gilbert, Jeffrey; Wallace, Robert; Blackmore, Carina; Wong, David; Karesh, William; Natterson, Barbara; Dugas, Raymond; Rubin, Carol

    2013-12-01

    A One Health approach considers the role of changing environments with regard to infectious and chronic disease risks affecting humans and nonhuman animals. Recent disease emergence events have lent support to a One Health approach. In 2010, the Stone Mountain Working Group on One Health Proof of Concept assembled and evaluated the evidence regarding proof of concept of the One Health approach to disease prediction and control. Aspects examined included the feasibility of integrating human, animal, and environmental health and whether such integration could improve disease prediction and control efforts. They found evidence to support each of these concepts but also identified the need for greater incorporation of environmental and ecosystem factors into disease assessments and interventions. The findings of the Working Group argue for larger controlled studies to evaluate the comparative effectiveness of the One Health approach.

  1. A Bayesian paradigm for decision-making in proof-of-concept trials.

    Science.gov (United States)

    Pulkstenis, Erik; Patra, Kaushik; Zhang, Jianliang

    2017-01-01

    Decision-making is central to every phase of drug development, and especially at the proof of concept stage where risk and evidence must be weighed carefully, often in the presence of significant uncertainty. The decision to proceed or not to large expensive Phase 3 trials has significant implications to both patients and sponsors alike. Recent experience has shown that Phase 3 failure rates remain high. We present a flexible Bayesian quantitative decision-making paradigm that evaluates evidence relative to achieving a multilevel target product profile. A framework for operating characteristics is provided that allows the drug developer to design a proof-of-concept trial in light of its ability to support decision-making rather than merely achieve statistical significance. Operating characteristics are shown to be superior to traditional p-value-based methods. In addition, discussion related to sample size considerations, application to interim futility analysis and incorporation of prior historical information is evaluated.

  2. Nutrition, Exercise, and Wellness Treatment in bipolar disorder: proof of concept for a consolidated intervention

    OpenAIRE

    Sylvia, Louisa G; Salcedo, Stephanie; Bernstein, Emily E; Baek, Ji Hyun; Nierenberg, Andrew A.; Deckersbach, Thilo

    2013-01-01

    Background This pilot study examines the proof of concept of a consolidated Nutrition, Exercise, and Wellness Treatment (NEW Tx) for overweight individuals with bipolar disorder. Findings Five participants completed NEW Tx, a 20-week individual cognitive behavioral therapy-based treatment comprising three modules: Nutrition teaches appropriate serving sizes and balanced diet; Exercise emphasizes increasing weekly physical activity; Wellness focuses on skills for healthy decision-making. Parti...

  3. Nutrition, Exercise, and Wellness Treatment in bipolar disorder: proof of concept for a consolidated intervention

    OpenAIRE

    Sylvia, Louisa G; Salcedo, Stephanie; Bernstein, Emily E; Baek, Ji Hyun; Nierenberg, Andrew A.; Deckersbach, Thilo

    2013-01-01

    Background: This pilot study examines the proof of concept of a consolidated Nutrition, Exercise, and Wellness Treatment (NEW Tx) for overweight individuals with bipolar disorder. Findings: Five participants completed NEW Tx, a 20-week individual cognitive behavioral therapy-based treatment comprising three modules: Nutrition teaches appropriate serving sizes and balanced diet; Exercise emphasizes increasing weekly physical activity; Wellness focuses on skills for healthy decision-making. Par...

  4. Global Combat Support System-Marine Corps Proof-of-Concept for Dashboard Analytics

    Science.gov (United States)

    2014-12-01

    applications within Oracle. JDeveloper integrates development features for Java, HTML5 , SOA, Web , Mobile, Database, XML, and Web services which...GCSS-MC. D. SCOPE AND METHODOLOGY 1. Scope This research is focused on the design and development of a dashboard environment proof-of-concept web ...description of the development methods used in the creation of our web -based application. It starts with a brief history of Oracle and Oracle

  5. Flow-Control Systems Proof of Concept for Snowmelt Runoff at McMurdo Station, Antarctica

    Science.gov (United States)

    2017-01-01

    ER D C/ CR RE L TR -1 7- 1 Engineering for Polar Operations , Logistics, and Research (EPOLAR) Flow-Control Systems Proof of Concept for...online library at http://acwc.sdp.sirsi.net/client/default. Engineering for Polar Operations , Logistics, and Research (EPOLAR) ERDC/CRREL TR-17-1...Antarctic Infrastructure and Logistics Arlington, VA 22230 Under Engineering for Polar Operations , Logistics, and Research (EPOLAR) EP-ANT-15-04

  6. Development of an Ontology Based Forensic Search Mechanism: Proof of Concept

    Directory of Open Access Journals (Sweden)

    Jill Slay

    2006-03-01

    Full Text Available This paper examines the problems faced by Law Enforcement in searching large quantities of electronic evidence. It examines the use of ontologies as the basis for new forensic software filters and provides a proof of concept tool based on an ontological design. It demonstrates that efficient searching is produced through the use of such a design and points to further work that might be carried out to extend this concept.

  7. Radiobiological Determination of Dose Escalation and Normal Tissue Toxicity in Definitive Chemoradiation Therapy for Esophageal Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Warren, Samantha, E-mail: Samantha.warren@oncology.ox.ac.uk [Department of Oncology, Gray Institute of Radiation Oncology and Biology, University of Oxford, Oxford (United Kingdom); Partridge, Mike [Department of Oncology, Gray Institute of Radiation Oncology and Biology, University of Oxford, Oxford (United Kingdom); Carrington, Rhys [Velindre Cancer Centre, Velindre Hospital, Cardiff (United Kingdom); Hurt, Chris [Wales Cancer Trials Unit, School of Medicine, Heath Park, Cardiff (United Kingdom); Crosby, Thomas [Velindre Cancer Centre, Velindre Hospital, Cardiff (United Kingdom); Hawkins, Maria A. [Department of Oncology, Gray Institute of Radiation Oncology and Biology, University of Oxford, Oxford (United Kingdom)

    2014-10-01

    Purpose: This study investigated the trade-off in tumor coverage and organ-at-risk sparing when applying dose escalation for concurrent chemoradiation therapy (CRT) of mid-esophageal cancer, using radiobiological modeling to estimate local control and normal tissue toxicity. Methods and Materials: Twenty-one patients with mid-esophageal cancer were selected from the SCOPE1 database (International Standard Randomised Controlled Trials number 47718479), with a mean planning target volume (PTV) of 327 cm{sup 3}. A boost volume, PTV2 (GTV + 0.5 cm margin), was created. Radiobiological modeling of tumor control probability (TCP) estimated the dose required for a clinically significant (+20%) increase in local control as 62.5 Gy/25 fractions. A RapidArc (RA) plan with a simultaneously integrated boost (SIB) to PTV2 (RA{sub 62.5}) was compared to a standard dose plan of 50 Gy/25 fractions (RA{sub 50}). Dose-volume metrics and estimates of normal tissue complication probability (NTCP) for heart and lungs were compared. Results: Clinically acceptable dose escalation was feasible for 16 of 21 patients, with significant gains (>18%) in tumor control from 38.2% (RA{sub 50}) to 56.3% (RA{sub 62.5}), and only a small increase in predicted toxicity: median heart NTCP 4.4% (RA{sub 50}) versus 5.6% (RA{sub 62.5}) P<.001 and median lung NTCP 6.5% (RA{sub 50}) versus 7.5% (RA{sub 62.5}) P<.001. Conclusions: Dose escalation to the GTV to improve local control is possible when overlap between PTV and organ-at-risk (<8% heart volume and <2.5% lung volume overlap for this study) generates only negligible increase in lung or heart toxicity. These predictions from radiobiological modeling should be tested in future clinical trials.

  8. Pharmacological cardioversion of atrial fibrillation--a double-blind, randomized, placebo-controlled, multicentre, dose-escalation study of AZD1305 given intravenously

    DEFF Research Database (Denmark)

    Rónaszéki, Aladár; Alings, Marco; Egstrup, Kenneth

    2011-01-01

    AZD1305 is a combined ion channel blocker developed for the treatment of atrial fibrillation (AF). The aim of this study was to determine whether AZD1305 was effective in converting AF to sinus rhythm (SR)....

  9. Randomized, double-blind, placebo-controlled, proof-of-concept study of the cortical spreading depression inhibiting agent tonabersat in migraine prophylaxis

    DEFF Research Database (Denmark)

    Goadsby, P J; Ferrari, M D; Csanyi, A

    2009-01-01

    Tonabersat is a novel putative migraine prophylactic agent with an unique stereospecific binding site in the brain. Tonabersat has been shown, in animal models, to inhibit experimentally induced cortical spreading depression, the likely underlying mechanism for migraine aura, and cerebrovascular ...

  10. Dose escalation in permanent brachytherapy for prostate cancer: dosimetric and biological considerations

    Energy Technology Data Exchange (ETDEWEB)

    Li, X Allen [Department of Radiation Oncology, University of Maryland, School of Medicine, 22 South Greene Street, Baltimore, MD 21201-1595 (United States); Wang, Jian Z [Department of Radiation Oncology, University of Maryland, School of Medicine, 22 South Greene Street, Baltimore, MD 21201-1595 (United States); Stewart, Robert D [School of Health Sciences, Purdue University, West Lafayette, IN 47907-1338 (United States); Di Biase, Steven J [Department of Radiation Oncology, University of Maryland, School of Medicine, 22 South Greene Street, Baltimore, MD 21201-1595 (United States)

    2003-09-07

    No prospective dose escalation study for prostate brachytherapy (PB) with permanent implants has been reported. In this work, we have performed a dosimetric and biological analysis to explore the implications of dose escalation in PB using {sup 125}I and {sup 103}Pd implants. The concept of equivalent uniform dose (EUD), proposed originally for external-beam radiotherapy (EBRT), is applied to low dose rate brachytherapy. For a given {sup 125}I or {sup 103}Pd PB, the EUD for tumour that corresponds to a dose distribution delivered by EBRT is calculated based on the linear quadratic model. The EUD calculation is based on the dose volume histogram (DVH) obtained retrospectively from representative actual patient data. Tumour control probabilities (TCPs) are also determined in order to compare the relative effectiveness of different dose levels. The EUD for normal tissue is computed using the Lyman model. A commercial inverse treatment planning algorithm is used to investigate the feasibility of escalating the dose to prostate with acceptable dose increases in the rectum and urethra. The dosimetric calculation is performed for five representative patients with different prostate sizes. A series of PB dose levels are considered for each patient using {sup 125}I and {sup 103}Pd seeds. It is found that the PB prescribed doses (minimum peripheral dose) that give an equivalent EBRT dose of 64.8, 70.2, 75.6 and 81 Gy with a fraction size of 1.8 Gy are 129, 139, 150 and 161 Gy for {sup 125}I and 103, 112, 122 and 132 Gy for {sup 103}Pd implants, respectively. Estimates of the EUD and TCP for a series of possible prescribed dose levels (e.g., 145, 160, 170 and 180 Gy for {sup 125}I and 125, 135, 145 and 155 for {sup 103}Pd implants) are tabulated. The EUD calculation was found to depend strongly on DVHs and radiobiological parameters. The dosimetric calculations suggest that the dose to prostate can be escalated without a substantial increase in both rectal and urethral dose

  11. Impact of dose escalation and adaptive radiotherapy for cervical cancers on tumour shrinkage—a modelling study

    Science.gov (United States)

    Røthe Arnesen, Marius; Paulsen Hellebust, Taran; Malinen, Eirik

    2017-03-01

    Tumour shrinkage occurs during fractionated radiotherapy and is regulated by radiation induced cellular damage, repopulation of viable cells and clearance of dead cells. In some cases additional tumour shrinkage during external beam therapy may be beneficial, particularly for locally advanced cervical cancer where a small tumour volume may simplify and improve brachytherapy. In the current work, a mathematical tumour model is utilized to investigate how local dose escalation affects tumour shrinkage, focusing on implications for brachytherapy. The iterative two-compartment model is based upon linear-quadratic radiation response, a doubling time for viable cells and a half-time for clearance of dead cells. The model was individually fitted to clinical tumour volume data from fractionated radiotherapy of 25 cervical cancer patients. Three different fractionation patterns for dose escalation, all with an additional dose of 12.2 Gy, were simulated and compared to standard fractionation in terms of tumour shrinkage. An adaptive strategy where dose escalation was initiated after one week of treatment was also considered. For 22 out of 25 patients, a good model fit was achieved to the observed tumour shrinkage. A large degree of inter-patient variation was seen in predicted volume reduction following dose escalation. For the 10 best responding patients, a mean tumour volume reduction of 34  ±  3% (relative to standard treatment) was estimated at the time of brachytherapy. Timing of initiating dose escalation had a larger impact than the number of fractions applied. In conclusion, the model was found useful in evaluating the impact from dose escalation on tumour shrinkage. The results indicate that dose escalation could be conducted from the start of external beam radiotherapy in order to obtain additional tumour shrinkage before brachytherapy.

  12. Structure of proof of concept studies that precede a nonalcoholic steatohepatitis development program

    Science.gov (United States)

    Filozof, C; Goldstein, BJ; Cusi, K

    2016-01-01

    Surrogate endpoints for clinical proof of concept (POC) trials in nonalcoholic steatohepatitis (NASH) are based upon expert pathological review of liver biopsies. During early development, these long‐term POC studies (≥48 weeks) add cost and time to the “Go/No Go” decision process. However, it is possible to conduct short‐term noninvasive POC studies utilizing biomarkers and magnetic resonance imaging. Here, we discuss the use of shorter noninvasive POC studies relative to biopsy‐driven studies for drug development in NASH. PMID:28032901

  13. Supply Chain Based Solution to Prevent Fuel Tax Evasion: Proof of Concept Final Report

    Energy Technology Data Exchange (ETDEWEB)

    Capps, Gary J [ORNL; Lascurain, Mary Beth [ORNL; Franzese, Oscar [ORNL; Earl, Dennis Duncan [ORNL; West, David L [ORNL; McIntyre, Timothy J [ORNL; Chin, Shih-Miao [ORNL; Hwang, Ho-Ling [ORNL; Connatser, Raynella M [ORNL; Lewis Sr, Samuel Arthur [ORNL; Moore, Sheila A [ORNL

    2011-12-01

    The goal of this research was to provide a proof-of-concept (POC) system for preventing non-taxable (non-highway diesel use) or low-taxable (jet fuel) petrochemical products from being blended with taxable fuel products and preventing taxable fuel products from cross-jurisdiction evasion. The research worked to fill the need to validate the legitimacy of individual loads, offloads, and movements by integrating and validating, on a near-real-time basis, information from global positioning system (GPS), valve sensors, level sensors, and fuel-marker sensors.

  14. Robot-assisted shopping for the visually impaired: proof-of-concept design and feasibility evaluation.

    Science.gov (United States)

    Kulyukin, Vladimir; Gharpure, Chaitanya; Coster, Daniel

    2008-01-01

    This article presents RoboCart, a proof-of-concept prototype of a robotic shopping cart for the visually impaired in supermarkets. RoboCart autonomously leads shoppers to required locations and cues them through synthetic speech and a portable barcode reader to the salient features of the environment sufficient for product retrieval. In a longitudinal pilot feasibility study, visually impaired shoppers (n = 10) used the device to retrieve products in Lee's MarketPlace, a supermarket in Logan, Utah. The main finding is that RoboCart enables visually impaired shoppers to reliably and independently navigate to and retrieve products in a real supermarket.

  15. The proof of concept for 3-cm Altimetry using the Paris Interferometric Technique

    OpenAIRE

    Nogues-Correig, Oleguer; Ribó Vedrilla, Serni; Arco, Juan Carlos; Cardellach, Estel; Rius Jordán, Antonio; Valencia, Enric; Tarongí, José Miguel; Camps, Adriano; Van der Marel, Hans; Martín-Neira, Manuel

    2010-01-01

    © 2010 IEEE. Reprinted, with permission, from Nogués, O., Ribó, S., Arco, J. C., Cardellach, E., Rius, A., València, E., A. Camps, van der Marel, H., Martín-Neira, M., The proof of concept for 3-cm altimetry using the PARIS interferometric technique, Proceedings of IEEE International Geoscience and Remote Sensing Symposium (IEEE IGARSS), and july/2010. This material is posted here with permission of the IEEE. Such permission of the IEEE does not in any way imply IEEE endo...

  16. Pythia version 7-0.0 - a proof-of-concept version

    CERN Document Server

    Bertini, M; Sjöstrand, Torbjörn; Bertini, Marc; Lonnblad, Leif; Sjostrand, Torbjorn

    2001-01-01

    This document describes the first proof-of-concept version of the Pythia7 program. Pythia7 is a complete re-write of the Pythia program in C++. It is mainly intended to be a replacement for the `Lund' family of event generators, but is also a toolkit with a structure suitable for implementing any event generator model. In this document, the structure of the program is presented both from the user and the developer point of view. It is not intended to be a complete manual, but together with the documentation provided in the distribution, it should be sufficient to start working with the program.

  17. Proof-of-Concept Studies for a Local Tie Monitoring System

    Science.gov (United States)

    Schmeing, Benno; Behrend, Dirk; Gipson, John; Nothnagel, Axel

    2010-01-01

    We present preliminary results of proof-of-concept studies for an automatic monitoring system of local site ties. The system is based on the usage of robotic total stations. A set of tests were performed with a Leica TCA2003 total station on the local network of Goddard s Geophysical and Astronomical Observatory (GGAO) and the 5-m VLBI antenna at this site. Both the TCA2003 and the VLBI antenna are controlled from a Matlab-coded control program. Running specific observational programs, data were collected that indicate that the reference point of the VLBI antenna can be automatically determined with an accuracy of 1 mm or better.

  18. Development of a Flexible Laser Hardening & Machining Center and Proof of Concept on C-45 Steel

    Science.gov (United States)

    Bouquet, Jan; Van Camp, Dries; Vanhove, Hans; Clijsters, Stijn; Amirahmad, Mohammadi; Lauwers, Bert

    The production of hardened precision parts is conventionally done in 3 steps. Rough machining of a workpiece in soft stage is followed by a hardening step, usually a batch process, and finalized by a hard machining finishing step. To omit the inevitable time delay and loss of accuracy because of part re-clamping, these steps should be incorporated within one flexible machining center. This paper describes the development of this machining center which allowsmachining and laser hardening in one setup, followed by a proof of concept for hardening C45 steel on this setup.

  19. An Hourly Dose-Escalation Desensitization Protocol for Aspirin-Exacerbated Respiratory Disease.

    Science.gov (United States)

    Chen, Justin R; Buchmiller, Brett L; Khan, David A

    2015-01-01

    Aspirin desensitization followed by maintenance therapy effectively improves symptom control in patients with aspirin exacerbated respiratory disease (AERD). The majority of current desensitization protocols use 3-hour dosing intervals and often require 2 to 3 days to complete. We evaluated hourly dose escalations in a subset of patients with chronic rhinosinusitis, nasal polyps, and asthma who historically reacted to aspirin within 1 hour or were avoiding aspirin with the goal of developing a safe and efficient desensitization protocol. Fifty-seven aspirin desensitizations were performed under the hourly protocol. All patients had refractory nasal polyposis as an indication for aspirin desensitization. The clinical characteristics of each subject were analyzed in relation to aspects of his or her reactions during the procedure. Ninety-eight percent of study patients were successfully treated under the hourly protocol, including those with a history of severe reactions and intubation. None required further medication than is available in an outpatient allergy clinic. A total of 96% of reactors recorded a bronchial or naso-ocular reaction within 1 hour of the preceding dose. Of the total patients on this protocol, 40% were able to complete the procedure in a single day, and 60% within 2 days. Patients with AERD who have a history of symptoms less than 1 hour after aspirin exposure can be safely desensitized with a 1-hour dose-escalation protocol that can often be completed in a single day. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  20. Safety, tolerability and pharmacokinetics of 2-pyridylacetic acid, a major metabolite of betahistine, in a phase 1 dose escalation study in subjects with ADHD.

    Science.gov (United States)

    Moorthy, Ganesh; Sallee, Floyd; Gabbita, Prasad; Zemlan, Frank; Sallans, Larry; Desai, Pankaj B

    2015-10-01

    Betahistine, a potent histamine H3 receptor antagonist, is being developed for the treatment of attention deficit hyperactivity disorder (ADHD) that manifests with symptoms such as hyperactivity, impulsivity and inattention. This study describes the pharmacokinetics of betahistine in ADHD subjects at doses higher than 50 mg. These assessments were made during a randomized, placebo-controlled, single blind, dose escalation study to determine the safety, tolerability and pharmacokinetics of once daily doses of 50 mg, 100 mg and 200 mg of betahistine in subjects with ADHD. Plasma levels of 2-pyridylacetic acid (2-PAA), a major metabolite of betahistine were quantified using a validated LC-MS/MS method and used for pharmacokinetic analysis and dose proportionality of betahistine. A linear relationship was observed in Cmax and AUC0-4 of 2-PAA with the betahistine dose (R2 0.9989 and 0.9978, respectively) and dose proportionality coefficients (β) for the power model were 0.8684 (Cmax) and 1.007 (AUC0-4). A population pharmacokinetic model with first-order absorption of betahistine and metabolism to 2-PAA, followed by a first-order elimination of 2-PAA provides estimates of clearance that underscored the linear increase in systemic exposure with dose. There were no serious adverse events reported in the study, betahistine was safe and well tolerated at all the dose levels tested.

  1. SU-E-T-622: Identification and Improvement of Patients Eligible for Dose Escalation with Matched Plans

    Energy Technology Data Exchange (ETDEWEB)

    Bush, K; Holcombe, C; Kapp, D; Buyyounouski, M; Hancock, S; Xing, L; Atwood, T; King, M [Department of Radiation Oncology, Stanford School of Medicine, Stanford, CA (United States)

    2014-06-15

    Purpose: Radiation-therapy dose-escalation beyond 80Gy may improve tumor control rates for patients with localized prostate cancer. Since toxicity remains a concern, treatment planners must achieve dose-escalation while still adhering to dose-constraints for surrounding structures. Patientmatching is a machine-learning technique that identifies prior patients that dosimetrically match DVH parameters of target volumes and critical structures prior to actual treatment planning. We evaluated the feasibility of patient-matching in (1)identifying candidates for safe dose-escalation; and (2)improving DVH parameters for critical structures in actual dose-escalated plans. Methods: We analyzed DVH parameters from 319 historical treatment plans to determine which plans could achieve dose-escalation (8640cGy) without exceeding Zelefsky dose-constraints (rectal and bladder V47Gy<53%, and V75.6Gy<30%, max-point dose to rectum of 8550cGy, max dose to PTV< 9504cGy). We then estimated the percentage of cases that could achieve safe dose-escalation using software that enables patient matching (QuickMatch, Siris Medical, Mountain View, CA). We then replanned a case that had violated DVH constraints with DVH parameters from patient matching, in order to determine whether this previously unacceptable plan could be made eligible with this automated technique. Results: Patient-matching improved the percentage of patients eligible for dose-escalation from 40% to 63% (p=4.7e-4, t-test). Using a commercial optimizer augmented with patient-matching, we demonstrated a case where patient-matching improved the toxicity-profile such that dose-escalation would have been possible; this plan was rapidly achieved using patientmatching software. In this patient, all lower-dose constraints were met with both the denovo and patient-matching plan. In the patient-matching plan, maximum dose to the rectum was 8385cGy, while the denovo plan failed to meet the maximum rectal constraint at 8571c

  2. Daily-diary Evaluated Side Effects of Dose-escalation Radiotherapy of Prostate Cancer Using the Stereotactic Beamcath Technique

    Energy Technology Data Exchange (ETDEWEB)

    Fransson, Per; Bergstroem, Per; Loefroth, Per-Olov; Franzen, Lars; Henriksson, Roger; Widmark, Anders [Umeaa Univ. (Sweden). Dept. of Radiation Sciences

    2003-06-01

    The aim of this study was to evaluate self-assessed late side effects in patients with prostate cancer treated with frameless stereotactic dose-escalation radiotherapy using BeamCath, a new technique that has been developed for accurate positioning of the prostate at treatment set-up, and in which a specially designed urethral catheter containing high-density fiducial markers is used. The method was tested in the first 104 patients in a Scandinavian dose-escalation study with doses up to 76 Gy. Side effects were reported in a daily diary and evaluated at the start of treatment (baseline) and at 1-year follow-up. The patients were compared with those treated with conventional (n=53) and conformal techniques (n=175). Dose-escalation radiotherapy (76 Gy) decreased urinary frequency, urgency and starting problems at 1-year in comparison with baseline. The dose-escalation therapy did not induce any increase in gastrointestinal side effects in comparison with the effect of conformal therapy h70 Gy at the 1-year follow-up, apart from a slight increase in rectal mucus in the 76 Gy group. All groups, except patients receiving the 74 Gy with smaller fields, reported a slight increase in gastrointestinal toxicity at 1-year compared with baseline. Dose-escalation radiotherapy of prostate cancer using the BeamCath technique did not induce any significant increase in late side effects in comparison with conformal technique.

  3. Effect of aerobic exercise on cancer-associated cognitive impairment: A proof-of-concept RCT.

    Science.gov (United States)

    Campbell, K L; Kam, J W Y; Neil-Sztramko, S E; Liu Ambrose, T; Handy, T C; Lim, H J; Hayden, S; Hsu, L; Kirkham, A A; Gotay, C C; McKenzie, D C; Boyd, L A

    2017-01-11

    Change in cognitive ability is a commonly reported adverse effect by breast cancer survivors. The underlying etiology of cognitive complaints is unclear and to date, there is limited evidence for effective intervention strategies. Exercise has been shown to improve cognitive function in older adults and animal models treated with chemotherapy. This proof-of-concept randomized controlled trial tested the effect of aerobic exercise versus usual lifestyle on cognitive function in postmenopausal breast cancer survivors. Women, aged 40 to 65 years, postmenopausal, stages I to IIIA breast cancer, and who self-reported cognitive dysfunction following chemotherapy treatment, were recruited and randomized to a 24-week aerobic exercise intervention (EX; n = 10) or usual lifestyle control (CON; n = 9). Participants completed self-report measures of the impact of cognitive issues on quality of life (Functional Assessment of Cancer Therapy-Cognitive version 3), objective neuropsychological testing, and functional magnetic resonance imaging at baseline and 24 weeks. Compared to CON, EX had a reduced time to complete a processing speed test (trail making test-A) (-14.2 seconds, P proof-of-concept results for the potential of aerobic exercise to improve cancer-related cognitive impairment and will serve to inform the development of future trials. Copyright © 2017 John Wiley & Sons, Ltd.

  4. Computer-Supported Feedback Message Tailoring for Healthcare Providers in Malawi: Proof-of-Concept.

    Science.gov (United States)

    Landis-Lewis, Zach; Douglas, Gerald P; Hochheiser, Harry; Kam, Matthew; Gadabu, Oliver; Bwanali, Mwatha; Jacobson, Rebecca S

    2015-01-01

    Although performance feedback has the potential to help clinicians improve the quality and safety of care, healthcare organizations generally lack knowledge about how this guidance is best provided. In low-resource settings, tools for theory-informed feedback tailoring may enhance limited clinical supervision resources. Our objectives were to establish proof-of-concept for computer-supported feedback message tailoring in Malawi, Africa. We conducted this research in five stages: clinical performance measurement, modeling the influence of feedback on antiretroviral therapy (ART) performance, creating a rule-based message tailoring process, generating tailored messages for recipients, and finally analysis of performance and message tailoring data. We retrospectively generated tailored messages for 7,448 monthly performance reports from 11 ART clinics. We found that tailored feedback could be routinely generated for four guideline-based performance indicators, with 35% of reports having messages prioritized to optimize the effect of feedback. This research establishes proof-of-concept for a novel approach to improving the use of clinical performance feedback in low-resource settings and suggests possible directions for prospective evaluations comparing alternative designs of feedback messages.

  5. Stone/tissue differentiation for Holmium laser lithotripsy using autofluorescence: Clinical proof of concept study.

    Science.gov (United States)

    Lange, Birgit; Jocham, Dieter; Brinkmann, Ralf; Cordes, Jens

    2017-04-01

    Holmium laser lithotripsy is the gold standard for intracorporeal fragmentation of urinary calculi. Usually, a visible beam is superimposed on the IR treatment laser as an aiming beam to guide the surgeon. In vitro tests showed that this aiming beam (532 nm, power proof of concept study with eight patients. For this, a modulated excitation/detection scheme (lock-in technique) was implemented. A frequency-doubled, diode-pumped solid-state laser module (532 nm, modulation frequency 66 Hz, average power 0.3 mW) was coupled via a dichroic mirror with the Holmium lithotripsy laser into the treatment fiber. The fluorescence signal entering the treatment fiber was detected via another dichroic mirror with a photodiode and a lock-in amplifier. In most instances (94%), the calculus of a patient gave a signal which was at least twice the maximum signal of ureteral tissue. The results of our proof of concept study indicate that measuring the fluorescence signal of a green aiming beam could be used to implement a feedback loop for Holmium laser lithotripsy. Preventing the laser being fired on tissue, this would increase the safety of the procedure. Lasers Surg. Med. 49:361-365, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  6. A Proof-of-Concept Randomized Controlled Study of Gabapentin: Effects on Cannabis Use, Withdrawal and Executive Function Deficits in Cannabis-Dependent Adults

    Science.gov (United States)

    Mason, Barbara J; Crean, Rebecca; Goodell, Vivian; Light, John M; Quello, Susan; Shadan, Farhad; Buffkins, Kimberly; Kyle, Mark; Adusumalli, Murali; Begovic, Adnan; Rao, Santosh

    2012-01-01

    There are no FDA-approved pharmacotherapies for cannabis dependence. Cannabis is the most widely used illicit drug in the world, and patients seeking treatment for primary cannabis dependence represent 25% of all substance use admissions. We conducted a phase IIa proof-of-concept pilot study to examine the safety and efficacy of a calcium channel/GABA modulating drug, gabapentin, for the treatment of cannabis dependence. A 12-week, randomized, double-blind, placebo-controlled clinical trial was conducted in 50 unpaid treatment-seeking male and female outpatients, aged 18–65 years, diagnosed with current cannabis dependence. Subjects received either gabapentin (1200 mg/day) or matched placebo. Manual-guided, abstinence-oriented individual counseling was provided weekly to all participants. Cannabis use was measured by weekly urine toxicology and by self-report using the Timeline Followback Interview. Cannabis withdrawal symptoms were assessed using the Marijuana Withdrawal Checklist. Executive function was measured using subtests from the Delis–Kaplan Executive Function System. Relative to placebo, gabapentin significantly reduced cannabis use as measured both by urine toxicology (p=0.001) and by the Timeline Followback Interview (p=0.004), and significantly decreased withdrawal symptoms as measured by the Marijuana Withdrawal Checklist (ptreatment of cannabis dependence that merits further study, and provides an alternative conceptual framework for treatment of addiction aimed at restoring homeostasis in brain stress systems that are dysregulated in drug dependence and withdrawal. PMID:22373942

  7. Antipsychotic dose escalation as a trigger for Neuroleptic Malignant Syndrome (NMS: literature review and case series report

    Directory of Open Access Journals (Sweden)

    Langan Julie

    2012-11-01

    Full Text Available Abstract Background “Neuroleptic malignant syndrome” (NMS is a potentially fatal idiosyncratic reaction to any medication which affects the central dopaminergic system. Between 0.5% and 1% of patients exposed to antipsychotics develop the condition. Mortality rates may be as high as 55% and many risk factors have been reported. Although rapid escalation of antipsychotic dose is thought to be an important risk factor, to date it has not been the focus of a published case series or scientifically defined. Description We aimed to identify cases of NMS and review risk factors for its development with a particular focus on rapid dose escalation in the 30 days prior to onset. A review of the literature on rapid dose escalation was undertaken and a pragmatic definition of “rapid dose escalation” was made. NMS cases were defined using DSM-IV criteria and systematically identified within a secondary care mental health service. A ratio of titration rate was calculated for each NMS patient and “rapid escalators” and “non rapid escalators” were compared. 13 cases of NMS were identified. A progressive mean dose increase 15 days prior to the confirmed episode of NMS was observed (241.7 mg/day during days 1–15 to 346.9 mg/day during days 16–30 and the mean ratio of dose escalation for NMS patients was 1.4. Rapid dose escalation was seen in 5/13 cases and non rapid escalators had markedly higher daily cumulative antipsychotic dose compared to rapid escalators. Conclusions Rapid dose escalation occurred in less than half of this case series (n = 5, 38.5%, although there is currently no consensus on the precise definition of rapid dose escalation. Cumulative antipsychotic dose – alongside other known risk factors - may also be important in the development of NMS.

  8. Radiation Therapy Dose Escalation for Glioblastoma Multiforme in the Era of Temozolomide

    Energy Technology Data Exchange (ETDEWEB)

    Badiyan, Shahed N.; Markovina, Stephanie; Simpson, Joseph R.; Robinson, Clifford G.; DeWees, Todd [Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri (United States); Tran, David D.; Linette, Gerry [Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri (United States); Jalalizadeh, Rohan [Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri (United States); Dacey, Ralph; Rich, Keith M.; Chicoine, Michael R.; Dowling, Joshua L.; Leuthardt, Eric C.; Zipfel, Gregory J.; Kim, Albert H. [Department of Neurosurgery, Washington University School of Medicine, St. Louis, Missouri (United States); Huang, Jiayi, E-mail: jhuang@radonc.wustl.edu [Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri (United States)

    2014-11-15

    Purpose: To review clinical outcomes of moderate dose escalation using high-dose radiation therapy (HDRT) in the setting of concurrent temozolomide (TMZ) in patients with newly diagnosed glioblastoma multiforme (GBM), compared with standard-dose radiation therapy (SDRT). Methods and Materials: Adult patients aged <70 years with biopsy-proven GBM were treated with SDRT (60 Gy at 2 Gy per fraction) or with HDRT (>60 Gy) and TMZ from 2000 to 2012. Biological equivalent dose at 2-Gy fractions was calculated for the HDRT assuming an α/β ratio of 5.6 for GBM. Results: Eighty-one patients received SDRT, and 128 patients received HDRT with a median (range) biological equivalent dose at 2-Gy fractions of 64 Gy (61-76 Gy). Overall median follow-up time was 1.10 years, and for living patients it was 2.97 years. Actuarial 5-year overall survival (OS) and progression-free survival (PFS) rates for patients that received HDRT versus SDRT were 12.4% versus 13.2% (P=.71), and 5.6% versus 4.1% (P=.54), respectively. Age (P=.001) and gross total/near-total resection (GTR/NTR) (P=.001) were significantly associated with PFS on multivariate analysis. Younger age (P<.0001), GTR/NTR (P<.0001), and Karnofsky performance status ≥80 (P=.001) were associated with improved OS. On subset analyses, HDRT failed to improve PFS or OS for those aged <50 years or those who had GTR/NTR. Conclusion: Moderate radiation therapy dose escalation above 60 Gy with concurrent TMZ does not seem to improve clinical outcomes for patients with GBM.

  9. Caspofungin dose escalation for invasive candidiasis due to resistant Candida albicans.

    Science.gov (United States)

    Wiederhold, Nathan P; Najvar, Laura K; Bocanegra, Rosie A; Kirkpatrick, William R; Patterson, Thomas F

    2011-07-01

    Previous in vivo studies have reported caspofungin dose escalation to be effective against Candida glabrata with reduced susceptibility. We hypothesized that higher doses of caspofungin would be effective against invasive candidiasis caused by the more virulent species Candida albicans, including isolates resistant to this echinocandin. Immunocompetent mice were inoculated with one of three C. albicans isolates, including one susceptible and two resistant isolates with different FKS1 hot spot 1 point mutations. Mice received daily caspofungin treatment for 7 days and were then followed off therapy for 2 weeks to assess survival. Kidney tissue and blood were collected, and fungal burden and serum (1 → 3)-β-D-glucan were measured. Significant differences in virulence were observed among the three C. albicans isolates, which translated into differences in responses to caspofungin. The most virulent of the resistant isolates studied (isolate 43001; Fks1p F641S) did not respond to caspofungin doses of up to 10 mg/kg of body weight, as there were no differences in survival (survival range, 0 to 12% with treatment), tissue burden, or (1 → 3)-β-D-glucan concentration compared to those for untreated controls. Higher doses of caspofungin did improve survival against the second resistant isolate (53264; Fks1p S645P) that demonstrated reduced virulence (5 and 10 mg/kg; 80% survival). In contrast, caspofungin doses as low as 1 mg/kg improved survival (85 to 95%) and reduced tissue burden and (1 → 3)-β-D-glucan concentration against the susceptible isolate (ATCC 90028). These data suggest that caspofungin dose escalation for invasive candidiasis may not be consistently effective against resistant C. albicans isolates, and this may be associated with the virulence of the strain.

  10. Strategy for stochastic dose-rate induced enhanced elimination of malignant tumour without dose escalation.

    Science.gov (United States)

    Paul, Subhadip; Roy, Prasun Kumar

    2016-09-01

    The efficacy of radiation therapy, a primary modality of cancer treatment, depends in general upon the total radiation dose administered to the tumour during the course of therapy. Nevertheless, the delivered radiation also irradiates normal tissues and dose escalation procedure often increases the elimination of normal tissue as well. In this article, we have developed theoretical frameworks under the premise of linear-quadratic-linear (LQL) model using stochastic differential equation and Jensen's inequality for exploring the possibility of attending to the two therapeutic performance objectives in contraposition-increasing the elimination of prostate tumour cells and enhancing the relative sparing of normal tissue in fractionated radiation therapy, within a prescribed limit of total radiation dose. Our study predicts that stochastic temporal modulation in radiation dose-rate appreciably enhances prostate tumour cell elimination, without needing dose escalation in radiation therapy. However, constant higher dose-rate can also enhance the elimination of tumour cells. In this context, we have shown that the sparing of normal tissue with stochastic dose-rate is considerably more than the sparing of normal tissue with the equivalent constant higher dose-rate. Further, by contrasting the stochastic dose-rate effects under LQL and linear-quadratic (LQ) models, we have also shown that the LQ model over-estimates stochastic dose-rate effect in tumour and under-estimates the stochastic dose-rate effect in normal tissue. Our study indicates the possibility of utilizing stochastic modulation of radiation dose-rate for designing enhanced radiation therapy protocol for cancer.

  11. The Role of Age on Dose Limiting Toxicities (DLTs) in Phase I Dose-escalation Trials

    Science.gov (United States)

    Schwandt, A; Harris, P. J.; Hunsberger, S.; Deleporte, A.; Smith, G. L.; Vulih, D.; Anderson, B. D.; Ivy, S. P.

    2016-01-01

    Purpose Elderly oncology patients are not enrolled in early phase trials in proportion to the numbers of geriatric patients with cancer. There may be concern that elderly patients will not tolerate investigational agents as well as younger patients resulting in a disproportionate number of dose-limiting toxicities (DLTs). Recent single-institution studies provide conflicting data on the relationship between age and DLT. Experimental Design We retrospectively reviewed data about patients treated on single-agent, dose-escalation, phase I clinical trials sponsored by the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute. Patients’ dose levels were described as percentage of maximum tolerated dose (%MTD), the highest dose level at which <33% of patients had a DLT, or recommended phase II dose (RP2D). Mixed-effect logistic regression models were used to analyze relationships between the probability of a DLT and age and other explanatory variables. Results Increasing dose, increasing age, and worsening performance status (PS) were significantly related to an increased probability of a DLT in this model (p<0.05). There was no association between dose level administered and age (p=0.57). Conclusions This analysis of phase I dose-escalation trials involving over 500 patients older than 70 years of age, is the largest reported. As age and dose level increased and PS worsened, the probability of a DLT increased. While increasing age was associated with occurrence of DLT, this risk remained within accepted thresholds of risk for phase I trials. There was no evidence of age bias on enrollment of patients on low or high dose levels. PMID:25028396

  12. Collection, synthesis, and interpretation of evidence: a proof-of-concept study in COPD.

    Science.gov (United States)

    Di Scala, L; Kerman, J; Neuenschwander, B

    2013-05-10

    We present a clinical proof-of-concept (PoC) study in chronic obstructive pulmonary disease with the objective of assessing the bronchodilatory effect of an experimental drug as compared with an active control treatment. In such an exploratory Phase II setting, we discuss the formal inclusion of relevant historical information and tailored PoC criteria for the purpose of a more efficient use of the available evidence to support clinical decision making. We provide guidance with regard to practical and methodological aspects for assessing the relevance of the historical data, synthesizing the evidence via a meta-analytic-predictive approach, and defining transparent statistical PoC decision criteria that are aligned with the clinical context. The case study was implemented using the Bayesian approach, which offers an ideal framework for the early phases of drug development. Copyright © 2013 John Wiley & Sons, Ltd.

  13. Development of a pseudo/anonymised primary care research database: Proof-of-concept study.

    Science.gov (United States)

    MacRury, Sandra; Finlayson, Jim; Hussey-Wilson, Susan; Holden, Samantha

    2016-06-01

    General practice records present a comprehensive source of data that could form a variety of anonymised or pseudonymised research databases to aid identification of potential research participants regardless of location. A proof-of-concept study was undertaken to extract data from general practice systems in 15 practices across the region to form pseudo and anonymised research data sets. Two feasibility studies and a disease surveillance study compared numbers of potential study participants and accuracy of disease prevalence, respectively. There was a marked reduction in screening time and increase in numbers of potential study participants identified with the research repository compared with conventional methods. Accurate disease prevalence was established and enhanced with the addition of selective text mining. This study confirms the potential for development of national anonymised research database from general practice records in addition to improving data collection for local or national audits and epidemiological projects.

  14. Proof-of-concept and advancement of the CellFlux concept

    Science.gov (United States)

    Odenthal, Christian; Steinmann, Wolf-Dieter

    2016-05-01

    The CellFlux storage system is a new concept for reducing the costs of medium to high temperature thermal energy storage. Initially designed for solar thermal power plants, the concept is suitable for industrial processes and power to heat applications as well. This paper gives first results of a new pilot scale plant set up at DLR in Stuttgart as a proof of concept. Experimental results are used for the validation of a simplified model. The model is apllied to calculate pareto optimal storage configurations in terms of necessary storage mass and exergetic efficiency, suitable for two types of solar thermal power plants. Particularly for applications having larger temperature differences, high exergetic efficiencies at low costs for the storage material can be achieved.

  15. Development and testing of the Perseus proof-of-concept aircraft. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Langford, J.S. [Aurora Flight Sciences Corp., Manassas, VA (United States)

    1993-02-26

    Many areas of global climate change research could benefit from a flexible, affordable, and near-term platform that could provide in situ measurements in the upper troposphere and lower stratosphere. To provide such a capability, the Perseus unmanned science research aircraft was proposed in 1989. As a first step toward the development of Perseus, a proof-of-concept (POC) demonstrator was constructed and tested during 1990 and 1991. The POC was a full scale Perseus airframe intended to validate the structural, aerodynamic, and flight control technologies for the Perseus within a total budget of about $1.5 million. Advanced propulsion systems needed for the operational Perseus were not covered in the POC program due to funding limitations. This report documents the design, development, and testing of the Perseus POC.

  16. Approach Bias Modification in Food Craving-A Proof-of-Concept Study.

    Science.gov (United States)

    Brockmeyer, Timo; Hahn, Carolyn; Reetz, Christina; Schmidt, Ulrike; Friederich, Hans-Christoph

    2015-09-01

    The aim of the present proof-of-concept study was to test a novel cognitive bias modification (CBM) programme in an analogue sample of people with subclinical bulimic eating disorder (ED) psychopathology. Thirty participants with high levels of trait food craving were trained to make avoidance movements in response to visual food stimuli in an implicit learning paradigm. The intervention comprised ten 15-minute sessions over a 5-week course. At baseline, participants showed approach and attentional biases towards high-caloric palatable food that were both significantly reduced and turned into avoidance biases after the training. Participants also reported pronounced reductions in both trait and cue-elicited food craving and in ED symptoms as well. The overall evaluation of the training by the participants was positive. The specific CBM programme tested in this pilot trial promises to be an effective and feasible way to alter automatic action tendencies towards food in people suffering from bulimic ED psychopathology.

  17. Similarity-based disease risk assessment for personal genomes: proof of concept.

    Science.gov (United States)

    Woo, Jung Hoon; Lai, Albert M; Chung, Wendy K; Weng, Chunhua

    2011-01-01

    The increasing availability of personal genome data has led to escalating needs by consumers to understand the implications of their gene sequences. At present, poorly integrated genetic knowledge has not met these needs. This proof-of-concept study proposes a similarity-based approach to assess the disease risk predisposition for personal genomes. We hypothesize that the semantic similarity between a personal genome and a disease can indicate the disease risks in the person. We developed a knowledge network that integrates existing knowledge of genes, diseases, and symptoms from six sources using the Semantic Web standard, Resource Description Framework (RDF). We then used latent relationships between genes and diseases derived from our knowledge network to measure the semantic similarity between a personal genome and a genetic disease. For demonstration, we showed the feasibility of assessing the disease risks in one personal genome and discussed related methodology issues.

  18. Genetic influences on schizophrenia and subcortical brain volumes: large-scale proof of concept.

    Science.gov (United States)

    Franke, Barbara; Stein, Jason L; Ripke, Stephan; Anttila, Verneri; Hibar, Derrek P; van Hulzen, Kimm J E; Arias-Vasquez, Alejandro; Smoller, Jordan W; Nichols, Thomas E; Neale, Michael C; McIntosh, Andrew M; Lee, Phil; McMahon, Francis J; Meyer-Lindenberg, Andreas; Mattheisen, Manuel; Andreassen, Ole A; Gruber, Oliver; Sachdev, Perminder S; Roiz-Santiañez, Roberto; Saykin, Andrew J; Ehrlich, Stefan; Mather, Karen A; Turner, Jessica A; Schwarz, Emanuel; Thalamuthu, Anbupalam; Yao, Yin; Ho, Yvonne Y W; Martin, Nicholas G; Wright, Margaret J; O'Donovan, Michael C; Thompson, Paul M; Neale, Benjamin M; Medland, Sarah E; Sullivan, Patrick F

    2016-03-01

    Schizophrenia is a devastating psychiatric illness with high heritability. Brain structure and function differ, on average, between people with schizophrenia and healthy individuals. As common genetic associations are emerging for both schizophrenia and brain imaging phenotypes, we can now use genome-wide data to investigate genetic overlap. Here we integrated results from common variant studies of schizophrenia (33,636 cases, 43,008 controls) and volumes of several (mainly subcortical) brain structures (11,840 subjects). We did not find evidence of genetic overlap between schizophrenia risk and subcortical volume measures either at the level of common variant genetic architecture or for single genetic markers. These results provide a proof of concept (albeit based on a limited set of structural brain measures) and define a roadmap for future studies investigating the genetic covariance between structural or functional brain phenotypes and risk for psychiatric disorders.

  19. Proof of Concept: Model Based Bionic Muscle with Hyperbolic Force-Velocity Relation

    Directory of Open Access Journals (Sweden)

    D. F. B. Haeufle

    2012-01-01

    Full Text Available Recently, the hyperbolic Hill-type force-velocity relation was derived from basic physical components. It was shown that a contractile element CE consisting of a mechanical energy source (active element AE, a parallel damper element (PDE, and a serial element (SE exhibits operating points with hyperbolic force-velocity dependency. In this paper, a technical proof of this concept was presented. AE and PDE were implemented as electric motors, SE as a mechanical spring. The force-velocity relation of this artificial CE was determined in quick release experiments. The CE exhibited hyperbolic force-velocity dependency. This proof of concept can be seen as a well-founded starting point for the development of Hill-type artificial muscles.

  20. Early recognition of coeliac disease through community pharmacies: a proof of concept study.

    Science.gov (United States)

    Urwin, Heidi; Wright, David; Twigg, Michael; McGough, Norma

    2016-10-01

    Setting Fifteen community pharmacies in the UK. Objective Proof of concept study to test the use of community pharmacies for active case finding of patients with coeliac disease. Methods Customers accessing over-the counter and prescription medicines indicated in the treatment of possible symptoms of coeliac disease over a 6 month period were offered a free point of care test. All patients were given advice regarding the test results and those who tested positive were advised to make an appointment with their general practitioner. Patients and pharmacists involved in service provision were asked to complete a satisfaction survey. Pharmacists were additionally invited to undertake interviews to better understand their views on the service. Main outcome measures Feasibility of service, acceptability to stakeholders and proportion testing positive for coeliac disease. Results Of the 551 individuals tested, 52 (9.4 %) tested positive. 277 (50.3 %) were tested for accessing irritable bowel syndrome treatment, 142 (25.8 %) due to presenting for diarrhoea. The proportion of patients testing positive with different symptoms or for different treatments were similar. Of 43 customers who returned the satisfaction survey, all would recommend the service to others, believing the community pharmacy to be a suitable location. Community pharmacists believed that it enabled them to improve relationships with their customers and that medical practices were receptive to the service. Conclusion This proof of concept study has shown that community pharmacies using a point of care test can effectively recognise and refer patients for confirmatory coeliac disease testing with high levels of customer and service provider satisfaction.

  1. Support vector machines for automated snoring detection: proof-of-concept.

    Science.gov (United States)

    Samuelsson, Laura B; Rangarajan, Anusha A; Shimada, Kenji; Krafty, Robert T; Buysse, Daniel J; Strollo, Patrick J; Kravitz, Howard M; Zheng, Huiyong; Hall, Martica H

    2017-03-01

    Snoring has been shown to be associated with adverse physical and mental health, independent of the effects of sleep disordered breathing. Despite increasing evidence for the risks of snoring, few studies on sleep and health include objective measures of snoring. One reason for this methodological limitation is the difficulty of quantifying snoring. Conventional methods may rely on manual scoring of snore events by trained human scorers, but this process is both time- and labor-intensive, making the measurement of objective snoring impractical for large or multi-night studies. The current study is a proof-of-concept to validate the use of support vector machines (SVM), a form of machine learning, for the automated scoring of an objective snoring signal. An SVM algorithm was trained and tested on a set of approximately 150,000 snoring and non-snoring data segments, and F-scores for SVM performance compared to visual scoring performance were calculated using the Wilcoxon signed rank test for paired data. The ability of the SVM algorithm to discriminate snore from non-snore segments of data did not differ statistically from visual scorer performance (SVM F-score = 82.46 ± 7.93 versus average visual F-score = 88.35 ± 4.61, p = 0.2786), supporting SVM snore classification ability comparable to visual scorers. In this proof-of-concept, we established that the SVM algorithm performs comparably to trained visual scorers, supporting the use of SVM for automated snoring detection in future studies.

  2. Kaiser Permanente Northern California pregnancy database: Description and proof of concept study.

    Science.gov (United States)

    Zerbo, Ousseny; Chan, Berwick; Goddard, Kristin; Lewis, Ned; Bok, Karin; Klein, Nicola P; Baxter, Roger

    2016-11-04

    We describe the establishment of a dynamic database linking mothers to newborns with the goal of studying vaccine safety in both pregnant women and their children and provide results of a study utilizing this database as a proof of concept. All Kaiser Permanente Northern California (KPNC) live births and their mothers were eligible for inclusion in the pregnancy database. We used the medical record number (MRN), a unique identifier, to retrieve information about events that occurred during the pregnancy and at delivery and linked this same MRN to newborns for post-partum follow up. We conducted a retrospective cohort study to evaluate the association between receipt of tetanus, diphtheria and acellular pertussis (Tdap) vaccine during pregnancy and fever 0-3days after the first dose of diphtheria tetanus and acellular pertussis (DTaP) vaccine in the infant. The study included infants who were born at ⩾37weeks gestation from January 1, 2009 - October 1, 2015 and who received their first DTaP vaccine between 6 and 10weeks of age. We utilized diagnostic codes from inpatient, emergency department, outpatient clinics, and telephone calls. We identified fever using ICD 9 code 780.6, recorded temperature ⩾101 degree Fahrenheit, or parental report. The database contained the starting and ending date of each pregnancy and basic demographic characteristics of mothers and infants. There were 859,699 women and 873,753 children in the database as of January 2016. The proof of concept study included 148,699 infants. In a multivariable logistic regression analysis, Tdap vaccination during pregnancy was not associated with infant fever 0-3daysafter first dose of DTaP (adjusted odds ratio=0.92, 95% CI 0.82-1.04). The KPNC pregnancy database can be used for studies investigating exposure during pregnancy and outcomes in mothers and/or infants, particularly monitoring vaccine safety and effectiveness. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. Helistroke: neurointerventionalist helicopter transport for interventional stroke treatment: proof of concept and rationale.

    Science.gov (United States)

    Hui, Ferdinand K; El Mekabaty, Amgad; Schultz, Jacky; Hong, Kelvin; Horton, Karen; Urrutia, Victor; Naqvi, Imama; Brast, Shawn; Lynch, John K; Nadareishvili, Zurab

    2017-05-02

    It is increasingly recognized that time is one of the key determinants in acute stroke outcome when interventional stroke therapy is applied. With increasing device efficacy and understanding of imaging triage options, reducing pre-treatment time loss may be a critical component of improving interventional stroke outcomes for the population at large. Time sensitive procedures such as organ harvest have transported physicians to the patient site to improve time to procedure. Applying this same principle to interventional stroke management may be a valid paradigm. Previous logistical deliberation with hospital and Medevac companies was carried out to provide the rationale and funding for helicopter transfer of a neurointerventionalist to an in-network hospital with an on-site angiographic suite. An appropriate patient with large vessel occlusion and an NIH Stroke Scale score >8 was identified. MRI was performed, then the Medevac transport system was activated and the intervention was carried out. Times were collected during the case and assessed for time efficiency. The proof of concept case was identified and Medevac was consulted at 12:13 after verifying that no in-house emergencies would prevent physician departure. Weather clearance was obtained and stroke intervention confirmed as a go at 12:24. Groin puncture occurred at 13:07 and the intervention was completed at 13:41. The total time from decision-to-treat to groin puncture was 43 min and groin closure was completed at 77 min from decision-to-treat. This proof of concept case is presented for logistical, financial and use-case analysis. As it is a first case, times can likely be improved. We assert that this model may be another option in the spoke-and-hub design of stroke systems of care. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  4. Proof of concept of the ability of the kinect to quantify upper extremity function in dystrophinopathy.

    Science.gov (United States)

    Lowes, Linda P; Alfano, Lindsay N; Yetter, Brent A; Worthen-Chaudhari, Lise; Hinchman, William; Savage, Jordan; Samona, Patrick; Flanigan, Kevin M; Mendell, Jerry R

    2013-03-14

    Individuals with dystrophinopathy lose upper extremity strength in proximal muscles followed by those more distal. Current upper extremity evaluation tools fail to fully capture changes in upper extremity strength and function across the disease spectrum as they tend to focus solely on distal ability. The Kinect by Microsoft is a gaming interface that can gather positional information about an individual's upper extremity movement which can be used to determine functional reaching volume, velocity of movement, and rate of fatigue while playing an engaging video game. The purpose of this study was to determine the feasibility of using the Kinect platform to assess upper extremity function in individuals with dystrophinopathy across the spectrum of abilities. Investigators developed a proof-of-concept device, ACTIVE (Abilities Captured Through Interactive Video Evaluation), to measure functional reaching volume, movement velocity, and rate of fatigue. Five subjects with dystrophinopathy and 5 normal controls were tested using ACTIVE during one testing session. A single subject with dystrophinopathy was simultaneously tested with ACTIVE and a marker-based motion analysis system to establish preliminary validity of measurements. ACTIVE proof-of-concept ranked the upper extremity abilities of subjects with dystrophinopathy by Brooke score, and also differentiated them from performance of normal controls for the functional reaching volume and velocity tests. Preliminary test-retest reliability of the ACTIVE for 2 sequential trials was excellent for functional reaching volume (ICC=0.986, pproof-of-concept demonstrates that newly available gaming technology has potential to be used to create a low-cost, widely-accessible and functional upper extremity outcome measure for use with children and adults with dystrophinopathy.

  5. External Vision Systems (XVS) proof-of-concept flight test evaluation

    Science.gov (United States)

    Shelton, Kevin J.; Williams, Steven P.; Kramer, Lynda J.; Arthur, Jarvis J.; Prinzel, Lawrence; Bailey, Randall E.

    2014-06-01

    NASA's Fundamental Aeronautics Program, High Speed Project is performing research, development, test and evaluation of flight deck and related technologies to support future low-boom, supersonic configurations (without forward-facing windows) by use of an eXternal Vision System (XVS). The challenge of XVS is to determine a combination of sensor and display technologies which can provide an equivalent level of safety and performance to that provided by forward-facing windows in today's aircraft. This flight test was conducted with the goal of obtaining performance data on see-and-avoid and see-to-follow traffic using a proof-of-concept XVS design in actual flight conditions. Six data collection flights were flown in four traffic scenarios against two different sized participating traffic aircraft. This test utilized a 3x1 array of High Definition (HD) cameras, with a fixed forward field-of-view, mounted on NASA Langley's UC-12 test aircraft. Test scenarios, with participating NASA aircraft serving as traffic, were presented to two evaluation pilots per flight - one using the proof-of-concept (POC) XVS and the other looking out the forward windows. The camera images were presented on the XVS display in the aft cabin with Head-Up Display (HUD)-like flight symbology overlaying the real-time imagery. The test generated XVS performance data, including comparisons to natural vision, and post-run subjective acceptability data were also collected. This paper discusses the flight test activities, its operational challenges, and summarizes the findings to date.

  6. Proof of concept in cardiovascular risk: the paradoxical findings in blood pressure and lipid abnormalities

    Directory of Open Access Journals (Sweden)

    Fuchs FD

    2012-07-01

    Full Text Available Flavio Danni Fuchs, Sandra Costa Fuchs, Leila Beltrami Moreira, Miguel GusDivision of Cardiology and Postgraduate Studies Program in Cardiology, Hospital de Clinicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, BrazilAbstract: High blood pressure and lipoprotein abnormalities were identified by many cohort studies as the major risk factors for cardiovascular disease. Laboratory experiments apparently confirmed their role in the causation of atherosclerosis, but a proof of concept requires the corroboration by clinical trials in human beings. The size of benefit in clinical trials regarding the control of high blood pressure was within the estimations of risk provided by cohort studies. For a reduction of 10 mmHg in systolic blood pressure or 5 mmHg in diastolic blood pressure, the relative risk reduction of coronary heart disease was 22% (95% confidence interval 27%–17% in a meta-analysis of clinical trials, close to the estimation of reduction of 25% (95% confidence interval 23%–27% provided by a meta-analysis of cohort studies. The corresponding values for stroke were 41% (95% confidence interval 33%–48% in clinical trials compared to a cohort risk prediction of 36% (95% confidence interval 34%–38%. This efficacy was shared by all blood pressure-lowering drugs. The same figure has not paradoxically happened with drugs that act over abnormalities of cholesterol and lipoproteins. Only statins, which have other beneficial actions as well, have consistently lowered the incidence of cardiovascular diseases, an efficacy that was not reproduced by older and newer quite potent lipid drugs. The adverse effects of these drugs may nullify their beneficial effects over lipoproteins and abnormalities of lipoproteins may only be surrogate markers of the underlying real risks.Keywords: proof of concept, hypertension, lipoproteins, clinical trials

  7. External Vision Systems (XVS) Proof-of-Concept Flight Test Evaluation

    Science.gov (United States)

    Shelton, Kevin J.; Williams, Steven P.; Kramer, Lynda J.; Arthur, Jarvis J.; Prinzel, Lawrence, III; Bailey, Randall E.

    2014-01-01

    NASA's Fundamental Aeronautics Program, High Speed Project is performing research, development, test and evaluation of flight deck and related technologies to support future low-boom, supersonic configurations (without forward-facing windows) by use of an eXternal Vision System (XVS). The challenge of XVS is to determine a combination of sensor and display technologies which can provide an equivalent level of safety and performance to that provided by forward-facing windows in today's aircraft. This flight test was conducted with the goal of obtaining performance data on see-and-avoid and see-to-follow traffic using a proof-of-concept XVS design in actual flight conditions. Six data collection flights were flown in four traffic scenarios against two different sized participating traffic aircraft. This test utilized a 3x1 array of High Definition (HD) cameras, with a fixed forward field-of-view, mounted on NASA Langley's UC-12 test aircraft. Test scenarios, with participating NASA aircraft serving as traffic, were presented to two evaluation pilots per flight - one using the proof-of-concept (POC) XVS and the other looking out the forward windows. The camera images were presented on the XVS display in the aft cabin with Head-Up Display (HUD)-like flight symbology overlaying the real-time imagery. The test generated XVS performance data, including comparisons to natural vision, and post-run subjective acceptability data were also collected. This paper discusses the flight test activities, its operational challenges, and summarizes the findings to date.

  8. SU-C-BRA-01: 18F-NaF PET/CT-Directed Dose Escalation in Stereotactic Body Radiotherapy for Spine Oligometastases From Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Wu, L [Cancer Hospital of Shantou University Medical College, Shantou, Guangdong (China); University of Nevada, Las Vegas, Las Vegas, NV (United States); Zhang, W; Li, M; Peng, X; Xie, L; Lin, Z [Cancer Hospital of Shantou University Medical College, Shantou, Guangdong (China); Kwee, S [The Queen’s Medical Center, Honolulu, HI (United States); Wang, H; Kuang, Y [University of Nevada, Las Vegas, Las Vegas, NV (United States)

    2015-06-15

    Purpose: To investigate the technical feasibility of SBRT dose painting using {sup 18}F-NaF positron emission tomography (PET) scans guidance in patients with spine oligometastases from prostate cancer. Methods: As a proof of concept, six patients with 14 spine oligometastatic lesions from prostate cancer who had {sup 18}F-NaF PET/CT scan prior to treatment were retrospectively included. GTV{sub reg} was delineated according to the regular tumor boundary shown on PET and/or CT images; and GTV{sub MATV} was contoured based on a net metabolically active tumor volume (MATV) defined by 60% of the SUV{sub max} values on {sup 18}F-NaF PET images. The PTVs (PTV{sub reg} and PTV{sub MATV}) were defined as respective GTVs (plus involved entire vertebral body for PTV{sub reg}) with a 3-mm isotropic expansion margin. Three 1-fraction SBRT plans using VMAT technique along with 10 MV FFF beams (Plan{sub 24Gy}, Plan{sub 24–27Gy}, and Plan{sub 24–30Gy}) were generated for each patient. All plans included a dose of 24 Gy prescribed to PTV{sub reg}. The Plan{sub 24–27Gy} and Plan{sub 24–30Gy} also included a simultaneous boost dose of 27 Gy or 30 Gy prescribed to the PTV{sub MATV}, respectively. The feasibility of 18F-NaF PET-guided SBRT dose escalation was evaluated by its ability to achieve the prescription dose objectives while adhering to organ-at-risk (OAR) dose constraints. The normal tissue complication probabilities (NTCP) calculated by radiological models were also compared between the plans. Results: In all 33 SBRT plans generated, the planning objectives and dose constraints were met without exception. Plan{sub 24–27Gy} and Plan{sub 24–30Gy} had a significantly higher dose in PTV{sub MATV} than Plan{sub 24Gy} (p < 0.05), respectively, while maintaining a similar OAR sparing profile and NTCP values. Conclusion: Using VMAT with FFF beams to incorporate a simultaneous {sup 18}F-NaF PET-guided radiation boost dose up to 30 Gy into a SBRT plan is technically

  9. Inhomogeneous dose escalation increases expected local control for NSCLC patients with lymph node involvement without increased mean lung dose

    DEFF Research Database (Denmark)

    Nielsen, Tine B; Hansen, Olfred; Schytte, Tine;

    2014-01-01

    in mediastinum, and the thorax wall. The dose was escalated using a TCP model implemented into the planning system. The difference in TCP values between the homogeneous and inhomogeneous plans were evaluated using two different TCP models. RESULTS: Dose escalation was possible for all patients. TCP values based...

  10. Does selective pleural irradiation of malignant pleural mesothelioma allow radiation dose escalation. A planning study

    Energy Technology Data Exchange (ETDEWEB)

    Botticella, A.; Defraene, G. [KU Leuven - University of Leuven, Department of Oncology, Experimental Radiation Oncology, Leuven (Belgium); Nackaerts, K. [KU Leuven - University of Leuven, University Hospitals Leuven, Department of Respiratory Medicine, Leuven (Belgium); Deroose, C. [KU Leuven - University of Leuven, University Hospitals Leuven, Nuclear Medicine, Leuven (Belgium); Coolen, J. [KU Leuven - University of Leuven, University Hospitals Leuven, Radiology Department, Leuven (Belgium); Nafteux, P. [University Hospitals Leuven, Department of Thoracic Surgery, Leuven (Belgium); Vanstraelen, B. [University Hospitals Leuven, Department of Radiation Oncology, Leuven (Belgium); Joosten, S.; Michiels, L.A.W. [Fontys University of Applied Science, Institute Paramedical Studies, Medical Imaging and Radiotherapeutic Techniques, Eindhoven (Netherlands); Peeters, S. [KU Leuven - University of Leuven, Department of Oncology, Experimental Radiation Oncology, Leuven (Belgium); University Hospitals Leuven, Department of Radiation Oncology, Leuven (Belgium); Ruysscher, D. de [KU Leuven - University of Leuven, Department of Oncology, Experimental Radiation Oncology, Leuven (Belgium); Maastricht University Medical Center, GROW - School for Oncology and Developmental Biology, Department of Radiation Oncology (MAASTRO Clinic), Maastricht (Netherlands)

    2017-04-15

    After lung-sparing radiotherapy for malignant pleural mesothelioma (MPM), local failure at sites of previous gross disease represents the dominant form of failure. Our aim is to investigate if selective irradiation of the gross pleural disease only can allow dose escalation. In all, 12 consecutive stage I-IV MPM patients (6 left-sided and 6 right-sided) were retrospectively identified and included. A magnetic resonance imaging-based pleural gross tumor volume (GTV) was contoured. Two sets of planning target volumes (PTV) were generated for each patient: (1) a ''selective'' PTV (S-PTV), originating from a 5-mm isotropic expansion from the GTV and (2) an ''elective'' PTV (E-PTV), originating from a 5-mm isotropic expansion from the whole ipsilateral pleural space. Two sets of volumetric modulated arc therapy (VMAT) treatment plans were generated: a ''selective'' pleural irradiation plan (SPI plan) and an ''elective'' pleural irradiation plan (EPI plan, planned with a simultaneous integrated boost technique [SIB]). In the SPI plans, the average median dose to the S-PTV was 53.6 Gy (range 41-63.6 Gy). In 4 of 12 patients, it was possible to escalate the dose to the S-PTV to >58 Gy. In the EPI plans, the average median doses to the E-PTV and to the S-PTV were 48.6 Gy (range 38.5-58.7) and 49 Gy (range 38.6-59.5 Gy), respectively. No significant dose escalation was achievable. The omission of the elective irradiation of the whole ipsilateral pleural space allowed dose escalation from 49 Gy to more than 58 Gy in 4 of 12 chemonaive MPM patients. This strategy may form the basis for nonsurgical radical combined modality treatment of MPM. (orig.) [German] Beim malignen Pleuramesotheliom (MPM) ist nach lungenschonender Radiotherapie das lokale Scheitern an Stellen eines frueheren, sichtbaren Tumors die dominierende Form des Scheiterns. Unser Ziel ist es, zu untersuchen, ob die selektive

  11. Permutation criteria to evaluate multiple clinical endpoints in a proof-of-concept study : lessons from Pre-RELAX-AHF

    NARCIS (Netherlands)

    Davison, Beth A.; Cotter, Gad; Sun, Hengrui; Chen, Li; Teerlink, John R.; Metra, Marco; Felker, G. Michael; Voors, Adriaan A.; Ponikowski, Piotr; Filippatos, Gerasimos; Greenberg, Barry; Teichman, Sam L.; Unemori, Elaine; Koch, Gary G.

    2011-01-01

    Clinically relevant endpoints cannot be routinely targeted with reasonable power in a small study. Hence, proof-of-concept studies are often powered to a primary surrogate endpoint. However, in acute heart failure (AHF) effects on surrogates have not translated into clinical benefit in confirmatory

  12. Safety and pharmacokinetics of ciprofloxacin dry powder for inhalation in cystic fibrosis: a phase I, randomized, single-dose, dose-escalation study.

    Science.gov (United States)

    Stass, Heino; Delesen, Heinz; Nagelschmitz, Johannes; Staab, Doris

    2015-04-01

    Reliable, reproducible deposition to the lung is a major prerequisite for the clinical use of inhaled drugs. Ciprofloxacin dry powder for inhalation (ciprofloxacin DPI; Bayer HealthCare AG, Leverkusen, Germany) is an antibacterial therapy in development using Novartis' PulmoSphere™ technology (Novartis Pharma AG, Basel, Switzerland) for the targeted delivery of ciprofloxacin to the lung via a T-326 inhaler. This randomized, single-blind, placebo-controlled, dose-escalation study investigated the safety, tolerability, and pharmacokinetics of single-dose ciprofloxacin DPI (32.5 mg [n=6] or 65 mg [n=6]) and matching placebo (n=4) in adult patients with cystic fibrosis and stable pulmonary status (forced expiratory volume in 1 sec ≥30%) who were colonized with Pseudomonas aeruginosa. Peak sputum concentrations of 34.9 mg/L (range 2.03-229) and 376 mg/L (8.95-1283) for ciprofloxacin 32.5 mg and 65 mg, respectively, indicated targeting of ciprofloxacin DPI to the lung. This contrasted with low systemic exposure (peak plasma concentrations: 0.0790 mg/L [32.5 mg] and 0.182 mg/L [65 mg]). Single-dose ciprofloxacin DPI 32.5 mg or 65 mg was well tolerated with similar incidences of adverse events across all groups. No deaths, discontinuations, treatment-related serious adverse events, or clinically relevant changes in laboratory parameters, vital signs, or lung function tests were reported. Lung targeting with high pulmonary concentrations of ciprofloxacin combined with low systemic exposure was confirmed. These results support further study of ciprofloxacin DPI as a potentially more convenient alternative to nebulized antibiotic solutions for managing chronic lung infections.

  13. Large-amplitude rotary induced-strain (LARIS) actuator proof-of-concept demonstrator

    Science.gov (United States)

    Giurgiutiu, Victor; Rogers, Craig A.; McNeil, Shane

    1997-06-01

    Induced-strain materials can produce very large forces and, hence, large energy density, but small actual displacements. A new concept for obtaining large-amplitude rotary displacements from small linear displacements generated by induced-strain material stacks is proposed. The concept utilizes the theory of twist-warping coupling in thin-wall open tubes. The theory of the proposed solid-state axial-to- rotary converter-amplifier, together with the appropriate bibliographical references, is given. A simple formula is generated for estimating the axial-to-rotary conversion- amplification coefficient from the geometrical length, L, and enclosed area, A, of the open tube. A large-displacement induced-strain rotary (LARIS) actuator proof-of-concept demonstrator was built and tested to verify and validate the theoretical developments. The LARIS actuator consisted of a 28 mm diameter, 1.2 m length open tube and a 120 micrometer, -1000 V PZT translator. The experimental set-up and the excitation and measuring equipment are fully described in the paper. A maximum rotary displacement of 8 degrees was measured, and the linear relationship between the rotation coefficient, the tube length, L, and the inverse of the enclosed area, A, was verified. An improved theoretical model, that accounts for the experimentally observed zero off-set, is also given. The theoretical developments and experimental tests presented in this paper show that the proposed LARIS actuator, based on a novel solid-state axial-to-rotary converter-amplifier utilizing the warping-torsion coupling of an open tube, is a viable design option, of great constructive simplicity and very low parts count. This concept can be successfully used in a series of aerospace and mechanical engineering applications, as for example in the actuation of adaptive control surfaces for aircraft wings and helicopter blades. The 8 degree rotary displacement capabilities measured on the proof-of-concept demonstrator can be easily

  14. Proof of concept non-invasive estimation of peripheral venous oxygen saturation.

    Science.gov (United States)

    Khan, Musabbir; Pretty, Chris G; Amies, Alexander C; Balmer, Joel; Banna, Houda E; Shaw, Geoffrey M; Geoffrey Chase, J

    2017-05-19

    Pulse oximeters continuously monitor arterial oxygen saturation. Continuous monitoring of venous oxygen saturation (SvO2) would enable real-time assessment of tissue oxygen extraction (O2E) and perfusion changes leading to improved diagnosis of clinical conditions, such as sepsis. This study presents the proof of concept of a novel pulse oximeter method that utilises the compliance difference between arteries and veins to induce artificial respiration-like modulations to the peripheral vasculature. These modulations make the venous blood pulsatile, which are then detected by a pulse oximeter sensor. The resulting photoplethysmograph (PPG) signals from the pulse oximeter are processed and analysed to develop a calibration model to estimate regional venous oxygen saturation (SpvO2), in parallel to arterial oxygen saturation estimation (SpaO2). A clinical study with healthy adult volunteers (n = 8) was conducted to assess peripheral SvO2 using this pulse oximeter method. A range of physiologically realistic SvO2 values were induced using arm lift and vascular occlusion tests. Gold standard, arterial and venous blood gas measurements were used as reference measurements. Modulation ratios related to arterial and venous systems were determined using a frequency domain analysis of the PPG signals. A strong, linear correlation (r (2)  = 0.95) was found between estimated venous modulation ratio (RVen) and measured SvO2, providing a calibration curve relating measured RVen to venous oxygen saturation. There is a significant difference in gradient between the SpvO2 estimation model (SpvO2 = 111 - 40.6*R) and the empirical SpaO2 estimation model (SpaO2 = 110 - 25*R), which yields the expected arterial-venous differences. Median venous and arterial oxygen saturation accuracies of paired measurements between pulse oximeter estimated and gold standard measurements were 0.29 and 0.65%, respectively, showing good accuracy of the pulse oximeter system. The main outcome

  15. Monolithic glass block lasercom terminal: hardware proof of concept and test results

    Science.gov (United States)

    Carlson, Robert T.; Drake, Marvin D.; Jaeger, Jerold L.

    1995-04-01

    We summarize a compact lasercom terminal implementation based on a previously described system concept, and report on measurements made on a prototype optical system built on internal MITRE funds. This paper discusses the fabrication and test of an innovative hardware proof-of-concept for an advanced satellite lasercom terminal with a ten-fold size, weight, and production cost reduction over current practice. We have built and tested a proof-of-concept of the optics portion of a full duplex `monolithic glass block' (MGB) lasercom terminal. The complete MGB optical system is only 6' X 4' X 0.5' and weighs less than a pound. A complete terminal which includes a 3 - 4 inch telescope and gimbal could be implemented for as little as 15 - 30 pounds. The optical system test results are reported. Our approach uses emerging technologies and a highly integrated system design, based on representative system requirements for satellite crosslinks. Technology evaluation and system trades led to a novel optics design for a lasercom terminal, based on thin film coatings and half-inch glass cubes. The emerging photonic technologies employed include liquid crystals for solid state switching, automatic gain control, and microradian alignment; multi-layer dielectric films for optical bandpass filters, dichroic separation, and polarization control; semiconductor lasers with microlens optics; and an original design where all the optics are realized in planar thin films incorporated on small glass substrates, nominally one-half inch in size. These glass cubes are permanently bonded together to form a monolithic ensemble. Hence, we have coined this implementation the monolithic glass block (MGB) approach. Fused silica is used throughout for reasons of superb radiation resistance and thermal stability. The thin film filters, switches, and polarizers perform all the necessary functions in collimated light. This approach is feasible because the optical paths have been dramatically reduced to

  16. Dose-Escalated Robotic SBRT for Stage I-II Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Robert eMeier

    2015-04-01

    Full Text Available Abstract: Stereotactic body radiotherapy (SBRT is the precise external delivery of very high-dose radiotherapy to targets in the body, with treatment completed in one to five fractions. SBRT should be an ideal approach for organ-confined prostate cancer because (I dose escalation should yield improved rates of cancer control; (II the unique radiobiology of prostate cancer favors hypofractionation and (III the conformal nature of SBRT minimizes high-dose radiation delivery to immediately adjacent organs, potentially reducing complications. This approach is also more convenient for patients, and is cheaper than intensity modulated radiotherapy (IMRT. Several external beam platforms are capable of delivering SBRT for early-stage prostate cancer, although most of the mature reported series have employed a robotic non-coplanar platform (i.e., CyberKnife. Several large studies report 5-year biochemical relapse rates which compare favorably to IMRT. Rates of late GU toxicity are similar to those seen with IMRT, and rates of late rectal toxicity may be less than with IMRT and low dose rate (LDR brachytherapy. Patient-reported quality of life (QOL outcomes appear similar to IMRT in the urinary domain. Bowel QOL may be less adversely affected by SBRT than with other radiation modalities. After five years of follow-up, SBRT delivered on a robotic platform is yielding outcomes at least as favorable as IMRT, and may be considered appropriate therapy for stage I-II prostate cancer.

  17. Biological equivalent dose studies for dose escalation in the stereotactic synchrotron radiation therapy clinical trials

    Energy Technology Data Exchange (ETDEWEB)

    Prezado, Y.; Fois, G.; Edouard, M.; Nemoz, C.; Renier, M.; Requardt, H.; Esteve, F.; Adam, JF.; Elleaume, H.; Bravin, A., E-mail: prezado@esrf.fr [ID17 Biomedical Beamline, European Synchrotron Radiation Facility (ESRF), 6 rue Jules Horowitz, BP 220, 38043 Grenoble Cedex (France)

    2009-03-15

    Synchrotron radiation is an innovative tool for the treatment of brain tumors. In the stereotactic synchrotron radiation therapy (SSRT) technique a radiation dose enhancement specific to the tumor is obtained. The tumor is loaded with a high atomic number (Z) element and it is irradiated in stereotactic conditions from several entrance angles. The aim of this work was to assess dosimetric properties of the SSRT for preparing clinical trials at the European Synchrotron Radiation Facility (ESRF). To estimate the possible risks, the doses received by the tumor and healthy tissues in the future clinical conditions have been calculated by using Monte Carlo simulations (PENELOPE code). The dose enhancement factors have been determined for different iodine concentrations in the tumor, several tumor positions, tumor sizes, and different beam sizes. A scheme for the dose escalation in the various phases of the clinical trials has been proposed. The biological equivalent doses and the normalized total doses received by the skull have been calculated in order to assure that the tolerance values are not reached.

  18. Dose-Escalated Robotic SBRT for Stage I-II Prostate Cancer.

    Science.gov (United States)

    Meier, Robert

    2015-01-01

    Stereotactic body radiotherapy (SBRT) is the precise external delivery of very high-dose radiotherapy to targets in the body, with treatment completed in one to five fractions. SBRT should be an ideal approach for organ-confined prostate cancer because (I) dose-escalation should yield improved rates of cancer control; (II) the unique radiobiology of prostate cancer favors hypofractionation; and (III) the conformal nature of SBRT minimizes high-dose radiation delivery to immediately adjacent organs, potentially reducing complications. This approach is also more convenient for patients, and is cheaper than intensity-modulated radiotherapy (IMRT). Several external beam platforms are capable of delivering SBRT for early-stage prostate cancer, although most of the mature reported series have employed a robotic non-coplanar platform (i.e., CyberKnife). Several large studies report 5-year biochemical relapse rates which compare favorably to IMRT. Rates of late GU toxicity are similar to those seen with IMRT, and rates of late rectal toxicity may be less than with IMRT and low-dose rate brachytherapy. Patient-reported quality of life (QOL) outcomes appear similar to IMRT in the urinary domain. Bowel QOL may be less adversely affected by SBRT than with other radiation modalities. After 5 years of follow-up, SBRT delivered on a robotic platform is yielding outcomes at least as favorable as IMRT, and may be considered appropriate therapy for stage I-II prostate cancer.

  19. Innovative Power Wheelchair Control Interface: A Proof-of-Concept Study.

    Science.gov (United States)

    Winkler, Sandra L; Romero, Sergio; Prather, Emily; Ramroop, Marisa; Slaibe, Emmy; Christensen, Matthew

    2016-01-01

    Some people without independent mobility are candidates for powered mobility but are unable to use a traditional power wheelchair joystick. This proof-of-concept study tested and further developed an innovative method of driving power wheelchairs for people whose impairments prevent them from operating commercial wheelchair controls. Our concept, Self-referenced Personal Orthotic Omni-purpose Control Interface (SPOOCI), is distinguished by referencing the control sensor not to the wheelchair frame but instead to the adjacent proximal lower-extremity segment via a custom-formed orthosis. Using a descriptive case-series design, we compared the pre-post functional power wheelchair driving skill data of 4 participants, measured by the Power Mobility Program, using descriptive analyses. The intervention consisted of standard-care power wheelchair training during 12 outpatient occupational or physical therapy sessions. All 4 participants who completed the 12-wk intervention improved their functional power wheelchair driving skills using SPOOCI, but only 3 were deemed safe to continue with power wheelchair driving.

  20. Transcranial Direct Current Stimulation Effects on Athletes’ Cognitive Performance: An Exploratory Proof of Concept Trial

    Directory of Open Access Journals (Sweden)

    Davimar Borduchi

    2016-11-01

    Full Text Available Among the 2016 Olympic and Paralympic Games unforgettable moments, one could not overlook performances by Phelps and Bolt, which challenge old premises about the maximum extension of individual supremacism in ultracompetitive modalities and the doping scandals. Different media channels resonated these two trends, with an unseen rise on discussions about traits and practices that may set ultrahigh performance athletes apart from the more ordinary ones. Yet, some key issues remain undebated. This paper aims to add to this debate, with a proof of concept trial, which investigates whether tDCS may serve as an aid for professional athletes. Ten professional athletes of three different modalities of (judo, N=4 athletes, swimming, N=3 athletes and rhythmic gymnastics, N=3 athletes received anodal stimulation (2mA for 20 minutes on the left dorsolateral prefrontal cortex for ten consecutive weekdays. We observed a positive effect of tDCS in their cognitive performance, including a significant improvement in alternated, sustained and divided attention and in memory scores. We also observed a decrease in Beck Depression Inventory scores (4.50 points in this non-clinical population. These preliminary results suggest that tDCS sessions may translate into competitive advantages for professional athletes and recommend the deepening of the discussion on its ethical use in sports, which is ultimately tied to the wider debate around the risks and opportunities that neuromodulation brings to the table.

  1. Proof-of-Concept Demonstration Results for Robotic Visual Servo Controllers

    Energy Technology Data Exchange (ETDEWEB)

    Chawda, P.V.

    2004-09-22

    There is significant motivation to provide robotic systems with improved autonomy as a means to significantly accelerate deactivation and decommissioning operations while also reducing the associated costs, removing human operators from hazardous environments, and reducing the required burden and skill of human operators. To achieve improved autonomy, fundamental research is focused on the challenges of developing visual servo controllers. The challenge in developing these controllers is that a camera provides 2-dimensional image information about the 3-dimensional Euclidean-space through a perspective (range dependent) projection that can be corrupted by uncertainty in the camera calibration matrix. Disturbances in this relationship (i.e., corruption in the sensor information) propagate erroneous information to the feedback controller of the robot, leading to potentially unpredictable task execution. This technical manual describes 3 proof-of-concept demonstrations of visual servo controllers developed from fundamental research aimed at these challenges. Specifically, one section describes the implementation of a cooperative visual servo control scheme with a camera-in-hand and a fixed camera to track a moving target despite uncertainty in the camera calibration and the unknown constant distance from the camera to a target where the camera is mounted on the end-effector of a 6 degrees-of-freedom hydraulic robot manipulator. The next section describes the implementation of 2 homography-based visual servo tracking and regulation controllers for a mobile robot with a calibrated camera despite an unknown time-varying distance from the camera to a target.

  2. Performance evaluation of a proof-of-concept 70 W internal reforming methanol fuel cell system

    Science.gov (United States)

    Avgouropoulos, G.; Schlicker, S.; Schelhaas, K.-P.; Papavasiliou, J.; Papadimitriou, K. D.; Theodorakopoulou, E.; Gourdoupi, N.; Machocki, A.; Ioannides, T.; Kallitsis, J. K.; Kolb, G.; Neophytides, S.

    2016-03-01

    A proof-of-concept 70 W Internal Reforming Methanol Fuel Cell (IRMFC) stack including Balance-of-Plant (BoP) was designed, assembled and tested. Advent TPS® high-temperature, polymer electrolyte membrane electrode assemblies were employed for fuel cell operation at 200 °C. In order to avoid phosphoric acid poisoning of the reformer, the anode electrocatalyst of each cell was indirectly adjoined, via a separation plate, to a highly active CuMnAlOx catalyst coated onto copper foam, which served as methanol reforming layer. The reformer was in-situ converting the methanol/steam feed to the required hydrogen (internal reforming concept) at 200 °C, which was readily oxidized at the anode electrodes. The operation of the IRMFC was supported through a number of BoP components consisting of a start-up subsystem (air blower, evaporator and monolithic burner), a combined afterburner/evaporator device, methanol/water supply and data acquisition units (reactants/products analysis, temperature control, flow control, system load/output control). Depending on the composition of the liquid MeOH/H2O feed streams, current densities up to 0.18 A cm-2 and power output up to 70 W could be obtained with remarkable repeatability. Specific targets for improvement of the efficiency were identified.

  3. Reservoir Cannulas for Pediatric Oxygen Therapy: A Proof-of-Concept Study

    Directory of Open Access Journals (Sweden)

    Grace Wu

    2016-01-01

    Full Text Available Hypoxemia is a complication of pneumonia—the leading infectious cause of death in children worldwide. Treatment generally requires oxygen-enriched air, but access in low-resource settings is expensive and unreliable. We explored use of reservoir cannulas (RCs, which yield oxygen savings in adults but have not been examined in children. Toddler, small child, and adolescent breathing profiles were simulated with artificial lung and airway models. An oxygen concentrator provided flow rates of 0 to 5 L/min via a standard nasal cannula (NC or RC, and delivered oxygen fraction (FdO2 was measured. The oxygen savings ratio (SR and absolute flow savings (AFS were calculated, comparing NC and RC. We demonstrated proof-of-concept that pendant RCs could conserve oxygen during pediatric therapy. SR mean and standard deviation were 1.1±0.2 to 1.4±0.4, 1.1±0.1 to 1.7±0.3, and 1.3±0.1 to 2.4±0.3 for toddler, small child, and adolescent models, respectively. Maximum AFS observed were 0.3±0.3, 0.2±0.1, and 1.4±0.3 L/min for the same models. RCs have the potential to reduce oxygen consumption during treatment of hypoxemia in children; however, further evaluation of products is needed, followed by clinical analysis in patients.

  4. Engineering of Saccharomyces cerevisiae for the production of dihydroxyacetone (DHA) from sugars: a proof of concept.

    Science.gov (United States)

    Nguyen, H T T; Nevoigt, E

    2009-11-01

    Dihydroxyacetone (DHA) has numerous industrial applications. In this work, we pursue the idea to produce DHA from sugars in the yeast Saccharomyces cerevisiae, via glycerol as an intermediate. Firstly, three glycerol dehydrogenase (GDH) genes from different microbial sources were expressed in yeast. Among them, the NAD(+)-dependent GDH of Hansenula polymorpha showed the highest glycerol-oxidizing activity. DHA concentration in shake-flask experiments was roughly 100mg/lDHA from 20g/l glucose, i.e. five times the wild-type level. This level was achieved only when cultures were subjected to osmotic stress, known to enhance glycerol production and accumulation in S. cerevisiae. Secondly, DHA kinase activity was abolished to prevent conversion of DHA to dihydroxyacetone phosphate (DHAP). The dak1Deltadak2Delta double-deletion mutant overexpressing H. polymorpha gdh produced 700mg/l DHA under the same conditions. Although current DHA yield and titer still need to be optimized, our approach provides the proof of concept for producing DHA from sugars in yeast.

  5. Automation of strategy using IDEF0 — A proof of concept

    Directory of Open Access Journals (Sweden)

    Gary R. Waissi

    2015-12-01

    Full Text Available The goal of this interdisciplinary paper is to show that an existing modeling language, Integration Definition for Function Modeling (IDEF0, is applicable for use in strategy modeling and for automation of strategic plan development and implementation. We will show how utilization of the systems modeling language IDEF0 simplifies strategic plan development, and moves strategic planning and management from a static, document-based approach to a model- and software-based approach. A sequence of examples, as a proof-of-concept, is shown to demonstrate the use of IDEF0 to translate document-based strategic plans to model-based plans. The advantages of IDEF0 include: a well-tested language, and comprehensive systems modeling technique. The resulting IDEF0 models are well-defined, well-structured, easy to understand, easy to modify and use, and can be extended to any depth of detail. It is noted, that while the paper focuses on small- and medium manufacturing enterprises (SME, the approach can be used for strategy development and strategy automation of any size company or organization.

  6. A Proof-of-Concept for Semantically Interoperable Federation of IoT Experimentation Facilities.

    Science.gov (United States)

    Lanza, Jorge; Sanchez, Luis; Gomez, David; Elsaleh, Tarek; Steinke, Ronald; Cirillo, Flavio

    2016-06-29

    The Internet-of-Things (IoT) is unanimously identified as one of the main pillars of future smart scenarios. The potential of IoT technologies and deployments has been already demonstrated in a number of different application areas, including transport, energy, safety and healthcare. However, despite the growing number of IoT deployments, the majority of IoT applications tend to be self-contained, thereby forming application silos. A lightweight data centric integration and combination of these silos presents several challenges that still need to be addressed. Indeed, the ability to combine and synthesize data streams and services from diverse IoT platforms and testbeds, holds the promise to increase the potentiality of smart applications in terms of size, scope and targeted business context. In this article, a proof-of-concept implementation that federates two different IoT experimentation facilities by means of semantic-based technologies will be described. The specification and design of the implemented system and information models will be described together with the practical details of the developments carried out and its integration with the existing IoT platforms supporting the aforementioned testbeds. Overall, the system described in this paper demonstrates that it is possible to open new horizons in the development of IoT applications and experiments at a global scale, that transcend the (silo) boundaries of individual deployments, based on the semantic interconnection and interoperability of diverse IoT platforms and testbeds.

  7. Integrated surface/subsurface permafrost thermal hydrology: Model formulation and proof-of-concept simulations

    Science.gov (United States)

    Painter, Scott L.; Coon, Ethan T.; Atchley, Adam L.; Berndt, Markus; Garimella, Rao; Moulton, J. David; Svyatskiy, Daniil; Wilson, Cathy J.

    2016-08-01

    The need to understand potential climate impacts and feedbacks in Arctic regions has prompted recent interest in modeling of permafrost dynamics in a warming climate. A new fine-scale integrated surface/subsurface thermal hydrology modeling capability is described and demonstrated in proof-of-concept simulations. The new modeling capability combines a surface energy balance model with recently developed three-dimensional subsurface thermal hydrology models and new models for nonisothermal surface water flows and snow distribution in the microtopography. Surface water flows are modeled using the diffusion wave equation extended to include energy transport and phase change of ponded water. Variation of snow depth in the microtopography, physically the result of wind scour, is modeled phenomenologically with a diffusion wave equation. The multiple surface and subsurface processes are implemented by leveraging highly parallel community software. Fully integrated thermal hydrology simulations on the tilted open book catchment, an important test case for integrated surface/subsurface flow modeling, are presented. Fine-scale 100 year projections of the integrated permafrost thermal hydrological system on an ice wedge polygon at Barrow Alaska in a warming climate are also presented. These simulations demonstrate the feasibility of microtopography-resolving, process-rich simulations as a tool to help understand possible future evolution of the carbon-rich Arctic tundra in a warming climate.

  8. Passive soil heating using an inexpensive infrared mirror design - a proof of concept

    Science.gov (United States)

    Rasmussen, C.; Gallery, R. E.; Fehmi, J. S.

    2015-09-01

    There is a need to understand the soil system response to warming in order to model the soil process response to predicted climate change. Current methods for soil warming include expensive and difficult to implement active and passive techniques. Here we test a simple, inexpensive in situ passive soil heating approach, based on easy to construct infrared mirrors that do not require automation or enclosures. The infrared mirrors consisted of 61 × 61 cm glass panels coated with infrared reflecting film. The mirrors as constructed are effective for soil heating in environments typified by an open vegetation canopy. Mirror tests were performed on three soils of varying texture, organic matter content, and heat capacity in a warm semi-arid environment. Results indicated that the infrared mirrors yielded significant heating and drying of soil surface and shallow subsurface relative to unwarmed control treatments, and that warming and drying effects were soil specific with greater potential warming on soils with lower volumetric heat capacity. Partial shading from the mirror frame did produce periods of relative cooling at specific times of the day but overall the mirrors yielded a net soil warming. The results demonstrate proof of concept that the infrared mirrors may be used to passively heat the near soil surface, providing an inexpensive, low-maintenance alternative to other passive and active soil heating technologies.

  9. Proof of Concept of Automated Collision Detection Technology in Rugby Sevens.

    Science.gov (United States)

    Clarke, Anthea C; Anson, Judith M; Pyne, David B

    2017-04-01

    Clarke, AC, Anson, JM, and Pyne, DB. Proof of concept of automated collision detection technology in rugby sevens. J Strength Cond Res 31(4): 1116-1120, 2017-Developments in microsensor technology allow for automated detection of collisions in various codes of football, removing the need for time-consuming postprocessing of video footage. However, little research is available on the ability of microsensor technology to be used across various sports or genders. Game video footage was matched with microsensor-detected collisions (GPSports) in one men's (n = 12 players) and one women's (n = 12) rugby sevens match. True-positive, false-positive, and false-negative events between video and microsensor-detected collisions were used to calculate recall (ability to detect a collision) and precision (accurately identify a collision). The precision was similar between the men's and women's rugby sevens game (∼0.72; scale 0.00-1.00); however, the recall in the women's game (0.45) was less than that for the men's game (0.69). This resulted in 45% of collisions for men and 62% of collisions for women being incorrectly labeled. Currently, the automated collision detection system in GPSports microtechnology units has only modest utility in rugby sevens, and it seems that a rugby sevens-specific algorithm is needed. Differences in measures between the men's and women's game may be a result of physical size, and strength, and physicality, as well as technical and tactical factors.

  10. Loving-Kindness Meditation to Target Affect in Mood Disorders: A Proof-of-Concept Study

    Directory of Open Access Journals (Sweden)

    Stefan G. Hofmann

    2015-01-01

    Full Text Available Conventional treatments for mood disorders primarily focus on reducing negative affect, but little on enhancing positive affect. Loving-kindness meditation (LKM is a traditional meditation practice directly oriented toward enhancing unconditional and positive emotional states of kindness towards oneself and others. We report here two independent and uncontrolled studies carried out at different centers, one in Boston, USA (n = 10, and one in Frankfurt, Germany (n = 8, to examine the potential therapeutic utility of a brief LKM group intervention for symptoms of dysthymia and depression. Results at both centers suggest that LKM was associated with large-sized effects on self-reported symptoms of depression (d = 3.33 and 1.90, negative affect (d = 1.98 and 0.92, and positive affect (d = 1.63 and 0.94. Large effects were also found for clinician-reported changes in depression, rumination and specific positive emotions, and moderate effects for changes in adaptive emotion regulation strategies. The qualitative data analyses provide additional support for the potential clinical utility of the intervention. This proof-of-concept evaluation of LKM as a clinical strategy warrants further investigation.

  11. A simplified chemistry module for atmospheric transport and dispersion models: Proof-of-concept using SCIPUFF

    Science.gov (United States)

    Burns, Douglas S.; Rottmann, Shawn D.; Plitz, Angela B. L.; Wiseman, Floyd L.; Moore, William; Chynwat, Veeradej

    2012-09-01

    An atmospheric chemistry module was developed to predict the fate of environmentally hazardous compounds discharged into the atmosphere. The computationally efficient model captures the diurnal variation within the environment and in the degradation rates of the released compounds, follows the formation of toxic degradation products, runs rapidly, and in principle can be integrated with any atmospheric transport and dispersion model. To accomplish this, a detailed atmospheric chemistry mechanism for a target toxic industrial compound (TIC) was reduced to a simple empirical effective degradation rate term (keff). Empirically derived decay functions for keff were developed as a function of important meteorological parameters such as solar flux, temperature, humidity, and cloud cover for various land uses and locations by statistically analyzing data generated from a detailed chemistry mechanism run over a wide range of (typical) atmospheric conditions. 1-Butene and two degradation products (propanal and nitrooxybutanone) were used as representative chemicals in the algorithm development for this proof-of-concept demonstration of the capability of the model. The quality of the developed model was evaluated via comparison with experimental chamber data and the results (decay rates) compared favorably for ethene, propene, and 1-butene (within a factor of two 75% or more of the time).

  12. Coupled anaerobic-aerobic treatment of whey wastewater in a sequencing batch reactor: proof of concept.

    Science.gov (United States)

    Frigon, J C; Bruneau, T; Moletta, R; Guiot, S R

    2007-01-01

    A proof of concept was performed in order to verify if the coupling of anaerobic and aerobic conditions inside the same digester could efficiently treat a reconstituted whey wastewater at 21 degrees C. The sequencing batch reactor (SBR) cycles combined initial anaerobic phase and final aerobic phase with reduced aeration. A series of 24 h cycles in 0.5 L digesters, with four different levels of oxygenation (none, 54, 108 and 182 mgO2 per gram of chemical oxygen demand (COD)), showed residual soluble chemical oxygen demand (sCOD) of 683 +/- 46, 720 +/- 33, 581 +/- 45, 1239 +/- 15 mg L(-1), respectively. Acetate and hydrogen specific activities were maintained for the anaerobic digester, but decreased by 10-25% for the acetate and by 20-50% for the hydrogen, in the coupled digesters. The experiment was repeated using 48 h cycles with limited aeration during 6 or 16 hours at 54 and 108 mgO2gCODinitial(-1), displaying residual sCOD of 177 +/- 43, 137 +/- 38, 104 +/- 22 and 112 +/- 9 mgL(-1) for the anaerobic and the coupled digesters, respectively. The coupled digesters recovered after a pH shock with residual sCOD as low as 132 mg L(-1) compared to 636 mg L(-1) for the anaerobic digester. With regard to the obtained results, the feasibility of the anaerobic-aerobic coupling in SBR digesters for the treatment of whey wastewater was demonstrated.

  13. Integrative Medical Care Plus Mindfulness Training for Patients With Congestive Heart Failure: Proof of Concept.

    Science.gov (United States)

    Kemper, Kathi J; Carmin, Cheryl; Mehta, Bella; Binkley, Phillip

    2016-10-01

    Congestive heart failure (CHF) has a high rate of morbidity and mortality. It is often accompanied by other medical and psychosocial comorbidities that complicate treatment and adherence. We conducted a proof of concept pilot project to determine the feasibility of providing integrative group medical visits plus mindfulness training for patients recently discharged with CHF. Patients were eligible if they had been discharged from an inpatient stay for CHF within the 12 months prior to the new program. The Compassionate Approach to Lifestyle and Mind-Body (CALM) Skills for Patients with CHF consisted of 8 weekly visits focusing on patient education about medications, diet, exercise, sleep, and stress management; group support; and training in mind-body skills such as mindfulness, self-compassion, and loving-kindness. Over two 8-week sessions, 8/11 (73%) patients completed at least 4 visits. The patients had an average age of 57 years. The most common comorbidities were weight gain, sleep problems, and fatigue. After the sessions, 100% of patients planned to make changes to their diet, exercise, and stress management practices. Over half of the patients who met with a pharmacist had a medication-related problem. Improvements were observed in depression, fatigue, and satisfaction with life. Integrative group visits focusing on healthy lifestyle, support, and skill-building are feasible even among CHF patients and should be evaluated in controlled trials as a patient-centered approach to improving outcomes related to improving medication management, depression, fatigue, and quality of life.

  14. Automated disposable small scale reactor for high throughput bioprocess development: a proof of concept study.

    Science.gov (United States)

    Bareither, Rachel; Bargh, Neil; Oakeshott, Robert; Watts, Kathryn; Pollard, David

    2013-12-01

    The acceleration of bioprocess development for biologics and vaccines can be enabled by automated high throughput technologies. This will alleviate the significant resource burden from the multi-factorial statistical experimentation required for controlling product quality attributes of complex biologics. Recent technology advances have improved clone evaluation and screening, but have struggled to combine the scale down criteria required for both high cell density cell culture and microbial processes, with sufficient automation and disposable technologies to accelerate process development. This article describes the proof of concept evaluations of an automated disposable small scale reactor for high throughput upstream process development. Characterization studies established the small scale stirred tank disposable 250 mL reactor as similar to those of lab and pilot scale. The reactor generated equivalent process performance for industrial biologics processes for therapeutic protein and monoclonal antibody production using CHO cell culture, Pichia pastoris and E. coli. This included similar growth, cell viability, product titer, and product quality. The technology was shown to be robust across multiple runs and met the requirements for the ability to run high cell density processes (>400 g/L wet cell weight) with exponential feeds and sophisticated event triggered processes. Combining this reactor into an automated array of reactors will ultimately be part of a high throughput process development strategy. This will combine upstream, small scale purification with rapid analytics that will dramatically shorten timelines and costs of developing biological processes.

  15. Proof of concept demonstration of novel technologies for lunar spacesuit dust mitigation

    Science.gov (United States)

    Manyapu, Kavya K.; De Leon, Pablo; Peltz, Leora; Gaier, James R.; Waters, Deborah

    2017-08-01

    A recent report by NASA identified dust/particulate mitigation techniques as a highly relevant study for future long-term planetary exploration missions (NASA, 2015). The deleterious effects of lunar dust on spacesuits discovered during the Apollo missions has compelled NASA to identify dust mitigation as a critical path for potential future lunar, asteroid and Mars missions. The complexity of spacesuit design has however constrained integrating existing dust cleaning technologies, formerly demonstrated on rigid surfaces, into the spacesuit system. Accordingly, this research is investigating novel methods to integrate dust mitigation technologies for use on spacesuits. We examine utilizing a novel combination of active and passive technologies integrated into the spacesuit outerlayer to alleviate dust contamination. Leveraging two specific technologies, the Electrodynamics Dust Shield (EDS) active technology and Work Function Matching Coating (WFM) passive technology, developed by NASA for rigid surfaces, we apply new high performance materials such as the Carbon Nanotube (CNT) flexible fibers to develop a spacesuit-integrated dust cleaning system. Through experiments conducted using JSC-1A lunar dust simulant on coupons made of spacesuit outerlayer material, feasibility of integrating the proposed dust cleaning system and its performance were assessed. Results from these preliminary experiments show that the integrated dust cleaning system is capable of removing 80-95% of dust from the spacesuit material demonstrating proof of concept. This paper describes the techniques and results from the experiments. Future challenges of implementing the proposed approach into fight suits are identified.

  16. Counter-ion complexes for enhanced drug loading in nanocarriers: Proof-of-concept and beyond.

    Science.gov (United States)

    Günday Türeli, Nazende; Türeli, Akif E; Schneider, Marc

    2016-09-25

    Enhanced drug loading is an important prerequisite of nanomedicines, to reach administration dose while reducing the amount of excipient. Considering biocompatible and biodegradable polymers such as PLGA, pH dependent solubility characteristics along with limited organic solvent solubility of the drug hampers nanoparticle (NP) preparation. To improve loading of such molecules, a method based on using counter ions for complex formation is proposed. Formed complex alters the intrinsic solubility of active substance via electrostatic interaction without chemical modification. A proof-of-concept study was conducted with sodium dodecyl sulfate as counter-ion to fluoroquinolone antibiotic ciprofloxacin. Complex formation resulted in suppressed pH dependent solubility over pH 1.2-9.0 and an additional -80 fold increase in organic solubility was achieved. In consequence, NPs prepared by microjet reactor technology have shown enhanced drug loading efficiencies (-78%) and drug loading of 14%. Moreover, the counter-ion concept was also demonstrated with another class of antibiotics, water soluble aminoglycosides gentamycin and tobramycin. In addition, the counter ion was substituted by degradable excipients such as phosphatidic acid derivatives. Successful implementation has proven the counter-ion concept to be a platform concept that can be successfully implemented for a variety of active substances and counter-ions to enhance drug loading in nanocarriers. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Online support groups for young women with breast cancer: a proof-of-concept study.

    Science.gov (United States)

    Stephen, Joanne; Rojubally, Adina; Linden, Wolfgang; Zhong, Lihong; Mackenzie, Gina; Mahmoud, Sahar; Giese-Davis, Janine

    2017-07-01

    This initial study examined a therapist-led, synchronous, online support group (OSG) with psycho-education (OSG + E) compared to self-help psycho-education (E). The study aims were to examine proof of concept-feasibility, acceptability, and usefulness-and to hone methods for a formal RCT. One hundred five young breast cancer survivors (<50 years) post-treatment were randomized either to OSG + E or E. OSG + E received a therapist-led 10-week synchronous online intervention. E received a self-help workbook. Assessments were at baseline, 10 weeks, and 3 months, with willing OSG + E members completing post-study interviews. Researchers used inductive analysis, generating qualitative themes for feasibility, acceptability, and usefulness. We examined trajectories for one primary and two secondary quantitative outcomes and a combined moderator to discover who preferentially benefitted from the intervention. Qualitative analyses revealed that synchronous chat was at times challenging, but minimal technical coaching, structure, set topics, and professional facilitation enabled conversations that were focused and meaningful. A combined moderator indicated that generally more women benefitted from OSG + E relative to E and particularly those women in semi-rural and rural areas. This study suggests that therapist-led synchronous OSGs are feasible, acceptable, and useful for young breast cancer survivors and that a future RCT with a larger sample size, perhaps more focused on non-urban areas, is needed to establish its effectiveness.

  18. Microwave bone imaging: a preliminary scanning system for proof-of-concept.

    Science.gov (United States)

    Ruvio, Giuseppe; Cuccaro, Antonio; Solimene, Raffaele; Brancaccio, Adriana; Basile, Bruno; Ammann, Max J

    2016-09-01

    This Letter introduces a feasibility study of a scanning system for applications in biomedical bone imaging operating in the microwave range 0.5-4 GHz. Mechanical uncertainties and data acquisition time are minimised by using a fully automated scanner that controls two antipodal Vivaldi antennas. Accurate antenna positioning and synchronisation with data acquisition enables a rigorous proof-of-concept for the microwave imaging procedure of a multi-layer phantom including skin, fat, muscle and bone tissues. The presence of a suitable coupling medium enables antenna miniaturisation and mitigates the impedance mismatch between antennas and phantom. The three-dimensional image of tibia and fibula is successfully reconstructed by scanning the multi-layer phantom due to the distinctive dielectric contrast between target and surrounding tissues. These results show the viability of a microwave bone imaging technology which is low cost, portable, non-ionising, and does not require specially trained personnel. In fact, as no a-priori characterisation of the antenna is required, the image formation procedure is very conveniently simplified.

  19. Adaptation of the global frameworks for community based rehabilitation in southern Africa: a proof of concept.

    Science.gov (United States)

    M'kumbuzi, Vyvienne Rp; Myezwa, Hellen

    2017-01-01

    Community based rehabilitation (CBR) has evolved over the last 30 years and now focuses on empowering persons with disabilities to access and benefit from a wide range of services. The essence and ethos of CBR is captured in several global frameworks, such as the UN Convention on the Rights of People with Disabilities (2006) and the CBR guidelines (2010). The latter contains the CBR matrix. All 15 countries in southern Africa are implementing CBR mostly in rural areas, but the policy framework to guide CBR in the region is unknown. The purpose of the study was to determine to what extent countries in southern Africa have adapted the global frameworks available for CBR. A CBR policy analysis using proof-of-concept methodology was undertaken. Policy documents on CBR were sought from relevant government departments or agencies. Multiple methods and media, including web searches, searches for grey literature, social media and contact through an elaborate network of colleagues working in the region, were employed to execute the search strategy. Data were organized using NVivo software, and three independent raters coded the emergent themes using the CBR matrix. Only Namibia, South Africa, Tanzania and Zimbabwe have specific policy content for CBR. These, however, lacked structure; the content was predominantly aligned to health. Inclusion of key international concepts such as mainstreaming and empowerment were superfluous when present. The CBR policy environment in southern Africa appears inadequate. Contingent factors that preclude adaptation of the global frameworks available for CBR appear to be at play. These warrant further investigation.

  20. A Probabilistic Framework for Risk Analysis of Widespread Flood Events: A Proof-of-Concept Study.

    Science.gov (United States)

    Schneeberger, Klaus; Huttenlau, Matthias; Winter, Benjamin; Steinberger, Thomas; Achleitner, Stefan; Stötter, Johann

    2017-07-27

    This article presents a flood risk analysis model that considers the spatially heterogeneous nature of flood events. The basic concept of this approach is to generate a large sample of flood events that can be regarded as temporal extrapolation of flood events. These are combined with cumulative flood impact indicators, such as building damages, to finally derive time series of damages for risk estimation. Therefore, a multivariate modeling procedure that is able to take into account the spatial characteristics of flooding, the regionalization method top-kriging, and three different impact indicators are combined in a model chain. Eventually, the expected annual flood impact (e.g., expected annual damages) and the flood impact associated with a low probability of occurrence are determined for a study area. The risk model has the potential to augment the understanding of flood risk in a region and thereby contribute to enhanced risk management of, for example, risk analysts and policymakers or insurance companies. The modeling framework was successfully applied in a proof-of-concept exercise in Vorarlberg (Austria). The results of the case study show that risk analysis has to be based on spatially heterogeneous flood events in order to estimate flood risk adequately. © 2017 Society for Risk Analysis.

  1. Proof of concept in cardiovascular risk: the paradoxical findings in blood pressure and lipid abnormalities

    Science.gov (United States)

    Fuchs, Flavio Danni; Fuchs, Sandra Costa; Moreira, Leila Beltrami; Gus, Miguel

    2012-01-01

    High blood pressure and lipoprotein abnormalities were identified by many cohort studies as the major risk factors for cardiovascular disease. Laboratory experiments apparently confirmed their role in the causation of atherosclerosis, but a proof of concept requires the corroboration by clinical trials in human beings. The size of benefit in clinical trials regarding the control of high blood pressure was within the estimations of risk provided by cohort studies. For a reduction of 10 mmHg in systolic blood pressure or 5 mmHg in diastolic blood pressure, the relative risk reduction of coronary heart disease was 22% (95% confidence interval 27%–17%) in a meta-analysis of clinical trials, close to the estimation of reduction of 25% (95% confidence interval 23%–27%) provided by a meta-analysis of cohort studies. The corresponding values for stroke were 41% (95% confidence interval 33%–48%) in clinical trials compared to a cohort risk prediction of 36% (95% confidence interval 34%–38%). This efficacy was shared by all blood pressure-lowering drugs. The same figure has not paradoxically happened with drugs that act over abnormalities of cholesterol and lipoproteins. Only statins, which have other beneficial actions as well, have consistently lowered the incidence of cardiovascular diseases, an efficacy that was not reproduced by older and newer quite potent lipid drugs. The adverse effects of these drugs may nullify their beneficial effects over lipoproteins and abnormalities of lipoproteins may only be surrogate markers of the underlying real risks. PMID:22870036

  2. Fluorescent particle tracers in surface hydrology: a proof of concept in a semi-natural hillslope

    Directory of Open Access Journals (Sweden)

    F. Tauro

    2012-08-01

    Full Text Available In this paper, a proof of concept experiment is conducted to assess the feasibility of tracing overland flow on an experimental hillslope plot via a novel fluorescent particle tracer. Experiments are performed by using beads of diameters ranging from 75 to 1180 μm. Particles are sensed through an experimental apparatus comprising a light source and a video acquisition unit. Runoff on the experimental plot is artificially simulated by using a custom-built rainfall system. Particle transits are detected through supervised methodologies requiring the presence of operators and unsupervised procedures based on image analysis techniques. Average flow velocity estimations are executed based on travel time measurements of the particles as they are dragged by the overland flow on the hillslope. Velocities are compared to flow measurements obtained using rhodamine dye. Experimental findings demonstrate the potential of the methodology for understanding overland flow dynamics in complex natural settings. In addition, insights on the optimization of particle size are presented based on the visibility of the beads and their accuracy in flow tracing.

  3. Automated point-of-care testing for ABO agglutination test: proof of concept and validation.

    Science.gov (United States)

    El Kenz, H; Corazza, F

    2015-07-01

    ABO-incompatible red blood cell transfusions still represent an important hazard in transfusion medicine. Therefore, some countries have introduced a systematic bedside ABO agglutination test checking that the right blood is given to the right patient. However, this strategy requires an extremely time-consuming learning programme and relies on a subjective interpretation of ABO test cards agglutination. We developed a prototype of a fully automated device performing the bedside agglutination test that could be completed by reading of a barcoded wristband. This POCT checks the ABO compatibility between the patient and the blood bag. Proof of concept and analytical validation of the prototype has been completed on 451 blood samples: 238 donor packed red blood cells, 137 consecutive unselected patients for whom a blood group determination had been ordered and on 76 patient samples selected with pathology that could possibly interfere with or impair performances of the assay. We observed 100% concordance for ABO blood groups between the POCT and the laboratory instrument. These preliminary results demonstrate the feasibility of ABO determination with a simple POCT device eliminating manipulation and subjective interpretation responsible for transfusion errors. This device should be linked to the blood bank system allowing all cross-check of the results. © 2015 International Society of Blood Transfusion.

  4. RB-ARD: A proof of concept rule-based abort

    Science.gov (United States)

    Smith, Richard; Marinuzzi, John

    1987-01-01

    The Abort Region Determinator (ARD) is a console program in the space shuttle mission control center. During shuttle ascent, the Flight Dynamics Officer (FDO) uses the ARD to determine the possible abort modes and make abort calls for the crew. The goal of the Rule-based Abort region Determinator (RB/ARD) project was to test the concept of providing an onboard ARD for the shuttle or an automated ARD for the mission control center (MCC). A proof of concept rule-based system was developed on a LMI Lambda computer using PICON, a knowdedge-based system shell. Knowdedge derived from documented flight rules and ARD operation procedures was coded in PICON rules. These rules, in conjunction with modules of conventional code, enable the RB-ARD to carry out key parts of the ARD task. Current capabilities of the RB-ARD include: continuous updating of the available abort mode, recognition of a limited number of main engine faults and recommendation of safing actions. Safing actions recommended by the RB-ARD concern the Space Shuttle Main Engine (SSME) limit shutdown system and powerdown of the SSME Ac buses.

  5. A Proof-of-Concept for Semantically Interoperable Federation of IoT Experimentation Facilities

    Directory of Open Access Journals (Sweden)

    Jorge Lanza

    2016-06-01

    Full Text Available The Internet-of-Things (IoT is unanimously identified as one of the main pillars of future smart scenarios. The potential of IoT technologies and deployments has been already demonstrated in a number of different application areas, including transport, energy, safety and healthcare. However, despite the growing number of IoT deployments, the majority of IoT applications tend to be self-contained, thereby forming application silos. A lightweight data centric integration and combination of these silos presents several challenges that still need to be addressed. Indeed, the ability to combine and synthesize data streams and services from diverse IoT platforms and testbeds, holds the promise to increase the potentiality of smart applications in terms of size, scope and targeted business context. In this article, a proof-of-concept implementation that federates two different IoT experimentation facilities by means of semantic-based technologies will be described. The specification and design of the implemented system and information models will be described together with the practical details of the developments carried out and its integration with the existing IoT platforms supporting the aforementioned testbeds. Overall, the system described in this paper demonstrates that it is possible to open new horizons in the development of IoT applications and experiments at a global scale, that transcend the (silo boundaries of individual deployments, based on the semantic interconnection and interoperability of diverse IoT platforms and testbeds.

  6. A Proof-of-Concept for Semantically Interoperable Federation of IoT Experimentation Facilities

    Science.gov (United States)

    Lanza, Jorge; Sanchez, Luis; Gomez, David; Elsaleh, Tarek; Steinke, Ronald; Cirillo, Flavio

    2016-01-01

    The Internet-of-Things (IoT) is unanimously identified as one of the main pillars of future smart scenarios. The potential of IoT technologies and deployments has been already demonstrated in a number of different application areas, including transport, energy, safety and healthcare. However, despite the growing number of IoT deployments, the majority of IoT applications tend to be self-contained, thereby forming application silos. A lightweight data centric integration and combination of these silos presents several challenges that still need to be addressed. Indeed, the ability to combine and synthesize data streams and services from diverse IoT platforms and testbeds, holds the promise to increase the potentiality of smart applications in terms of size, scope and targeted business context. In this article, a proof-of-concept implementation that federates two different IoT experimentation facilities by means of semantic-based technologies will be described. The specification and design of the implemented system and information models will be described together with the practical details of the developments carried out and its integration with the existing IoT platforms supporting the aforementioned testbeds. Overall, the system described in this paper demonstrates that it is possible to open new horizons in the development of IoT applications and experiments at a global scale, that transcend the (silo) boundaries of individual deployments, based on the semantic interconnection and interoperability of diverse IoT platforms and testbeds. PMID:27367695

  7. Development of a proof of concept low temperature 4He Superfluid Magnetic Pump

    Science.gov (United States)

    Jahromi, Amir E.; Miller, Franklin K.

    2017-03-01

    We describe the development and experimental results of a proof of concept Superfluid Magnetic Pump in this work. This novel low temperature, no moving part pump can replace the existing bellows-piston driven 4He or 3He-4He mixture compressor/circulators used in various sub Kelvin refrigeration systems such as dilution, Superfluid pulse tube, Stirling, or active magnetic regenerative refrigerators. Due to the superior thermal transport properties of sub-Lambda 4He this pump can also be used as a simple circulator to distribute cooling over large surface areas. Our pump was experimentally shown to produce a maximum flow rate of 440 mg/s (averaged over cycle), 665 mg/s (peak) and produced a maximum pressure difference of 2323 Pa using only the more common isotope of helium, 4He. This pump worked in an ;ideal; thermodynamic state: The experimental results matched with the theoretical values predicted by a computer model. Pump curves were developed to map the performance of this pump. This successful demonstration will enable this novel pump to be implemented in suitable sub Kelvin refrigeration systems.

  8. Photodynamic therapy in neurosurgery: a proof of concept of treatment planning system

    Science.gov (United States)

    Dupont, C.; Reyns, N.; Mordon, S.; Vermandel, M.

    2017-02-01

    Glioblastoma (GBM) is the most common primary brain tumor. PhotoDynamic Therapy (PDT) appears as an interesting research field to improve GBM treatment. Nevertheless, PDT cannot fit into the current therapeutic modalities according to several reasons: the lack of reliable and reproducible therapy schemes (devices, light delivery system), the lack of consensus on a photosensitizer and the absence of randomized and controlled multicenter clinical trial. The main objective of this study is to bring a common support for PDT planning. Here, we describe a proof of concept of Treatment Planning System (TPS) dedicated to interstitial PDT for GBM treatment. The TPS was developed with the integrated development environment C++ Builder XE8 and the environment ArtiMED, developed in our laboratory. This software enables stereotactic registration of DICOM images, light sources insertion and an accelerated CUDA GPU dosimetry modeling. Although, Monte-Carlo is more robust to describe light diffusion in biological tissue, analytical model accelerated by GPU remains relevant for dose preview or fast reverse planning processes. Finally, this preliminary work proposes a new tool to plan interstitial or intraoperative PDT treatment and might be included in the design of future clinical trials in order to deliver PDT straightforwardly and homogenously in investigator centers.

  9. Proof-of-Concept of a Millimeter-Wave Integrated Heterogeneous Network for 5G Cellular.

    Science.gov (United States)

    Okasaka, Shozo; Weiler, Richard J; Keusgen, Wilhelm; Pudeyev, Andrey; Maltsev, Alexander; Karls, Ingolf; Sakaguchi, Kei

    2016-08-25

    The fifth-generation mobile networks (5G) will not only enhance mobile broadband services, but also enable connectivity for a massive number of Internet-of-Things devices, such as wireless sensors, meters or actuators. Thus, 5G is expected to achieve a 1000-fold or more increase in capacity over 4G. The use of the millimeter-wave (mmWave) spectrum is a key enabler to allowing 5G to achieve such enhancement in capacity. To fully utilize the mmWave spectrum, 5G is expected to adopt a heterogeneous network (HetNet) architecture, wherein mmWave small cells are overlaid onto a conventional macro-cellular network. In the mmWave-integrated HetNet, splitting of the control plane (CP) and user plane (UP) will allow continuous connectivity and increase the capacity of the mmWave small cells. mmWave communication can be used not only for access linking, but also for wireless backhaul linking, which will facilitate the installation of mmWave small cells. In this study, a proof-of-concept (PoC) was conducted to demonstrate the practicality of a prototype mmWave-integrated HetNet, using mmWave technologies for both backhaul and access.

  10. Proof-of-Concept of a Millimeter-Wave Integrated Heterogeneous Network for 5G Cellular

    Directory of Open Access Journals (Sweden)

    Shozo Okasaka

    2016-08-01

    Full Text Available The fifth-generation mobile networks (5G will not only enhance mobile broadband services, but also enable connectivity for a massive number of Internet-of-Things devices, such as wireless sensors, meters or actuators. Thus, 5G is expected to achieve a 1000-fold or more increase in capacity over 4G. The use of the millimeter-wave (mmWave spectrum is a key enabler to allowing 5G to achieve such enhancement in capacity. To fully utilize the mmWave spectrum, 5G is expected to adopt a heterogeneous network (HetNet architecture, wherein mmWave small cells are overlaid onto a conventional macro-cellular network. In the mmWave-integrated HetNet, splitting of the control plane (CP and user plane (UP will allow continuous connectivity and increase the capacity of the mmWave small cells. mmWave communication can be used not only for access linking, but also for wireless backhaul linking, which will facilitate the installation of mmWave small cells. In this study, a proof-of-concept (PoC was conducted to demonstrate the practicality of a prototype mmWave-integrated HetNet, using mmWave technologies for both backhaul and access.

  11. Autologous Bone Marrow Mononuclear Cell Therapy for Autism: An Open Label Proof of Concept Study

    Directory of Open Access Journals (Sweden)

    Alok Sharma

    2013-01-01

    Full Text Available Cellular therapy is an emerging therapeutic modality with a great potential for the treatment of autism. Recent findings show that the major underlying pathogenetic mechanisms of autism are hypoperfusion and immune alterations in the brain. So conceptually, cellular therapy which facilitates counteractive processes of improving perfusion by angiogenesis and balancing inflammation by immune regulation would exhibit beneficial clinical effects in patients with autism. This is an open label proof of concept study of autologous bone marrow mononuclear cells (BMMNCs intrathecal transplantation in 32 patients with autism followed by multidisciplinary therapies. All patients were followed up for 26 months (mean 12.7. Outcome measures used were ISAA, CGI, and FIM/Wee-FIM scales. Positron Emission Tomography-Computed Tomography (PET-CT scan recorded objective changes. Out of 32 patients, a total of 29 (91% patients improved on total ISAA scores and 20 patients (62% showed decreased severity on CGI-I. The difference between pre- and postscores was statistically significant (P<0.001 on Wilcoxon matched-pairs signed rank test. On CGI-II 96% of patients showed global improvement. The efficacy was measured on CGI-III efficacy index. Few adverse events including seizures in three patients were controlled with medications. The encouraging results of this leading clinical study provide future directions for application of cellular therapy in autism.

  12. Polyamine inhibitors for treatment of feline oral squamous cell carcinoma: a proof-of-concept study.

    Science.gov (United States)

    Lewis, John R; O'Brien, Thomas G; Skorupski, Katherine A; Krick, Erika L; Reiter, Alexander M; Jennings, Michael W; Jurney, Carrie H; Shofer, F S

    2013-01-01

    This study assessed proof-of-concept for use of polyamine inhibitor 2-diluoromethylornithine (DFMO) as a treatment for oral squamous cell carcinoma (SCC) in client-owned cats. Polyamine levels in tumor tissue and normal oral mucosa were quantified before and after treatment. DFMO was administered orally to 14 client-owned cats with histologically confirmed oral SCC. Patients were monitored for gastrointestinal, dermatologic, auditory, hematological, and biochemical abnormalities. Total polyamine levels in tumor tissue decreased after treatment, as did the specific polyamine putrescine in both tumor tissue and normal mucosa. Ototoxicity was observed in 5 of 6 cats receiving pre- and post-treatment brainstem auditory evoked potential tests. Subclinical thrombocytopenia was observed in 6 of 14 cats. One cat showed mild post-anesthetic tremors that resolved without treatment. Oral administration of DFMO at doses used in this study resulted in significantly decreased tumor polyamine levels without life-threatening clinical or hematological toxicities. Further studies are warranted to explore pathophysiology of polyamine biochemistry and use of polyamine inhibitors in treatment of cats with oral SCC.

  13. A proof-of-concept randomized controlled study of gabapentin: effects on cannabis use, withdrawal and executive function deficits in cannabis-dependent adults.

    Science.gov (United States)

    Mason, Barbara J; Crean, Rebecca; Goodell, Vivian; Light, John M; Quello, Susan; Shadan, Farhad; Buffkins, Kimberly; Kyle, Mark; Adusumalli, Murali; Begovic, Adnan; Rao, Santosh

    2012-06-01

    There are no FDA-approved pharmacotherapies for cannabis dependence. Cannabis is the most widely used illicit drug in the world, and patients seeking treatment for primary cannabis dependence represent 25% of all substance use admissions. We conducted a phase IIa proof-of-concept pilot study to examine the safety and efficacy of a calcium channel/GABA modulating drug, gabapentin, for the treatment of cannabis dependence. A 12-week, randomized, double-blind, placebo-controlled clinical trial was conducted in 50 unpaid treatment-seeking male and female outpatients, aged 18-65 years, diagnosed with current cannabis dependence. Subjects received either gabapentin (1200 mg/day) or matched placebo. Manual-guided, abstinence-oriented individual counseling was provided weekly to all participants. Cannabis use was measured by weekly urine toxicology and by self-report using the Timeline Followback Interview. Cannabis withdrawal symptoms were assessed using the Marijuana Withdrawal Checklist. Executive function was measured using subtests from the Delis-Kaplan Executive Function System. Relative to placebo, gabapentin significantly reduced cannabis use as measured both by urine toxicology (p=0.001) and by the Timeline Followback Interview (p=0.004), and significantly decreased withdrawal symptoms as measured by the Marijuana Withdrawal Checklist (pGabapentin was also associated with significantly greater improvement in overall performance on tests of executive function (p=0.029). This POC pilot study provides preliminary support for the safety and efficacy of gabapentin for treatment of cannabis dependence that merits further study, and provides an alternative conceptual framework for treatment of addiction aimed at restoring homeostasis in brain stress systems that are dysregulated in drug dependence and withdrawal.

  14. Biological dose escalation and hypofractionation: what is there to be gained and how will it best be done?

    Science.gov (United States)

    Tree, A C; Alexander, E J; Van As, N J; Dearnaley, D P; Khoo, V

    2013-08-01

    The evidence supporting dose escalation for localised prostate cancer is widely accepted, but in tandem with improvements in biochemical control, dose escalation increases side-effects. In a scenario where most patients achieve control of their cancer, quality of life concerns predominate. Here we examine the biological ways in which an effective dose can be escalated without an unacceptable increase in toxicity. Possible avenues include exploiting the unusual radiobiology of prostate cancer by hypofractionation, the use of image guidance, adaptive planning and prostate motion management. We await with anticipation the results of large randomised trials of hypofractionation, moderate and profound, to establish whether we can further improve the balance between cure and quality of life.

  15. Dose-Escalation Study for Cardiac Radiosurgery in a Porcine Model

    Energy Technology Data Exchange (ETDEWEB)

    Blanck, Oliver, E-mail: oliver.blanck@uksh.de [Department of Radiation Oncology, University of Luebeck and University Medical Center Schleswig-Holstein, Campus Luebeck (Germany); CyberKnife Center Northern Germany, Guestrow (Germany); Bode, Frank [Medical Department II, University of Luebeck and University Medical Center Schleswig-Holstein, Campus Luebeck (Germany); Gebhard, Maximilian [Institute of Pathology, University of Luebeck and University Medical Center Schleswig-Holstein, Campus Luebeck (Germany); Hunold, Peter [Department of Radiology and Nuclear Medicine, University of Luebeck and University Medical Center Schleswig-Holstein, Campus Luebeck (Germany); Brandt, Sebastian [Department of Anaesthesiology and Intensive Care Medicine, University of Luebeck and University Medical Center Schleswig-Holstein, Campus Luebeck (Germany); Bruder, Ralf [Institute for Robotics and Cognitive Systems, University of Luebeck and University Medical Center Schleswig-Holstein, Campus Luebeck (Germany); Grossherr, Martin [Department of Anaesthesiology and Intensive Care Medicine, University of Luebeck and University Medical Center Schleswig-Holstein, Campus Luebeck (Germany); Vonthein, Reinhard [Institute of Medical Biometry and Statistics, University of Luebeck and University Medical Center Schleswig-Holstein, Campus Luebeck (Germany); Rades, Dirk [Department of Radiation Oncology, University of Luebeck and University Medical Center Schleswig-Holstein, Campus Luebeck (Germany); Dunst, Juergen [Department of Radiation Oncology, University of Luebeck and University Medical Center Schleswig-Holstein, Campus Luebeck (Germany); University Copenhagen (Denmark)

    2014-07-01

    Purpose: To perform a proof-of-principle dose-escalation study to radiosurgically induce scarring in cardiac muscle tissue to block veno-atrial electrical connections at the pulmonary vein antrum, similar to catheter ablation. Methods and Materials: Nine mini-pigs underwent pretreatment magnetic resonance imaging (MRI) evaluation of heart function and electrophysiology assessment by catheter measurements in the right superior pulmonary vein (RSPV). Immediately after examination, radiosurgery with randomized single-fraction doses of 0 and 17.5-35 Gy in 2.5-Gy steps were delivered to the RSPV antrum (target volume 5-8 cm{sup 3}). MRI and electrophysiology were repeated 6 months after therapy, followed by histopathologic examination. Results: Transmural scarring of cardiac muscle tissue was noted with doses ≥32.5 Gy. However, complete circumferential scarring of the RSPV was not achieved. Logistic regressions showed that extent and intensity of fibrosis significantly increased with dose. The 50% effective dose for intense fibrosis was 31.3 Gy (odds ratio 2.47/Gy, P<.01). Heart function was not affected, as verified by MRI and electrocardiogram evaluation. Adjacent critical structures were not damaged, as verified by pathology, demonstrating the short-term safety of small-volume cardiac radiosurgery with doses up to 35 Gy. Conclusions: Radiosurgery with doses >32.5 Gy in the healthy pig heart can induce circumscribed scars at the RSPV antrum noninvasively, mimicking the effect of catheter ablation. In our study we established a significant dose-response relationship for cardiac radiosurgery. The long-term effects and toxicity of such high radiation doses need further investigation in the pursuit of cardiac radiosurgery for noninvasive treatment of atrial fibrillation.

  16. Short-term Disulfiram to Reverse Latent HIV Infection: A Phase 2 Dose Escalation Study

    Science.gov (United States)

    Elliott, Julian H.; McMahon, James H.; Chang, Christina C.; Lee, Sulggi A.; Hartogensis, Wendy; Bumpus, Namandje; Savic, Rada; Roney, Janine; Hoh, Rebecca; Solomon, Ajantha; Piatak, Michael; Gorelick, Robert J.; Lifson, Jeff; Bacchetti, Peter; Deeks, Steven G.; Lewin, Sharon R.

    2016-01-01

    Background Disulfiram activates HIV transcription in a primary T-cell model of HIV latency and in a pilot clinical study increased plasma HIV RNA in individuals with adequate diulfiram exposure. Methods We conducted a prospective dose escalation study in order to optimise disulfiram exposure. Thirty people with HIV on suppressive antiretroviral therapy (ART) were enrolled, allocated sequentially to one of three dosing cohorts and received disulfiram daily for three days at a dose of 500mg, 1000mg or 2000mg. The primary endpoint was cell-associated unspliced (CA-US) HIV RNA in CD4+ T-cells. The study is registered with ClinicalTrials.gov, number NCT01944371. Findings The estimated fold increases in CA-US HIV RNA during and post-disulfiram for each cohort were: 500mg: 1·7 (95% confidence interval 1·3 – 2·2) and 2·1 (1·5 – 2·9); 1000mg: 1·9 (1·6 – 2·4) and 2·5 (1·9 – 3·3); and 2000mg: 1·6 (1·2 – 2·1) and 2·1 (1·5 – 3·1) respectively (p<0·003 for all). Disulfiram was well tolerated at all doses. Interpretation Short-term administration of disulfiram resulted in increases in CA-US HIV RNA at all doses, consistent with activating HIV latency. Disulfiram may be suited for future studies of combination and prolonged therapy to activate latent HIV. PMID:26614966

  17. Dose-escalated simultaneous integrated-boost treatment of prostate cancer patients via helical tomotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Geier, M.; Astner, S.T.; Duma, M.N.; Putzhammer, J.; Winkler, C.; Molls, M.; Geinitz, H. [Technische Univ. Muenchen (Germany). Klinik und Poliklinik fuer Strahlentherapie und Radiologische Onkologie; Jacob, V. [Universitaetsklinikum Freiburg (Germany). Klinik fuer Strahlenheilkunde; Nieder, C. [Nordland Hospital, Bodoe (Norway). Dept. of Oncology and Palliative Care; Tromsoe Univ. (Norway). Inst. of Clinical Medicine

    2012-05-15

    The goal of this work was to assess the feasibility of moderately hypofractionated simultaneous integrated-boost intensity-modulated radiotherapy (SIB-IMRT) with helical tomotherapy in patients with localized prostate cancer regarding acute side effects and dose-volume histogram data (DVH data). Acute side effects and DVH data were evaluated of the first 40 intermediate risk prostate cancer patients treated with a definitive daily image-guided SIB-IMRT protocol via helical tomotherapy in our department. The planning target volume including the prostate and the base of the seminal vesicles with safety margins was treated with 70 Gy in 35 fractions. The boost volume containing the prostate and 3 mm safety margins (5 mm craniocaudal) was treated as SIB to a total dose of 76 Gy (2.17 Gy per fraction). Planning constraints for the anterior rectal wall were set in order not to exceed the dose of 76 Gy prescribed to the boost volume. Acute toxicity was evaluated prospectively using a modified CTCAE (Common Terminology Criteria for Adverse Events) score. SIB-IMRT allowed good rectal sparing, although the full boost dose was permitted to the anterior rectal wall. Median rectum dose was 38 Gy in all patients and the median volumes receiving at least 65 Gy (V65), 70 Gy (V70), and 75 Gy (V75) were 13.5%, 9%, and 3%, respectively. No grade 4 toxicity was observed. Acute grade 3 toxicity was observed in 20% of patients involving nocturia only. Grade 2 acute intestinal and urological side effects occurred in 25% and 57.5%, respectively. No correlation was found between acute toxicity and the DVH data. This institutional SIB-IMRT protocol using daily image guidance as a precondition for smaller safety margins allows dose escalation to the prostate without increasing acute toxicity. (orig.)

  18. Decision Regret in Men Undergoing Dose-Escalated Radiation Therapy for Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Steer, Anna N. [Department of Radiation Oncology, North Coast Cancer Institute, Coffs Harbour (Australia); Aherne, Noel J., E-mail: noel.aherne@ncahs.health.nsw.gov.au [Department of Radiation Oncology, North Coast Cancer Institute, Coffs Harbour (Australia); Rural Clinical School Faculty of Medicine, University of New South Wales, Coffs Harbour (Australia); Gorzynska, Karen; Hoffman, Matthew; Last, Andrew; Hill, Jacques [Department of Radiation Oncology, North Coast Cancer Institute, Coffs Harbour (Australia); Shakespeare, Thomas P. [Department of Radiation Oncology, North Coast Cancer Institute, Coffs Harbour (Australia); Rural Clinical School Faculty of Medicine, University of New South Wales, Coffs Harbour (Australia)

    2013-07-15

    Purpose: Decision regret (DR) is a negative emotion associated with medical treatment decisions, and it is an important patient-centered outcome after therapy for localized prostate cancer. DR has been found to occur in up to 53% of patients treated for localized prostate cancer, and it may vary depending on treatment modality. DR after modern dose-escalated radiation therapy (DE-RT) has not been investigated previously, to our knowledge. Our primary aim was to evaluate DR in a cohort of patients treated with DE-RT. Methods and Materials: We surveyed 257 consecutive patients with localized prostate cancer who had previously received DE-RT, by means of a validated questionnaire. Results: There were 220 responses (85.6% response rate). Image-guided intensity modulated radiation therapy was given in 85.0% of patients and 3-dimensional conformal radiation therapy in 15.0%. Doses received included 73.8 Gy (34.5% patients), 74 Gy (53.6%), and 76 Gy (10.9%). Neoadjuvant androgen deprivation (AD) was given in 51.8% of patients and both neoadjuvant and adjuvant AD in 34.5%. The median follow-up time was 23 months (range, 12-67 months). In all, 3.8% of patients expressed DR for their choice of treatment. When asked whether they would choose DE-RT or AD again, only 0.5% probably or definitely would not choose DE-RT again, compared with 8.4% for AD (P<.01). Conclusion: Few patients treated with modern DE-RT express DR, with regret appearing to be lower than in previously published reports of patients treated with radical prostatectomy or older radiation therapy techniques. Patients experienced more regret with the AD component of treatment than with the radiation therapy component, with implications for informed consent. Further research should investigate regret associated with individual components of modern therapy, including AD, radiation therapy and surgery.

  19. Integrated boost IMRT with FET-PET-adapted local dose escalation in glioblastomas. Results of a prospective phase II study

    Energy Technology Data Exchange (ETDEWEB)

    Piroth, M.D.; Pinkawa, M.; Holy, R. [RWTH Aachen University Hospital (Germany). Dept. of Radiation Oncology; Forschungszentrum Juelich GmbH (DE). Juelich-Aachen Research Alliance (JARA) - Section JARA-Brain] (and others)

    2012-04-15

    Dose escalations above 60 Gy based on MRI have not led to prognostic benefits in glioblastoma patients yet. With positron emission tomography (PET) using [{sup 18}F]fluorethyl-L-tyrosine (FET), tumor coverage can be optimized with the option of regional dose escalation in the area of viable tumor tissue. In a prospective phase II study (January 2008 to December 2009), 22 patients (median age 55 years) received radiochemotherapy after surgery. The radiotherapy was performed as an MRI and FET-PET-based integrated-boost intensity-modulated radiotherapy (IMRT). The prescribed dose was 72 and 60 Gy (single dose 2.4 and 2.0 Gy, respectively) for the FET-PET- and MR-based PTV-FET{sub (72 Gy)} and PTV-MR{sub (60 Gy)}. FET-PET and MRI were performed routinely for follow-up. Quality of life and cognitive aspects were recorded by the EORTC-QLQ-C30/QLQ Brain20 and Mini-Mental Status Examination (MMSE), while the therapy-related toxicity was recorded using the CTC3.0 and RTOG scores. Median overall survival (OS) and disease-free survival (DFS) were 14.8 and 7.8 months, respectively. All local relapses were detected at least partly within the 95% dose volume of PTV-MR{sub (60 Gy)}. No relevant radiotherapy-related side effects were observed (excepted alopecia). In 2 patients, a pseudoprogression was observed in the MRI. Tumor progression could be excluded by FET-PET and was confirmed in further MRI and FET-PET imaging. No significant changes were observed in MMSE scores and in the EORTC QLQ-C30/QLQ-Brain20 questionnaires. Our dose escalation concept with a total dose of 72 Gy, based on FET-PET, did not lead to a survival benefit. Acute and late toxicity were not increased, compared with historical controls and published dose-escalation studies. (orig.)

  20. Strategies of dose escalation in the treatment of locally advanced non-small cell lung cancer: image guidance and beyond

    Directory of Open Access Journals (Sweden)

    Alexander eChi

    2014-06-01

    Full Text Available Radiation dose in the setting of chemo-radiation for locally advanced non-small cell lung cancer (NSCLC has been historically limited by the risk of normal tissue toxicity and this has been hypothesized to correlate with the poor results in regard to local tumor recurrences. Dose escalation, as a means to improve local control, with concurrent chemotherapy has been shown to be feasible with three-dimensional conformal radiotherapy in early phase studies with good clinical outcome. However, the potential superiority of moderate dose escalation to 74 Gy has not been shown in phase III randomized studies. In this review, the limitations in target volume definition in previous studies; and the factors that may be critical to safe dose escalation in the treatment of locally advanced NSCLC, such as respiratory motion management, image guidance, intensity modulation, FDG-PET incorporation in the treatment planning process, and adaptive radiotherapy, are discussed. These factors, along with novel treatment approaches that have emerged in recent years, are proposed to warrant further investigation in future trials in a more comprehensive and integrated fashion.

  1. Real-Time Dynamic Brake Assessment Proof of Concept Final Report

    Energy Technology Data Exchange (ETDEWEB)

    Lascurain, Mary Beth [ORNL; Franzese, Oscar [ORNL; Capps, Gary J [ORNL

    2011-11-01

    This proof-of-concept research was performed to explore the feasibility of using real-world braking data from commercial motor vehicles to make a diagnosis of brake condition similar to that of the performance-based brake tester (PBBT). This was done by determining the relationship between pressure and brake force (P-BF), compensating for the gross vehicle weight (GVW). The nature of this P-BF relationship (e.g., low braking force for a given brake application pressure) may indicate brake system problems. In order to determine the relationship between brake force and brake application pressure, a few key parameters of duty cycle information were collected. Because braking events are often brief, spanning only a few seconds, a sample rate of 10 Hz was needed. The algorithm under development required brake application pressure and speed (from which deceleration was calculated). Accurate weight estimation was also needed to properly derive the braking force from the deceleration. In order to ensure that braking force was the predominant factor in deceleration for the segments of data used in analysis, the data was screened for grade as well. Also, the analysis needed to be based on pressures above the crack pressure. The crack pressure is the pressure below which the individual brakes are not applied due the nature of the mechanical system. This value, which may vary somewhat from one wheel end to another, is approximately 10 psi. Therefore, only pressures 15 psi and above were used in the analysis. The Department of Energy s Medium Truck Duty Cycle research has indicated that under the real-world circumstances of the test vehicle brake pressures of up to approximately 30 psi can be expected. Several different types of data were collected during the testing task of this project. Constant-pressure stopping tests were conducted at several combinations of brake application pressure (15, 20, 25, and 30 psi), load conditions (moderately and fully laden), and speeds (20 and

  2. Feasibility of Telementoring for Microneurosurgical Procedures Using a Microscope: A Proof-of-Concept Study.

    Science.gov (United States)

    Ladd, Bryan M; Tackla, Ryan D; Gupte, Akshay; Darrow, David; Sorenson, Jeffery; Zuccarello, Mario; Grande, Andrew W

    2017-03-01

    Our pilot study evaluated the effectiveness of our telementoring-telescripting model to facilitate seamless communication between surgeons while the operating surgeon is using a microscope. As a first proof of concept, 4 students identified 20 anatomic landmarks on a dry human skull with or without telementoring guidance. To assess the ability to communicate operative information, a senior neurosurgery resident evaluated the student's ability and timing to complete a stepwise craniotomy on a cadaveric head, with and without telementoring guidance; a second portion included exposure of the anterior circulation. The mentor was able to annotate directly onto the operator's visual field, which was visible to the operator without looking away from the binocular view. The students showed that they were familiar with half (50% ± 10%) of the structures for identification and none was familiar with the steps to complete a craniotomy before using our system. With the guidance of a remote surgeon projected into the visual field of the microscope, the students were able to correctly identify 100% of the structures and complete a craniotomy. Our system also proved effective in guiding a more experienced neurosurgery resident through complex operative steps associated with exposure of the anterior circulation. Our pilot study showed a platform feasible in providing effective operative direction to inexperienced operators while operating using a microscope. A remote mentor was able to view the visual field of the microscope, annotate on the visual stream, and have the annotated stream appear in the binocular view for the operating mentee. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Ecologically sustainable weed management: How do we get from proof-of-concept to adoption?

    Science.gov (United States)

    Liebman, Matt; Baraibar, Bàrbara; Buckley, Yvonne; Childs, Dylan; Christensen, Svend; Cousens, Roger; Eizenberg, Hanan; Heijting, Sanne; Loddo, Donato; Merotto, Aldo; Renton, Michael; Riemens, Marleen

    2016-07-01

    Weed management is a critically important activity on both agricultural and non-agricultural lands, but it is faced with a daunting set of challenges: environmental damage caused by control practices, weed resistance to herbicides, accelerated rates of weed dispersal through global trade, and greater weed impacts due to changes in climate and land use. Broad-scale use of new approaches is needed if weed management is to be successful in the coming era. We examine three approaches likely to prove useful for addressing current and future challenges from weeds: diversifying weed management strategies with multiple complementary tactics, developing crop genotypes for enhanced weed suppression, and tailoring management strategies to better accommodate variability in weed spatial distributions. In all three cases, proof-of-concept has long been demonstrated and considerable scientific innovations have been made, but uptake by farmers and land managers has been extremely limited. Impediments to employing these and other ecologically based approaches include inadequate or inappropriate government policy instruments, a lack of market mechanisms, and a paucity of social infrastructure with which to influence learning, decision-making, and actions by farmers and land managers. We offer examples of how these impediments are being addressed in different parts of the world, but note that there is no clear formula for determining which sets of policies, market mechanisms, and educational activities will be effective in various locations. Implementing new approaches for weed management will require multidisciplinary teams comprised of scientists, engineers, economists, sociologists, educators, farmers, land managers, industry personnel, policy makers, and others willing to focus on weeds within whole farming systems and land management units. © 2016 by the Ecological Society of America.

  4. A field proof-of-concept of tomographic slug tests in an anisotropic littoral aquifer

    Science.gov (United States)

    Paradis, Daniel; Gloaguen, Erwan; Lefebvre, René; Giroux, Bernard

    2016-05-01

    Hydraulic tomography is increasingly recognized as a characterization approach that can image pathways or barriers to flow as well as their connectivity. In this study, we assess the performance of a transient analysis of tomographic slug test head data in estimating heterogeneity in horizontal hydraulic conductivity (Kh), hydraulic conductivity anisotropy (the ratio between vertical and horizontal hydraulic conductivity - Kv/Kh) and specific storage (Ss) under actual field conditions. The tomographic experiment was carried out between two wells in a moderately heterogeneous and highly anisotropic silt and sand littoral aquifer. In this field proof-of-concept, the inversion of the two-dimensional (2D) head dataset was computed with a 2D radial flow algorithm that considers Kh, Kv/Kh, Ss and wellbore storage effects. This study demonstrated that a transient analysis of tomographic slug tests is able to capture the key features of the littoral environment of the test: the vertical profiles of Kh and Kv are indeed in agreement with those from other field and laboratory tests, and Ss values exhibit physically plausible profiles. Furthermore, the simulation of independent inter-well hydraulic tests (slug and pumping tests screened over the entire aquifer) using resolved Kh, Kv/Kh and Ss tomograms produce responses very close to field observations. This study demonstrates that the effects of fine scale heterogeneity that induces K-anisotropy at larger scales can be captured through a transient analysis of tomographic slug tests, which are very difficult to quantify otherwise with conventional hydraulic tests, thus allowing a better representation of properties controlling flow and transport in aquifer systems.

  5. Multidimensional cognitive evaluation of patients with disorders of consciousness using EEG: A proof of concept study

    Directory of Open Access Journals (Sweden)

    Claire Sergent

    2017-01-01

    In the present study we built a unique EEG protocol that probed 8 dimensions of cognitive processing in a single 1.5 h session. This protocol probed variants of classical markers together with new markers of spatial attention, which has not yet been studied in these patients. The eight dimensions were: (1 own name recognition, (2 temporal attention, (3 spatial attention, (4 detection of spatial incongruence (5 motor planning, and (6,7,8 modulations of these effects by the global context, reflecting higher-level functions. This protocol was tested in 15 healthy control subjects and in 17 patients with various etiologies, among which 13 could be included in the analysis. The results in the control group allowed a validation and a specific description of the cognitive levels probed by each marker. At the single-subject level, this combined protocol allowed assessing the presence of both classical and newly introduced markers for each patient and control, and revealed that the combination of several markers increased diagnostic sensitivity. The presence of a high-level effect in any of the three tested domains distinguished between minimally conscious and vegetative patients, while the presence of low-level effects was similar in both groups. In summary, this study constitutes a validated proof of concept in favor of probing multiple cognitive dimensions to improve the evaluation of non-communicating patients. At a more conceptual level, this EEG tool can help achieve a better understanding of disorders of consciousness by exploring consciousness in its multiple cognitive facets.

  6. Proof of Concept of Integrated Load Measurement in 3D Printed Structures

    Science.gov (United States)

    Hinderdael, Michaël; Jardon, Zoé; Lison, Margot; De Baere, Dieter; Devesse, Wim; Strantza, Maria; Guillaume, Patrick

    2017-01-01

    Currently, research on structural health monitoring systems is focused on direct integration of the system into a component or structure. The latter results in a so-called smart structure. One example of a smart structure is a component with integrated strain sensing for continuous load monitoring. Additive manufacturing, or 3D printing, now also enables such integration of functions inside components. As a proof-of-concept, the Fused Deposition Modeling (FDM) technique was used to integrate a strain sensing element inside polymer (ABS) tensile test samples. The strain sensing element consisted of a closed capillary filled with a fluid and connected to an externally mounted pressure sensor. The volumetric deformation of the integrated capillary resulted in pressure changes in the fluid. The obtained pressure measurements during tensile testing are reported in this paper and compared to state-of-the-art extensometer measurements. The sensitivity of the 3D printed pressure-based strain sensor is primarily a function of the compressibility of the capillary fluid. Air- and watertightness are of critical importance for the proper functioning of the 3D printed pressure-based strain sensor. Therefore, the best after-treatment procedure was selected on basis of a comparative analysis. The obtained pressure measurements are linear with respect to the extensometer readings, and the uncertainty on the strain measurement of a capillary filled with water (incompressible fluid) is ±3.1 µstrain, which is approximately three times less sensitive than conventional strain gauges (±1 µstrain), but 32 times more sensitive than the same sensor based on air (compressible fluid) (±101 µstrain). PMID:28208779

  7. Design and proof of concept of an innovative very high temperature ceramic solar absorber

    Science.gov (United States)

    Leray, Cédric; Ferriere, Alain; Toutant, Adrien; Olalde, Gabriel; Peroy, Jean-Yves; Chéreau, Patrick; Ferrato, Marc

    2017-06-01

    Hybrid solar gas-turbine (HSGT) is an attractive technology to foster market penetration of CSP. HSGT offers some major advantages like for example high solar-to-electric conversion efficiency, reduced water requirement and low capital cost. A very high temperature solar receiver is needed when elevated solar share is claimed. A few research works, as reported by Karni et al. [8] and by Buck et al. [1], have been dedicated to solar receiver technologies able to deliver pressurized air at temperature above 750°C. The present work focuses on research aiming at developing an efficient and reliable solar absorber able to provide pressurized air at temperature up to 1000°C and more. A surface absorber technology is selected and a modular design of receiver is proposed in which each absorber module is made of BOOSTEC® SiC ceramic (silicon carbide) as bulk material with straight air channels inside. Early stage experimental works done at CNRS/PROMES on lab-scale absorbers showed that the thermo-mechanical behavior of this material is a critical issue, resulting in elevated probability of failure under severe conditions like large temperature gradient or steep variation of solar flux density in situations of cloud covering. This paper reports on recent progress made at CNRS/PROMES to address this critical issue. The design of the absorber has been revised and optimized according to thermo-mechanical numerical simulations, and an experimental proof of concept has been done on a pilot-scale absorber module at Themis solar tower facility.

  8. A small molecule (pluripotin as a tool for studying cancer stem cell biology: proof of concept.

    Directory of Open Access Journals (Sweden)

    Susan D Mertins

    Full Text Available BACKGROUND: Cancer stem cells (CSC are thought to be responsible for tumor maintenance and heterogeneity. Bona fide CSC purified from tumor biopsies are limited in supply and this hampers study of CSC biology. Furthermore, purified stem-like CSC subpopulations from existing tumor lines are unstable in culture. Finding a means to overcome these technical challenges would be a useful goal. In a first effort towards this, we examined whether a chemical probe that promotes survival of murine embryonic stem cells without added exogenous factors can alter functional characteristics in extant tumor lines in a fashion consistent with a CSC phenotype. METHODOLOGY/PRINCIPAL FINDINGS: The seven tumor lines of the NCI60 colon subpanel were exposed to SC-1 (pluripotin, a dual kinase and GTPase inhibitor that promotes self-renewal, and then examined for tumorigenicity under limiting dilution conditions and clonogenic activity in soft agar. A statistically significant increase in tumor formation following SC-1 treatment was observed (p<0.04. Cloning efficiencies and expression of putative CSC surface antigens (CD133 and CD44 were also increased. SC-1 treatment led to sphere formation in some colon tumor lines. Finally, SC-1 inhibited in vitro kinase activity of RSK2, and another RSK2 inhibitor increased colony formation implicating a role for this kinase in eliciting a CSC phenotype. CONCLUSIONS/SIGNIFICANCE: These findings validate a proof of concept study exposure of extant tumor lines to a small molecule may provide a tractable in vitro model for understanding CSC biology.

  9. Tele-pharmacy in rural Scotland: a proof of concept study.

    Science.gov (United States)

    Inch, Jackie; Notman, Frances; Watson, Margaret; Green, David; Baird, Robert; Ferguson, James; Hind, Caroline; McKinstry, Brian; Strath, Alison; Bond, Christine

    2017-06-01

    Technology enables medical services to be provided to rural communities. This proof of concept study assessed the feasibility and acceptability of delivering community pharmacy services (CPS; including advice, sale of over-the-counter products and dispensing of prescriptions) by tele-technology (the Telepharmacy Robotic Supply Service (TPRSS)) to a rural population in Scotland. Data collection included the following: postal surveys to local residents; focus groups/ interviews with pharmacists, other healthcare professionals (HCPs) and service users, at baseline and follow-up; TPRSS logs. Interviews/focus groups were audio-recorded, transcribed and thematically analysed. Descriptive statistics were reported for survey data. Qualitative results: Pre-installation: residents expressed satisfaction with current pharmacy access. HCPs believed the TPRSS would improve pharmacy access and reduce pressure on GPs. Concerns included costs, confidentiality, patient safety and 'fear' of technology. Post-installation: residents and pharmacy staff were positive, finding the service easy to use. Quantitative results: Pre-installation: almost half the respondents received regular prescription medicines and a third used an over-the-counter (OTC) medicine at least monthly. More than 80% (124/156) reported they would use the TPRSS. There was low awareness of the minor ailment service (MAS; 38%; 59/156). Post-installation: prescription ordering and OTC medicine purchase were used most frequently; the video link was used infrequently. Reasons for non-use were lack of need (36%; 40/112) and linkage to only one pharmacy (31%; 35/112). Community pharmacy services delivered remotely using tele-technology are feasible and acceptable. A larger study should be undertaken to confirm the potential of the TPRSS to reduce health inequalities in rural areas. © 2017 Royal Pharmaceutical Society.

  10. A TASER conducted electrical weapon with cardiac biomonitoring capability: Proof of concept and initial human trial.

    Science.gov (United States)

    Stopyra, Jason P; Ritter, Samuel I; Beatty, Jennifer; Johnson, James C; Kleiner, Douglas M; Winslow, James E; Gardner, Alison R; Bozeman, William P

    2016-10-01

    Despite research demonstrating the overall safety of Conducted Electrical Weapons (CEWs), commonly known by the brand name TASER(®), concerns remain regarding cardiac safety. The addition of cardiac biomonitoring capability to a CEW could prove useful and even lifesaving in the rare event of a medical crisis by detecting and analyzing cardiac rhythms during the period immediately after CEW discharge. To combine an electrocardiogram (ECG) device with a CEW to detect and store ECG signals while still allowing the CEW to perform its primary function of delivering an incapacitating electrical discharge. This work was performed in three phases. In Phase 1 standard law enforcement issue CEW cartridges were modified to demonstrate transmission of ECG signals. In Phase 2, a miniaturized ECG recorder was combined with a standard issue CEW and tested. In Phase 3, a prototype CEW with on-board cardiac biomonitoring was tested on human volunteers to assess its ability to perform its primary function of electrical incapacitation. Bench testing demonstrated that slightly modified CEW cartridge wires transmitted simulated ECG signals produced by an ECG rhythm generator and from a human volunteer. Ultimately, a modified CEW incorporating ECG monitoring successfully delivered incapacitating current to human volunteers and successfully recorded ECG signals from subcutaneous CEW probes after firing. An ECG recording device was successfully incorporated into a standard issue CEW without impeding the functioning of the device. This serves as proof-of-concept that safety measures such as cardiac biomonitoring can be incorporated into CEWs and possibly other law enforcement devices. Copyright © 2016 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.

  11. Minimally Invasive Direct Lateral Interbody Fusion (MIS-DLIF): Proof of Concept and Perioperative Results.

    Science.gov (United States)

    Abbasi, Hamid; Abbasi, Ali

    2017-01-14

    Minimally invasive direct lateral interbody fusion (MIS-DLIF) is a novel approach for fusions of the lumbar spine. In this proof of concept study, we describe the surgical technique and report our experience and the perioperative outcomes of the first nine patients who underwent this procedure. In this study we establish the safety and efficacy of this approach. MIS-DLIF was performed on 15 spinal levels in nine patients who failed to respond to conservative therapy for the treatment of a re-herniated disk, spondylolisthesis, or other severe disk disease of the lumbar spine. We recorded surgery time, blood loss, fluoroscopy time, patient-reported pain, and complications. Throughout the MIS-DLIF procedure, the surgeon is aided by biplanar fluoroscopic imaging to place an interbody graft or cage into the disc space through the interpleural space. A discectomy is performed in the same minimally invasive fashion. The procedure is usually completed with posterior pedicle screw fixation. MIS-DLIF took 44/85 minutes, on average, for 1/2 levels, with 54/112 ml of blood loss, and 0.3/1.7 days of hospital stay. Four of nine patients did not require overnight hospitalization and were discharged two to four hours after surgery. We did not encounter any clinically significant complications. At more than ninety days post surgery, the patients reported a statistically significant reduction of 4.5 points on a 10-point sliding pain scale. MIS-DLIF with pedicle screw fixation is a safe and clinically effective procedure for fusions of the lumbar spine. The procedure overcomes many of the limitations of the current minimally invasive approaches to the lumbar spine and is technically straightforward. MIS-DLIF has the potential to improve patient outcomes and reduce costs relative to the current standard of care and therefore warrants further investigation. We are currently expanding this study to a larger cohort and documenting long-term outcome data.

  12. Proof of Concept of Integrated Load Measurement in 3D Printed Structures.

    Science.gov (United States)

    Hinderdael, Michaël; Jardon, Zoé; Lison, Margot; De Baere, Dieter; Devesse, Wim; Strantza, Maria; Guillaume, Patrick

    2017-02-09

    Currently, research on structural health monitoring systems is focused on direct integration of the system into a component or structure. The latter results in a so-called smart structure. One example of a smart structure is a component with integrated strain sensing for continuous load monitoring. Additive manufacturing, or 3D printing, now also enables such integration of functions inside components. As a proof-of-concept, the Fused Deposition Modeling (FDM) technique was used to integrate a strain sensing element inside polymer (ABS) tensile test samples. The strain sensing element consisted of a closed capillary filled with a fluid and connected to an externally mounted pressure sensor. The volumetric deformation of the integrated capillary resulted in pressure changes in the fluid. The obtained pressure measurements during tensile testing are reported in this paper and compared to state-of-the-art extensometer measurements. The sensitivity of the 3D printed pressure-based strain sensor is primarily a function of the compressibility of the capillary fluid. Air- and watertightness are of critical importance for the proper functioning of the 3D printed pressure-based strain sensor. Therefore, the best after-treatment procedure was selected on basis of a comparative analysis. The obtained pressure measurements are linear with respect to the extensometer readings, and the uncertainty on the strain measurement of a capillary filled with water (incompressible fluid) is ±3.1 µstrain, which is approximately three times less sensitive than conventional strain gauges (±1 µstrain), but 32 times more sensitive than the same sensor based on air (compressible fluid) (±101 µstrain).

  13. Proof of Concept Study of Trade Space Configuration Tool for Spacecraft Design

    Science.gov (United States)

    Glidden, Geoffrey L.

    2009-01-01

    Spacecraft design is a very difficult and time consuming process because requirements and criteria are often changed or modified as the design is refined. Accounting for these adjustments in the design constraints plays a significant role in furthering the overall progress. There are numerous aspects and variables that hold significant influence on various characteristics of the design. This can be especially frustrating when attempting to conduct rapid trade space analysis on system configurations. Currently, the data and designs considered for trade space evaluations can only be displayed by using the traditional interfaces of Excel spreadsheets or CAD (Computer Aided Design) models. While helpful, these methods of analyzing the data from a systems engineering approach can be rather complicated and overwhelming. As a result, a proof of concept was conducted on a dynamic data visualization software called Thinkmap SDK (Software Developer Kit) to allow for better organization and understanding of the relationships between the various aspects that make up an entire design. The Orion Crew Module Aft Bay Subsystem was used as the test case for this study because the design and layout of many of the subsystem components will be significant in ensuring the overall center of gravity of the capsule is correct. A simplified model of this subsystem was created and programmed using Thinkmap SDK to create a preliminary prototype application of a Trade Space Configuration Tool. The completed application ensures that the core requirements for the Tool can be met. Further development is strongly suggested to produce a full prototype application to allow final evaluations and recommendations of the software capabilities.

  14. Towards soil property retrieval from space: Proof of concept using in situ observations

    Science.gov (United States)

    Bandara, Ranmalee; Walker, Jeffrey P.; Rüdiger, Christoph

    2014-05-01

    Soil moisture is a key variable that controls the exchange of water and energy fluxes between the land surface and the atmosphere. However, the temporal evolution of soil moisture is neither easy to measure nor monitor at large scales because of its high spatial variability. This is mainly a result of the local variation in soil properties and vegetation cover. Thus, land surface models are normally used to predict the evolution of soil moisture and yet, despite their importance, these models are based on low-resolution soil property information or typical values. Therefore, the availability of more accurate and detailed soil parameter data than are currently available is vital, if regional or global soil moisture predictions are to be made with the accuracy required for environmental applications. The proposed solution is to estimate the soil hydraulic properties via model calibration to remotely sensed soil moisture observation, with in situ observations used as a proxy in this proof of concept study. Consequently, the feasibility is assessed, and the level of accuracy that can be expected determined, for soil hydraulic property estimation of duplex soil profiles in a semi-arid environment using near-surface soil moisture observations under naturally occurring conditions. The retrieved soil hydraulic parameters were then assessed by their reliability to predict the root zone soil moisture using the Joint UK Land Environment Simulator model. When using parameters that were retrieved using soil moisture observations, the root zone soil moisture was predicted to within an accuracy of 0.04 m3/m3, which is an improvement of ∼0.025 m3/m3 on predictions that used published values or pedo-transfer functions.

  15. Moving Denitrifying Bioreactors beyond Proof of Concept: Introduction to the Special Section.

    Science.gov (United States)

    Christianson, Laura E; Schipper, Louis A

    2016-05-01

    Denitrifying bioreactors are organic carbon-filled excavations designed to enhance the natural process of denitrification for the simple, passive treatment of nitrate-nitrogen. Research on and installation of these bioreactors has accelerated within the past 10 years, particularly in watersheds concerned about high nonpoint-source nitrate loads and also for tertiary wastewater treatment. This special section, inspired by the meeting of the Managing Denitrification in Agronomic Systems Community at the 2014 Annual Meeting of the American Society of Agronomy, Crop Science Society of America, and Soil Science Society of America, aims to firmly establish that denitrifying bioreactors for treatment of nitrate in drainage waters, groundwater, and some wastewaters have moved beyond the proof of concept. This collection of 14 papers expands the peer-reviewed literature of denitrifying bioreactors into new locations, applications, and environmental conditions. There is momentum behind the pairing of wood-based bioreactors with other media (biochar, corn cobs) and in novel designs (e.g., use within treatment trains or use of baffles) to broaden applicability into new kinds of waters and pollutants and to improve performance under challenging field conditions such as cool early season agricultural drainage. Concerns about negative bioreactor by-products (nitrous oxide and hydrogen sulfide emissions, start-up nutrient flushing) are ongoing, but this translates into a significant research opportunity to develop more advanced designs and to fine tune management strategies. Future research must think more broadly to address bioreactor impacts on holistic watershed health and greenhouse gas balances and to facilitate collaborations that allow investigation of mechanisms within the bioreactor "black box."

  16. Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer's disease.

    Science.gov (United States)

    Koronyo, Yosef; Biggs, David; Barron, Ernesto; Boyer, David S; Pearlman, Joel A; Au, William J; Kile, Shawn J; Blanco, Austin; Fuchs, Dieu-Trang; Ashfaq, Adeel; Frautschy, Sally; Cole, Gregory M; Miller, Carol A; Hinton, David R; Verdooner, Steven R; Black, Keith L; Koronyo-Hamaoui, Maya

    2017-08-17

    Noninvasive detection of Alzheimer's disease (AD) with high specificity and sensitivity can greatly facilitate identification of at-risk populations for earlier, more effective intervention. AD patients exhibit a myriad of retinal pathologies, including hallmark amyloid β-protein (Aβ) deposits. Burden, distribution, cellular layer, and structure of retinal Aβ plaques were analyzed in flat mounts and cross sections of definite AD patients and controls (n = 37). In a proof-of-concept retinal imaging trial (n = 16), amyloid probe curcumin formulation was determined and protocol was established for retinal amyloid imaging in live patients. Histological examination uncovered classical and neuritic-like Aβ deposits with increased retinal Aβ42 plaques (4.7-fold; P = 0.0063) and neuronal loss (P = 0.0023) in AD patients versus matched controls. Retinal Aβ plaque mirrored brain pathology, especially in the primary visual cortex (P = 0.0097 to P = 0.0018; Pearson's r = 0.84-0.91). Retinal deposits often associated with blood vessels and occurred in hot spot peripheral regions of the superior quadrant and innermost retinal layers. Transmission electron microscopy revealed retinal Aβ assembled into protofibrils and fibrils. Moreover, the ability to image retinal amyloid deposits with solid-lipid curcumin and a modified scanning laser ophthalmoscope was demonstrated in live patients. A fully automated calculation of the retinal amyloid index (RAI), a quantitative measure of increased curcumin fluorescence, was constructed. Analysis of RAI scores showed a 2.1-fold increase in AD patients versus controls (P = 0.0031). The geometric distribution and increased burden of retinal amyloid pathology in AD, together with the feasibility to noninvasively detect discrete retinal amyloid deposits in living patients, may lead to a practical approach for large-scale AD diagnosis and monitoring. National Institute on Aging award (AG044897) and The Saban and The Marciano Family

  17. Improving ethanol productivity through self-cycling fermentation of yeast: a proof of concept.

    Science.gov (United States)

    Wang, Jie; Chae, Michael; Sauvageau, Dominic; Bressler, David C

    2017-01-01

    The cellulosic ethanol industry has developed efficient strategies for converting sugars obtained from various cellulosic feedstocks to bioethanol. However, any further major improvements in ethanol productivity will require development of novel and innovative fermentation strategies that enhance incumbent technologies in a cost-effective manner. The present study investigates the feasibility of applying self-cycling fermentation (SCF) to cellulosic ethanol production to elevate productivity. SCF is a semi-continuous cycling process that employs the following strategy: once the onset of stationary phase is detected, half of the broth volume is automatically harvested and replaced with fresh medium to initiate the next cycle. SCF has been shown to increase product yield and/or productivity in many types of microbial cultivation. To test whether this cycling process could increase productivity during ethanol fermentations, we mimicked the process by manually cycling the fermentation for five cycles in shake flasks, and then compared the results to batch operation. Mimicking SCF for five cycles resulted in regular patterns with regards to glucose consumption, ethanol titer, pH, and biomass production. Compared to batch fermentation, our cycling strategy displayed improved ethanol volumetric productivity (the titer of ethanol produced in a given cycle per corresponding cycle time) and specific productivity (the amount of ethanol produced per cellular biomass) by 43.1 ± 11.6 and 42.7 ± 9.8%, respectively. Five successive cycles contributed to an improvement of overall productivity (the aggregate amount of ethanol produced at the end of a given cycle per total processing time) and the estimated annual ethanol productivity (the amount of ethanol produced per year) by 64.4 ± 3.3 and 33.1 ± 7.2%, respectively. This study provides proof of concept that applying SCF to ethanol production could significantly increase productivities, which will help strengthen the

  18. Machine learning methods to predict child posttraumatic stress: a proof of concept study.

    Science.gov (United States)

    Saxe, Glenn N; Ma, Sisi; Ren, Jiwen; Aliferis, Constantin

    2017-07-10

    The care of traumatized children would benefit significantly from accurate predictive models for Posttraumatic Stress Disorder (PTSD), using information available around the time of trauma. Machine Learning (ML) computational methods have yielded strong results in recent applications across many diseases and data types, yet they have not been previously applied to childhood PTSD. Since these methods have not been applied to this complex and debilitating disorder, there is a great deal that remains to be learned about their application. The first step is to prove the concept: Can ML methods - as applied in other fields - produce predictive classification models for childhood PTSD? Additionally, we seek to determine if specific variables can be identified - from the aforementioned predictive classification models - with putative causal relations to PTSD. ML predictive classification methods - with causal discovery feature selection - were applied to a data set of 163 children hospitalized with an injury and PTSD was determined three months after hospital discharge. At the time of hospitalization, 105 risk factor variables were collected spanning a range of biopsychosocial domains. Seven percent of subjects had a high level of PTSD symptoms. A predictive classification model was discovered with significant predictive accuracy. A predictive model constructed based on subsets of potentially causally relevant features achieves similar predictivity compared to the best predictive model constructed with all variables. Causal Discovery feature selection methods identified 58 variables of which 10 were identified as most stable. In this first proof-of-concept application of ML methods to predict childhood Posttraumatic Stress we were able to determine both predictive classification models for childhood PTSD and identify several causal variables. This set of techniques has great potential for enhancing the methodological toolkit in the field and future studies should seek to

  19. Comparative spatial genetics and epigenetics of plant populations: heuristic value and a proof of concept.

    Science.gov (United States)

    Herrera, Carlos M; Medrano, Mónica; Bazaga, Pilar

    2016-04-01

    Despite the recent upsurge of interest on natural epigenetic variation of nonmodel organisms, factors conditioning the spatial structure of epigenetic diversity in wild plant populations remain virtually unexplored. We propose that information on processes shaping natural epigenetic variation can be gained using the spatial structure of genetic diversity as null model. Departures of epigenetic isolation-by-distance (IBD) patterns from genetic IBD patterns for the same sample, particularly differences in slope of similarity-distance regressions, will reflect the action of factors that operate specifically on epigenetic variation, including imperfect transgenerational inheritance and responsiveness to environmental factors of epigenetic marks. As a proof of concept, we provide a comparative analysis of spatial genetic and epigenetic structure of 200 mapped individuals of the perennial herb Helleborus foetidus. Plants were fingerprinted using nuclear microsatellites, amplified fragment length polymorphisms (AFLP) and methylation-sensitive AFLP markers. Expectations from individual-level IBD patterns were tested by means of kinship-distance regressions. Both genetic and epigenetic similarity between H. foetidus individuals conformed to theoretical expectations under individual-level IBD models. Irrespective of marker type, there were significant negative linear relationships between the kinship coefficient for plant pairs and their spatial separation. Regression slopes were significantly steeper for epigenetic markers. Epigenetic similarity between individuals was much greater than genetic similarity at shortest distances, such epigenetic 'kinship excess' tending to decrease as plant separation increased. Results suggest that moderate-to-high heritability and responsiveness to local environments are major drivers of epigenetic spatial structure in H. foetidus, and illustrate the heuristic value of comparing genetic and epigenetic spatial structure for formulating

  20. Big Data, Predictive Analytics, and Quality Improvement in Kidney Transplantation: A Proof of Concept.

    Science.gov (United States)

    Srinivas, T R; Taber, D J; Su, Z; Zhang, J; Mour, G; Northrup, D; Tripathi, A; Marsden, J E; Moran, W P; Mauldin, P D

    2017-03-01

    We sought proof of concept of a Big Data Solution incorporating longitudinal structured and unstructured patient-level data from electronic health records (EHR) to predict graft loss (GL) and mortality. For a quality improvement initiative, GL and mortality prediction models were constructed using baseline and follow-up data (0-90 days posttransplant; structured and unstructured for 1-year models; data up to 1 year for 3-year models) on adult solitary kidney transplant recipients transplanted during 2007-2015 as follows: Model 1: United Network for Organ Sharing (UNOS) data; Model 2: UNOS & Transplant Database (Tx Database) data; Model 3: UNOS, Tx Database & EHR comorbidity data; and Model 4: UNOS, Tx Database, EHR data, Posttransplant trajectory data, and unstructured data. A 10% 3-year GL rate was observed among 891 patients (2007-2015). Layering of data sources improved model performance; Model 1: area under the curve (AUC), 0.66; (95% confidence interval [CI]: 0.60, 0.72); Model 2: AUC, 0.68; (95% CI: 0.61-0.74); Model 3: AUC, 0.72; (95% CI: 0.66-077); Model 4: AUC, 0.84, (95 % CI: 0.79-0.89). One-year GL (AUC, 0.87; Model 4) and 3-year mortality (AUC, 0.84; Model 4) models performed similarly. A Big Data approach significantly adds efficacy to GL and mortality prediction models and is EHR deployable to optimize outcomes. © 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

  1. Validation, Proof-of-Concept, and Postaudit of the Groundwater Flow and Transport Model of the Project Shoal Area

    Energy Technology Data Exchange (ETDEWEB)

    Ahmed Hassan

    2004-09-01

    The groundwater flow and radionuclide transport model characterizing the Shoal underground nuclear test has been accepted by the State of Nevada Division of Environmental Protection. According to the Federal Facility Agreement and Consent Order (FFACO) between DOE and the State of Nevada, the next steps in the closure process for the site are then model validation (or postaudit), the proof-of-concept, and the long-term monitoring stage. This report addresses the development of the validation strategy for the Shoal model, needed for preparing the subsurface Corrective Action Decision Document-Corrective Action Plan and the development of the proof-of-concept tools needed during the five-year monitoring/validation period. The approach builds on a previous model, but is adapted and modified to the site-specific conditions and challenges of the Shoal site.

  2. Development of Proof-of-Concept Units for the Advanced Medium-Sized Mobile Power Sources (AMMPS) Program

    Energy Technology Data Exchange (ETDEWEB)

    Andriulli, JB

    2002-04-03

    The purpose of this report is to document the development of the proof-of-concept units within the Advanced Medium-sized Mobile Power Sources (AMMPS) program. The design used a small, lightweight diesel engine, a permanent magnet alternator, power electronics and digital controls as outlined in the philosophy detailed previously. One small proof-of-concept unit was completed and delivered to the military. The unit functioned well but was not optimized at the time of delivery to the military. A tremendous amount of experience was gained during this phase that can be used in the development of any follow-on AMMPS production systems. Lessons learned and recommendations for follow-on specifications are provided. The unit demonstrated that significant benefits are possible with the new design philosophy. Trade-offs will have to be made but many of the advantages appear to be within the technical grasp of the market.

  3. The Development of a Glucose Dehydrogenase 3D-Printed Glucose Sensor: A Proof-of-Concept Study.

    Science.gov (United States)

    Adams, Anngela; Malkoc, Aldin; La Belle, Jeffrey T

    2017-06-01

    This work represents a preliminary proof-of-concept design and verification of a 3D-printed glucose biosensor. The proof of concept presented is the first example of glucose dehydrogenase sensor fabricated by a 3D-printer while maintaining similar features to current lab-industry standards. The sensor was verified to detect physiological glucose concentrations between 0 and 400 mg/dL with a linear coefficient as high as .97. This study showed that it was possible to use 3D-printed technology to create a biosensor sensitive to glucose detection. As availability and functionality of 3D-printers expands, this technology has the potential to be an option for diabetes management. This preliminary study shows that the 3D-printed sensor platform holds promise for sensitive glucose detection.

  4. Impact of responder definition on the enriched enrollment randomized withdrawal trial design for establishing proof of concept in neuropathic pain.

    Science.gov (United States)

    Hewitt, David J; Ho, Tony W; Galer, Bradley; Backonja, Miroslav; Markovitz, Paul; Gammaitoni, Arnold; Michelson, David; Bolognese, James; Alon, Achilles; Rosenberg, Elizabeth; Herman, Gary; Wang, Hao

    2011-03-01

    The objective of this study was to evaluate how enrichment for responders increases assay sensitivity in an enriched enrollment randomized withdrawal (EERW) proof-of-concept (POC) study in neuropathic pain. Adults with moderate to severe peripheral neuropathic pain entered a 3- to 4-day screening period, followed by a 12-day titration to the highest tolerated dose that provided pain control (pregabalin 50-200mg t.i.d.), and then a 9-day maintenance period. Subjects were stratified as primary responders (⩾30%), secondary responders (⩾10% to proof-of-concept study to optimize assay sensitivity and efficiently determine the analgesic potential of a new treatment for neuropathic pain. Copyright © 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  5. Virtual Reality-Based Attention Bias Modification Training for Social Anxiety: A Feasibility and Proof of Concept Study

    OpenAIRE

    Urech, Antoine; Krieger, Tobias; Chesham, Alvin; Mast, Fred W.; Berger, Thomas

    2015-01-01

    Attention bias modification (ABM) programs have been considered as a promising new approach for the treatment of various disorders, including social anxiety disorder (SAD). However, previous studies yielded ambiguous results regarding the efficacy of ABM in SAD. The present proof-of-concept study investigates the feasibility of a newly developed virtual reality (VR)-based dot-probe training paradigm. It was designed to facilitate attentional disengagement from threatening stimuli in socially ...

  6. Using the automata processor for fast pattern recognition in high energy physics experiments-A proof of concept

    Science.gov (United States)

    Wang, Michael H. L. S.; Cancelo, Gustavo; Green, Christopher; Guo, Deyuan; Wang, Ke; Zmuda, Ted

    2016-10-01

    We explore the Micron Automata Processor (AP) as a suitable commodity technology that can address the growing computational needs of pattern recognition in High Energy Physics (HEP) experiments. A toy detector model is developed for which an electron track confirmation trigger based on the Micron AP serves as a test case. Although primarily meant for high speed text-based searches, we demonstrate a proof of concept for the use of the Micron AP in a HEP trigger application.

  7. Using the automata processor for fast pattern recognition in high energy physics experiments—A proof of concept

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Michael H.L.S., E-mail: mwang@fnal.gov [Fermi National Accelerator Laboratory, Batavia, IL 60510 (United States); Cancelo, Gustavo; Green, Christopher [Fermi National Accelerator Laboratory, Batavia, IL 60510 (United States); Guo, Deyuan; Wang, Ke [University of Virginia, Charlottesville, VA 22904 (United States); Zmuda, Ted [Fermi National Accelerator Laboratory, Batavia, IL 60510 (United States)

    2016-10-01

    We explore the Micron Automata Processor (AP) as a suitable commodity technology that can address the growing computational needs of pattern recognition in High Energy Physics (HEP) experiments. A toy detector model is developed for which an electron track confirmation trigger based on the Micron AP serves as a test case. Although primarily meant for high speed text-based searches, we demonstrate a proof of concept for the use of the Micron AP in a HEP trigger application.

  8. Targeting pain catastrophization in patients with fibromyalgia using virtual reality exposure therapy: a proof-of-concept study

    OpenAIRE

    Morris, Linzette Deidrè; Louw, Quinette Abegail; Grimmer, Karen Anne; Meintjes, Ernesta

    2015-01-01

    [Purpose] Pain catastrophizing is a key predictor of poor compliance to exercises among patients with fibromyalgia syndrome. Alteration of pain catastrophizing in this group is thus warranted. This study aimed to provide proof-of-concept of a novel virtual reality exposure therapy program as treatment for exercise-related pain catastrophizing in patients with fibromyalgia syndrome. [Subjects and Methods] An exploratory, case-controlled study was conducted (fibromyalgia syndrome group and matc...

  9. Advanced Information Processing System (AIPS) proof-of-concept system functional design I/O network system services

    Science.gov (United States)

    1985-01-01

    The function design of the Input/Output (I/O) services for the Advanced Information Processing System (AIPS) proof of concept system is described. The data flow diagrams, which show the functional processes in I/O services and the data that flows among them, are contained. A complete list of the data identified on the data flow diagrams and in the process descriptions are provided.

  10. Design and Control of a Proof-of-Concept Active Jet Engine Intake Using Shape Memory Alloy Actuators

    Science.gov (United States)

    Song, Gangbing; Ma, Ning; Penney, Nicholas; Barr, Todd; Lee, Ho-Jun; Arnold, Steven M.

    2004-01-01

    The design and control of a novel proof-of-concept active jet engine intake using Nickel-Titanium (Ni-Ti or Nitinol) shape memory alloy (SMA) wire actuators is used to demonstrate the potential of an adaptive intake to improve the fuel efficiency of a jet engine. The Nitinol SMA material is selected for this research due to the material's ability to generate large strains of up to 5 percent for repeated operations, a high power-to-weight ratio, electrical resistive actuation, and easy fabrication into a variety of shapes. The proof-of-concept engine intake employs an overlapping leaf design arranged in a concentric configuration. Each leaf is mounted on a supporting bar that rotates upon actuation by SMA wires electrical resistive heating. Feedback control is enabled through the use of a laser range sensor to detect the movement of a leaf and determine the radius of the intake area. Due to the hysteresis behavior inherent in SMAs, a nonlinear robust controller is used to direct the SMA wire actuation. The controller design utilizes the sliding-mode approach to compensate for the nonlinearities associated with the SMA actuator. Feedback control experiments conducted on a fabricated proof-of-concept model have demonstrated the capability to precisely control the intake area and achieve up to a 25 percent reduction in intake area. The experiments demonstrate the feasibility of engine intake area control using the proposed design.

  11. Pharmaceutical development of an amorphous solid dispersion formulation of elacridar hydrochloride for proof-of-concept clinical studies.

    Science.gov (United States)

    Sawicki, E; Schellens, J H M; Beijnen, J H; Nuijen, B

    2017-04-01

    A novel tablet formulation containing an amorphous solid dispersion (ASD) of elacridar hydrochloride was developed with the purpose to resolve the drug's low solubility in water and to conduct proof-of-concept clinical studies. Elacridar is highly demanded for proof-of-concept clinical trials that study the drug's suitability to boost brain penetration and bioavailability of numerous anticancer agents. Previously, clinical trials with elacridar were performed with a tablet containing elacridar hydrochloride. However, this tablet formulation resulted in poor and unpredictable absorption which was caused by the low aqueous solubility of elacridar hydrochloride. Twenty four different ASDs were produced and dissolution was compared to crystalline elacridar hydrochloride and a crystalline physical mixture. The formulation with highest dissolution was characterized for amorphicity. Subsequently, a tablet was developed and monitored for chemical/physical stability for 12 months at +15-25 °C, +2-8 °C and -20 °C. The ASD powder was composed of freeze dried elacridar hydrochloride-povidone K30-sodium dodecyl sulfate (1:6:1, w/w/w), appeared fully amorphous and resulted in complete dissolution whereas crystalline elacridar hydrochloride resulted in only 1% dissolution. The ASD tablets contained 25 mg elacridar hydrochloride and were stable for at least 12 months at -20 °C. The ASD tablet was considered feasible for proof-of-concept clinical studies and is now used as such.

  12. What is Proof of Concept Research and how does it Generate Epistemic and Ethical Categories for Future Scientific Practice?

    Science.gov (United States)

    Kendig, Catherine Elizabeth

    2016-06-01

    "Proof of concept" is a phrase frequently used in descriptions of research sought in program announcements, in experimental studies, and in the marketing of new technologies. It is often coupled with either a short definition or none at all, its meaning assumed to be fully understood. This is problematic. As a phrase with potential implications for research and technology, its assumed meaning requires some analysis to avoid it becoming a descriptive category that refers to all things scientifically exciting. I provide a short analysis of proof of concept research and offer an example of it within synthetic biology. I suggest that not only are there activities that circumscribe new epistemological categories but there are also associated normative ethical categories or principles linked to the research. I examine these and provide an outline for an alternative ethical account to describe these activities that I refer to as "extended agency ethics". This view is used to explain how the type of research described as proof of concept also provides an attendant proof of principle that is the result of decision-making that extends across practitioners, their tools, techniques, and the problem solving activities of other research groups.

  13. Adjunctive minocycline treatment for major depressive disorder: A proof of concept trial.

    Science.gov (United States)

    Dean, Olivia M; Kanchanatawan, Buranee; Ashton, Melanie; Mohebbi, Mohammadreza; Ng, Chee Hong; Maes, Michael; Berk, Lesley; Sughondhabirom, Atapol; Tangwongchai, Sookjaroen; Singh, Ajeet B; McKenzie, Helen; Smith, Deidre J; Malhi, Gin S; Dowling, Nathan; Berk, Michael

    2017-08-01

    Conventional antidepressant treatments result in symptom remission in 30% of those treated for major depressive disorder, raising the need for effective adjunctive therapies. Inflammation has an established role in the pathophysiology of major depressive disorder, and minocycline has been shown to modify the immune-inflammatory processes and also reduce oxidative stress and promote neuronal growth. This double-blind, randomised, placebo-controlled trial examined adjunctive minocycline (200 mg/day, in addition to treatment as usual) for major depressive disorder. This double-blind, randomised, placebo-controlled trial investigated 200 mg/day adjunctive minocycline (in addition to treatment as usual) for major depressive disorder. A total of 71 adults with major depressive disorder ( Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition) were randomised to this 12-week trial. Outcome measures included the Montgomery-Asberg Depression Rating Scale (primary outcome), Clinical Global Impression-Improvement and Clinical Global Impression-Severity, Hamilton Anxiety Rating Scale, Quality of Life Enjoyment and Satisfaction Questionnaire, Social and Occupational Functioning Scale and the Range of Impaired Functioning Tool. The study was registered on the Australian and New Zealand Clinical Trials Register: www.anzctr.org.au , #ACTRN12612000283875. Based on mixed-methods repeated measures analysis of variance at week 12, there was no significant difference in Montgomery-Asberg Depression Rating Scale scores between groups. However, there were significant differences, favouring the minocycline group at week 12 for Clinical Global Impression-Improvement score - effect size (95% confidence interval) = -0.62 [-1.8, -0.3], p = 0.02; Quality of Life Enjoyment and Satisfaction Questionnaire score - effect size (confidence interval) = -0.12 [0.0, 0.2], p depressive disorder. Further studies are warranted to confirm the potential of this accessible agent to optimise

  14. A randomised controlled trial of the efficacy and safety of allopurinol dose escalation to achieve target serum urate in people with gout.

    Science.gov (United States)

    Stamp, Lisa K; Chapman, Peter T; Barclay, Murray L; Horne, Anne; Frampton, Christopher; Tan, Paul; Drake, Jill; Dalbeth, Nicola

    2017-09-01

    To determine the efficacy and safety of allopurinol dose escalation using a treat-to-target serum urate (SU) approach. A randomised, controlled, parallel-group, comparative clinical trial was undertaken. People with gout receiving at least creatinine clearance (CrCL)-based allopurinol dose for ≥1 month and SU ≥6 mg/dL were recruited. Participants were randomised to continue current dose (control) or allopurinol dose escalation for 12 months. In the dose escalation group, allopurinol was increased monthly until SU was treatment target in most people with gout. Allopurinol dose escalation is well tolerated. ANZCTR12611000845932; Results. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  15. Multidimensional cognitive evaluation of patients with disorders of consciousness using EEG: A proof of concept study.

    Science.gov (United States)

    Sergent, Claire; Faugeras, Frédéric; Rohaut, Benjamin; Perrin, Fabien; Valente, Mélanie; Tallon-Baudry, Catherine; Cohen, Laurent; Naccache, Lionel

    2017-01-01

    sensitivity. The presence of a high-level effect in any of the three tested domains distinguished between minimally conscious and vegetative patients, while the presence of low-level effects was similar in both groups. In summary, this study constitutes a validated proof of concept in favor of probing multiple cognitive dimensions to improve the evaluation of non-communicating patients. At a more conceptual level, this EEG tool can help achieve a better understanding of disorders of consciousness by exploring consciousness in its multiple cognitive facets.

  16. Minimally Invasive Direct Lateral Interbody Fusion (MIS-DLIF): Proof of Concept and Perioperative Results

    Science.gov (United States)

    Abbasi, Hamid

    2017-01-01

    Background Minimally invasive direct lateral interbody fusion (MIS-DLIF) is a novel approach for fusions of the lumbar spine. In this proof of concept study, we describe the surgical technique and report our experience and the perioperative outcomes of the first nine patients who underwent this procedure. Study design/setting In this study we establish the safety and efficacy of this approach. MIS-DLIF was performed on 15 spinal levels in nine patients who failed to respond to conservative therapy for the treatment of a re-herniated disk, spondylolisthesis, or other severe disk disease of the lumbar spine. We recorded surgery time, blood loss, fluoroscopy time, patient-reported pain, and complications. Methods Throughout the MIS-DLIF procedure, the surgeon is aided by biplanar fluoroscopic imaging to place an interbody graft or cage into the disc space through the interpleural space. A discectomy is performed in the same minimally invasive fashion. The procedure is usually completed with posterior pedicle screw fixation. Results MIS-DLIF took 44/85 minutes, on average, for 1/2 levels, with 54/112 ml of blood loss, and 0.3/1.7 days of hospital stay. Four of nine patients did not require overnight hospitalization and were discharged two to four hours after surgery. We did not encounter any clinically significant complications. At more than ninety days post surgery, the patients reported a statistically significant reduction of 4.5 points on a 10-point sliding pain scale. Conclusions MIS-DLIF with pedicle screw fixation is a safe and clinically effective procedure for fusions of the lumbar spine. The procedure overcomes many of the limitations of the current minimally invasive approaches to the lumbar spine and is technically straightforward. MIS-DLIF has the potential to improve patient outcomes and reduce costs relative to the current standard of care and therefore warrants further investigation. We are currently expanding this study to a larger cohort and

  17. Exploration of chromatic aberration for multiplanar imaging: proof of concept with implications for fast, efficient autofocus.

    Science.gov (United States)

    Weinigel, Martin; Kellner, Albert L; Price, Jeffrey H

    2009-12-01

    Image-based autofocus determines focus directly from the specimen (as opposed to reflective surface positioning with an offset), but sequential acquisition of a stack of images to measure resolution/sharpness and find best focus is slower than reflective positioning. Simultaneous imaging of multiple focal planes, which is also useful for 3D imaging of live cells, is faster but requires complicated optics. With color CCD cameras and white light sources commonly available, we asked if axial chromatic aberration can be utilized to acquire multiple focal planes simultaneously, and if it can be controlled through a range sufficient for practical use. For proof of concept, we theoretically and experimentally explored the focal differences between three narrow wavelength bands on a 3-chip color CCD camera with and without glass inserts of various thicknesses and dispersions. Ray tracing yielded changes in foci of 0.65-0.9 microm upon insertion of 12.5-mm thick glass samples for green (G, 522 nm) vs. blue (B, 462 nm) and green vs. red (G-R, 604 nm). On a microscope: (1) With no glass inserts, the differences in foci were 2.15 microm (G-B) and 0.43 microm (G-R); (2) With glass inserts, the maximum change in foci for G vs. B was 0.44 microm and for G vs. R was 0.26 microm; and (3) An 11.3 mm thick N-BK7 glass insert shifted the foci 0.9 microm (R), 0.6 microm (G), and 0.35 microm (B), such that the B and R foci were farther apart (2.1 microm vs. 1.7 microm) and the R and G foci were closer together (0.25 microm vs. 0.45 microm). The slopes of the differences in foci were dependent on thickness, index of refraction, and dispersion. The measured differences in foci are comparable to the axial steps of 0.1-0.24 microm commonly used for autofocus, and focal plane separation can be altered by inserting optical elements of various dispersions and thicknesses. By enabling acquisition of multiple, axially offset images simultaneously, chromatic aberration, normally an imaging pariah

  18. Hyperbrain features of team mental models within a juggling paradigm: a proof of concept

    Directory of Open Access Journals (Sweden)

    Edson Filho

    2016-09-01

    Full Text Available Background Research on cooperative behavior and the social brain exists, but little research has focused on real-time motor cooperative behavior and its neural correlates. In this proof of concept study, we explored the conceptual notion of shared and complementary mental models through EEG mapping of two brains performing a real-world interactive motor task of increasing difficulty. We used the recently introduced participative “juggling paradigm,” and collected neuro-physiological and psycho-social data. We were interested in analyzing the between-brains coupling during a dyadic juggling task, and in exploring the relationship between the motor task execution, the jugglers’skill level and the task difficulty. We also investigated how this relationship could be mirrored in the coupled functional organization of the interacting brains. Methods To capture the neural schemas underlying the notion of shared and complementary mental models, we examined the functional connectivity patterns and hyperbrain features of a juggling dyad involved in cooperative motor tasks of increasing difficulty. Jugglers’ cortical activity was measured using two synchronized 32-channel EEG systems during dyadic juggling performed with 3, 4, 5 and 6 balls. Individual and hyperbrain functional connections were quantified through coherence maps calculated across all electrode pairs in the theta and alpha bands (4–8 and 8–12 Hz. Graph metrics were used to typify the global topology and efficiency of the functional networks for the four difficulty levels in the theta and alpha bands. Results Results indicated that, as task difficulty increased, the cortical functional organization of the more skilled juggler became progressively more segregated in both frequency bands, with a small-world organization in the theta band during easier tasks, indicative of a flow-like state in line with the neural efficiency hypothesis. Conversely, more integrated functional patterns

  19. Preparation for the Proof of Concept Flight of the Veggie Plant Growth Chamber

    Science.gov (United States)

    Massa, Gioia; Morrow, Robert; Hummerick, Mary; Newsham, Gerard; Wheeler, Raymond

    2012-01-01

    Veggie is a small plant growth chamber designed and built by ORBITEC that will fly to the International Space Station on SpaceX-3, scheduled for the summer of 2013. Ultimately Veggie will be used for research, education and outreach, and crew recreation. We want to demonstrate the functionality of this hardware by testing a scenario that could allow the crew to grow and consume fresh vegetables. Veggie will be collapsed and transported flat in a cargo transfer bag, and deployed on orbit, where it will be installed in an EXPRESS rack. The chamber consists of three subsystems: an LED light cap, a transparent bellows, and a root mat reservoir assembly. The bellows and flexible support arms allow the distance between plants and light cap to be adjusted for different ages and types of plants. Researchers at Kennedy Space Center and ORBITEC have been working to develop the plant growth interfaces for the proof of concept flight. We have developed a rooting pillow, consisting of a small bag containing media, time release fertilizer, seeds, and a wicking surface to conduct water from the root mat reservoir. Prototype pillows have been tested and results have influenced the design of flight pillows, which will be modified for microgravity from flight-approved materials. Several studies have been conducted selecting species and comparing media types in analog systems. Water content seems to be the most important factor differentiating media types in these small growth volumes (100 mL). Media type also influenced microbial levels on plants. Since produce sanitizing agents are not currently approved for growing food crops on orbit, plants and media types having very low microbial levels are being selected. Lettuce, mizuna, and other salad greens typically have microbial counts less than 10(exp 4) colony forming units and thus are good candidates for spaceflight. As we approach flight verification testing, we will finalize species, media selection, harvesting, and microbial

  20. A Proof of Concept Experiment for Reducing Skin Friction by Using a Micro-Blowing Technique

    Science.gov (United States)

    Hwang, Danny P.

    1996-01-01

    A proof of concept experiment for reducing skin friction has been conducted in the Advanced Nozzle and Engine Components Test Facility at the NASA Lewis Research Center. In this unique concept, called the micro-blowing technique (MBT), an extremely small amount of air was blown vertically through very small holes to reduce the surface roughness and to control the gradient of the flow velocity profile on the surface thereby reducing skin friction. Research revealed that the skin was the most important factor to make this concept achievable. The proposed skin consisted of two layers. The inner layer was a low permeable porous skin for distributing the blowing air evenly while the outer layer with small holes controlled the vertical or nearly vertical blowing air. Preliminary experimental results showed that the MBT has the potential of a very large reduction in skin friction below the skin friction of a nonporous plain flat plate. Of the skins tested, three have been identified as the MBT skins. They provided very low unblown skin friction such that a large skin friction reduction, below a flat plate value, was achieved with very small amounts of blowing air. The reduction in skin friction of 55 percent was achieved at the Mach number of 0.3 for the exhaust pressure of 0.85 atm, and 60 percent reduction was obtained for the exhaust pressure of 0.24 atm (corresponding to 10 700-m altitude) at the same Mach number. A significant reduction in skin friction of over 25 percent was achieved for the exhaust pressure of 0.24 atm at the Mach number of 0.7. This implied that the MBT could be applied to a wide range of flight conditions. It is also believed that additional 10 percent reduction could be obtained by eliminating the gap between the inner layer and the outer layer. The aspect ratio of the vertical small holes for the outer layer of the MBT skin should be larger than 4 based on the preliminary conclusion from this test. Many experiments are needed to find out the

  1. Therapeutic NOTCH3 cysteine correction in CADASIL using exon skipping: in vitro proof of concept.

    Science.gov (United States)

    Rutten, Julie W; Dauwerse, Hans G; Peters, Dorien J M; Goldfarb, Andrew; Venselaar, Hanka; Haffner, Christof; van Ommen, Gert-Jan B; Aartsma-Rus, Annemieke M; Lesnik Oberstein, Saskia A J

    2016-04-01

    . Transfection of these antisense oligonucleotides into CADASIL patient-derived cerebral vascular smooth muscle cells resulted in successful exon skipping, without abrogating NOTCH3 signalling. Combined, these data provide proof of concept for this novel application of exon skipping, and are a first step towards the development of a rational therapeutic approach applicable to up to 94% of CADASIL-causing mutations.

  2. RNA interference technology to control pest sea lampreys--a proof-of-concept.

    Directory of Open Access Journals (Sweden)

    George Heath

    Full Text Available The parasitic sea lamprey (Petromyzon marinus has caused extensive losses to commercial fish stocks of the upper Great Lakes of North America. Methods of controlling the sea lamprey include trapping, barriers to prevent migration, and use of a chemical lampricide (3-trifluoromethyl-4-nitrophenol to kill the filter-feeding larvae. Concerns about the non-specificity of these methods have prompted continued development of species-specific methods to control lampreys outside their native range. In this study, we considered the utility of RNA interference to develop a sea lamprey-specific lampricide. Injection of six different short interfering, double-stranded RNAs (siRNAs into lamprey embryos first confirmed that the siRNAs could reduce the targeted transcript levels by more than 50%. Two size classes of lamprey larvae were then fed the siRNAs complexed with liposomes, and three of the siRNAs (targeting elongation factor 1α, calmodulin, and α-actinin reduced transcript levels 2.5, 3.6, and 5.0-fold, respectively, within the lamprey midsections. This is not only the first demonstration of RNAi in lampreys, but it is also the first example of delivery of siRNAs to a non-mammalian vertebrate through feeding formulations. One of the siRNA treatments also caused increased mortality of the larvae following a single feeding of siRNAs, which suggests that prolonged or multiple feedings of siRNAs could be used to kill filter-feeding larvae within streams, following development of a slow-release formulation. The genes targeted in this study are highly conserved across many species, and only serve as a proof-of-concept demonstration that siRNAs can be used in lampreys. Given that RNA interference is a sequence-specific phenomenon, it should be possible to design siRNAs that selectively target gene sequences that are unique to sea lampreys, and thus develop a technology to control these pests without adversely affecting non-target species.

  3. Fatigue design of a mechanically biocompatible lattice for a proof-of-concept femoral stem.

    Science.gov (United States)

    Arabnejad Khanoki, Sajad; Pasini, Damiano

    2013-06-01

    A methodology is proposed to design a spatially periodic microarchitectured material for a two-dimensional femoral implant under walking gait conditions. The material is composed of a graded lattice with controlled property distribution that minimizes concurrently bone resorption and interface failure. The periodic microstructure of the material is designed for fatigue fracture caused by cyclic loadings on the hip joint as a result of walking. The bulk material of the lattice is Ti6AL4V and its microstructure is assumed free of defects. The Soderberg diagram is used for the fatigue design under multiaxial loadings. Two cell topologies, square and Kagome, are chosen to obtain optimized property gradients for a two-dimensional implant. Asymptotic homogenization (AH) theory is used to address the multiscale mechanics of the implant as well as to capture the stress and strain distribution at both the macro and the microscale. The microstress distribution found with AH is also compared with that obtained from a detailed finite element analysis. For the maximum value of the von Mises stress, we observe a deviation of 18.6% in unit cells close to the implant boundary, where the AH assumption of spatial periodicity of the fluctuating fields ceases to hold. In the second part of the paper, the metrics of bone resorption and interface shear stress are used to benchmark the graded cellular implant with existing prostheses made of fully dense titanium implant. The results show that the amount of initial postoperative bone loss for square and Kagome lattice implants decreases, respectively, by 53.8% and 58%. In addition, the maximum shear interface failure at the distal end is significantly reduced by about 79%. A set of proof-of-concepts of planar implants have been fabricated via Electron Beam Melting (EBM) to demonstrate the manufacturability of Ti6AL4V into graded lattices with alternative cell size. Optical microscopy has been used to measure the morphological parameters

  4. Tomotherapy PET-guided dose escalation. A dosimetric feasibility study for patients with malignant pleural mesothelioma

    Energy Technology Data Exchange (ETDEWEB)

    Maggio, Angelo; Cutaia, Claudia; Di Dia, Amalia; Bresciani, Sara; Miranti, Anna; Poli, Matteo; Stasi, Michele [Candiolo Cancer Institute - FPO, IRCCS, Medical Physics, Turin (Italy); Del Mastro, Elena; Garibaldi, Elisabetta; Gabriele, Pietro [Candiolo Cancer Institute - FPO, IRCCS, Radiotherapy Department, Turin (Italy)

    2016-02-15

    The aim of this study was to investigate whether a safe escalation of the dose to the pleural cavity and PET/CT-positive areas in patients with unresectable malignant pleural mesothelioma (MPM) is possible using helical tomotherapy (HT). We selected 12 patients with MPM. Three planning strategies were investigated. In the first strategy (standard treatment), treated comprised a prescribed median dose to the planning target volume (PTV) boost (PTV{sub 1}) of 64.5 Gy (range: 56 Gy/28 fractions to 66 Gy/30 fractions) and 51 Gy (range: 50.4 Gy/28 fractions to 54 Gy/30 fractions) to the pleura PTV (PTV{sub 2}). Thereafter, for each patient, two dose escalation plans were generated prescribing 62.5 and 70 Gy (2.5 and 2.8 Gy/fraction, respectively) to the PTV{sub 1} and 56 Gy (2.24 Gy/fraction) to the PTV{sub 2}, in 25 fractions. Dose-volume histogram (DVH) constraints and normal tissue complication probability (NTCP) calculations were used to evaluate the differences between the plans. For all plans, the 95 % PTVs received at least 95 % of the prescribed dose. For all patients, it was possible to perform the dose escalation in accordance with the Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) constraints for organs at risk (OARs). The average contralateral lung dose was < 8 Gy. NTCP values for OARs did not increase significantly compared with the standard treatment (p > 0.05), except for the ipsilateral lung. For all plans, the lung volume ratio was strongly correlated with the V{sub 20}, V{sub 30}, and V{sub 40} DVHs of the lung (p < 0.0003) and with the lung mean dose (p < 0.0001). The results of this study suggest that by using HT it is possible to safely escalate the dose delivery to at least 62.5 Gy in PET-positive areas while treating the pleural cavity to 56 Gy in 25 fractions without significantly increasing the dose to the surrounding normal organs. (orig.) [German] Ziel war es, zu untersuchen, ob mit der helikalen Tomotherapie (HT) eine

  5. Placebo-Controlled Trials, Ethics of

    NARCIS (Netherlands)

    van der Graaf, R; Rid, Annette

    2015-01-01

    There are often good scientific and ethical reasons for using placebo controls in clinical trials. At the same time placebo use is controversial, especially when an established effective treatment is being withheld from the control group. This article gives an overview of the key ethical positions

  6. Placebo-Controlled Trials, Ethics of

    NARCIS (Netherlands)

    van der Graaf, R; Rid, Annette

    2015-01-01

    There are often good scientific and ethical reasons for using placebo controls in clinical trials. At the same time placebo use is controversial, especially when an established effective treatment is being withheld from the control group. This article gives an overview of the key ethical positions i

  7. Is Androgen Deprivation Therapy Necessary in All Intermediate-Risk Prostate Cancer Patients Treated in the Dose Escalation Era?

    Energy Technology Data Exchange (ETDEWEB)

    Castle, Katherine O., E-mail: kocastle@mdanderson.org [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Hoffman, Karen E.; Levy, Lawrence B.; Lee, Andrew K.; Choi, Seungtaek; Nguyen, Quynh N.; Frank, Steven J.; Pugh, Thomas J.; McGuire, Sean E.; Kuban, Deborah A. [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States)

    2013-03-01

    Purpose: The benefit of adding androgen deprivation therapy (ADT) to dose-escalated radiation therapy (RT) for men with intermediate-risk prostate cancer is unclear; therefore, we assessed the impact of adding ADT to dose-escalated RT on freedom from failure (FFF). Methods: Three groups of men treated with intensity modulated RT or 3-dimensional conformal RT (75.6-78 Gy) from 1993-2008 for prostate cancer were categorized as (1) 326 intermediate-risk patients treated with RT alone, (2) 218 intermediate-risk patients treated with RT and ≤6 months of ADT, and (3) 274 low-risk patients treated with definitive RT. Median follow-up was 58 months. Recursive partitioning analysis based on FFF using Gleason score (GS), T stage, and pretreatment PSA concentration was applied to the intermediate-risk patients treated with RT alone. The Kaplan-Meier method was used to estimate 5-year FFF. Results: Based on recursive partitioning analysis, intermediate-risk patients treated with RT alone were divided into 3 prognostic groups: (1) 188 favorable patients: GS 6, ≤T2b or GS 3+4, ≤T1c; (2) 71 marginal patients: GS 3+4, T2a-b; and (3) 68 unfavorable patients: GS 4+3 or T2c disease. Hazard ratios (HR) for recurrence in each group were 1.0, 2.1, and 4.6, respectively. When intermediate-risk patients treated with RT alone were compared to intermediate-risk patients treated with RT and ADT, the greatest benefit from ADT was seen for the unfavorable intermediate-risk patients (FFF, 74% vs 94%, respectively; P=.005). Favorable intermediate-risk patients had no significant benefit from the addition of ADT to RT (FFF, 94% vs 95%, respectively; P=.85), and FFF for favorable intermediate-risk patients treated with RT alone approached that of low-risk patients treated with RT alone (98%). Conclusions: Patients with favorable intermediate-risk prostate cancer did not benefit from the addition of ADT to dose-escalated RT, and their FFF was nearly as good as patients with low-risk disease

  8. A Randomized, Controlled Proof-of-Concept Trial of an Internet-Based, Therapist-Assisted Self-Management Treatment for Posttraumatic Stress Disorder

    National Research Council Canada - National Science Library

    Bryant, Richard A; Engel, Charles C; Litz, Brett T; Papa, Anthony

    2007-01-01

    Objective: The authors report an 8-week randomized, controlled proof-of-concept trial of a new therapist-assisted, Internet-based, self-management cognitive behavior therapy versus Internet-based supportive...

  9. The Glacier and Land Ice Surface Topography Interferometer: An Airborne Proof-of-concept Mapping Sensor

    Science.gov (United States)

    Moller, D.; Hensley, S.; Chuang, C.; Fisher, C.; Muellerschoen, R.; Milligan, L.; Sadowy, G.; Rignot, E. J.

    2009-12-01

    In May 2009 a new radar technique for mapping ice surface topography was demonstrated in a Greenland campaign as part of the NASA International Polar Year activities. This was achieved by integrating a Ka-band single-pass interferometric synthetic radar on the NASA Dryden Gulfstream III for a coordinated deployment. Although the technique of using radar interferometry for mapping terrain has been demonstrated before, this is the first such application at millimeter-wave frequencies. This proof-of-concept demonstration was motivated by the Glacier and Land Ice Surface Topography Interferometer (GLISTIN) Instrument Incubator Program and furthermore, highly leveraged existing ESTO hardware and software assets (the Unmanned Airborne Vehicle Synthetic Aperture Radar (UAVSAR) and processor and the PR2 (precipitation radar 2) RF assembly and power amplifier). Initial Ka-band test flights occurred in March and April of 2009 followed by the Greenland deployment. Instrument performance indicates swath widths over the ice between 5-7km, with height precisions ranging from 30cm-3m at a posting of 3m x 3m. However, for this application the electromagnetic wave will penetrate an unknown amount into the snow cover thus producing an effective bias that must be calibrated. This penetration will be characterized as part of this program and is expected to vary as a function of snow wetness and radar incidence angle. To evaluate this, we flew a coordinated collection with the NASA Wallops Airborne Topographic Mapper on a transect from Greenland’s Summit its West coast. This flight included two field calibration sites at Colorado Institute for Research in Environmental Science’s Swiss Camp and the National Science Foundation’s Summit station. Additional collections entailed flying a grid over Jakobshavn glacier which were repeated after 6 days to reveal surface dynamics. In this time frame we were able to observe horizontal motion of over 1km on the glacier. While developed for

  10. Proof-of-Concept Experiments on a Gallium-Based Ignitron for Pulsed Power Applications

    Science.gov (United States)

    Ali, H. K.; Hanson, V. S.; Polzin, K. A.; Pearson, J. B.

    2015-01-01

    ignitron designs have used mercury as the liquid metal cathode, owing to its presence as a liquid at room temperatures and a vapor pressure of 10 Pa (75 mtorr) at room temperature. While these are favorable properties, there are obvious environmental and personal safety concerns with the storage, handling, and use of mercury and its compounds. The purpose of the present work was to fabricate and test an ignitron that used as its cathode an alternate liquid metal that was safe to handle and store. To that end, an ignitron test article that used liquid gallium as the cathode material was developed and tested. Gallium is a metal that has a melting temperature of 29.76 C, which is slightly above room temperature, and a boiling point of over 2,300 C at atmospheric pressure. This property makes gallium the element with the largest relative difference between melting and boiling points. Gallium has a limited role in biology, and when ingested, it will be subsequently processed by the body and expelled rather than accumulating to toxic levels. The next section of this Technical Memorandum (TM) provides background information on the development of mercury-based ignitrons, which serves as the starting point for the development of the gallium-based variant. Afterwards, the experimental hardware and setup used in proof-of-concept testing of a basic gallium ignitron are presented. Experimental data, consisting of discharge voltage and current waveforms as well as high-speed imaging of the gallium arc discharge in the gallium ignitron test article, are presented to demonstrate the efficacy of the concept. Discussion of the data and suggestions on improvements for future iterations of the design are presented in the final two sections of this TM.

  11. Urban Form Energy Use and Emissions in China: Preliminary Findings and Model Proof of Concept

    Energy Technology Data Exchange (ETDEWEB)

    Aden, Nathaniel; Qin, Yining; Fridley, David

    2010-12-15

    Urbanization is reshaping China's economy, society, and energy system. Between 1990 and 2008 China added more than 300 million new urban residents, bringing the total urbanization rate to 46%. The ongoing population shift is spurring energy demand for new construction, as well as additional residential use with the replacement of rural biomass by urban commercial energy services. This project developed a modeling tool to quantify the full energy consequences of a particular form of urban residential development in order to identify energy- and carbon-efficient modes of neighborhood-level development and help mitigate resource and environmental implications of swelling cities. LBNL developed an integrated modeling tool that combines process-based lifecycle assessment with agent-based building operational energy use, personal transport, and consumption modeling. The lifecycle assessment approach was used to quantify energy and carbon emissions embodied in building materials production, construction, maintenance, and demolition. To provide more comprehensive analysis, LBNL developed an agent-based model as described below. The model was applied to LuJing, a residential development in Jinan, Shandong Province, to provide a case study and model proof of concept. This study produced results data that are unique by virtue of their scale, scope and type. Whereas most existing literature focuses on building-, city-, or national-level analysis, this study covers multi-building neighborhood-scale development. Likewise, while most existing studies focus exclusively on building operational energy use, this study also includes embodied energy related to personal consumption and buildings. Within the boundaries of this analysis, food is the single largest category of the building energy footprint, accounting for 23% of the total. On a policy level, the LCA approach can be useful for quantifying the energy and environmental benefits of longer average building lifespans. In

  12. A Positive Psychology Intervention for Patients with an Acute Coronary Syndrome: Treatment Development and Proof-of-Concept Trial.

    Science.gov (United States)

    Huffman, Jeff C; Millstein, Rachel A; Mastromauro, Carol A; Moore, Shannon V; Celano, Christopher M; Bedoya, C Andres; Suarez, Laura; Boehm, Julia K; Januzzi, James L

    2016-10-01

    Positive psychological constructs are associated with superior outcomes in cardiac patients, but there has been minimal study of positive psychology (PP) interventions in this population. Our objective was to describe the intervention development and pilot testing of an 8-week phone-based PP intervention for patients following an acute coronary syndrome (ACS). Initial intervention development and single-arm proof-of-concept trial, plus comparison of the PP intervention to a subsequently-recruited treatment as usual (TAU) cohort. PP development utilized existing literature, expert input, and qualitative interview data in ACS patients. In the proof-of-concept trial, the primary outcomes were feasibility and acceptability, measured by rates of exercise completion and participant ratings of exercise ease/utility. Secondary outcomes were pre-post changes in psychological outcomes and TAU comparisons, measured using effect sizes (Cohen's d). The PP intervention and treatment manual were successfully created. In the proof-of-concept trial, 17/23 PP participants (74 %) completed at least 5 of 8 exercises. Participants rated the ease (M = 7.4/10; SD = 2.1) and utility (M = 8.1/10, SD = 1.6) of PP exercises highly. There were moderate pre-post improvements (ds = .46-.69) in positive affect, anxiety, and depression, but minimal effects on dispositional optimism (d = .08). Compared to TAU participants (n = 22), PP participants demonstrated greater improvements in positive affect, anxiety, and depression (ds = . 47-.71), but not optimism. A PP intervention was feasible, well-accepted, and associated with improvements in most psychological measures among cardiac patients. These results provide support for a larger trial focusing on behavioral outcomes.

  13. Can openEHR archetypes be used in a national context? The Danish archetype proof-of-concept project.

    Science.gov (United States)

    Bernstein, Knut; Tvede, Ida; Petersen, Jan; Bredegaard, Kirsten

    2009-01-01

    Semantic interoperability and secondary use of data are important informatics challenges in modern healthcare. Connected Digital Health Denmark is investigating if the openEHR reference model, archetypes and templates could be used for representing and exchanging clinical content specification and could become a candidate for a national logical infrastructure for semantic interoperability. The Danish archetype proof-of-concept project has tried out some elements of the openEHR methodology in cooperation with regions and vendors. The project has pointed out benefits and challenges using archetypes, and has identified barriers that need to be addressed in the next steps.

  14. Combined cognitive–behavioural and mindfulness programme for people living with dystonia : a proof-of-concept study

    OpenAIRE

    Sandhu, Harbinder; Bernstein, C. J.; Davies, G.(Imperial College, London, UK); Tang, Nicole K. Y.; Belhag, M; Tingle, A.; Field, M; Foss, Jonathan G. K.; Lindahl, A; Underwood, M. (Martin) M.D.; Ellard, David R.

    2016-01-01

    Objectives To design and test the delivery of an intervention targeting the non-motor symptoms of dystonia and pilot key health and well-being questionnaires in this population.\\ud \\ud Design A proof-of-concept study to test the delivery, acceptability, relevance, structure and content for a 3-day group residential programme for the management of dystonia.\\ud \\ud Setting Participants were recruited from a single botulinum toxin clinic. The intervention was delivered in the community.\\ud \\ud P...

  15. Impact of obesity on outcomes after definitive dose-escalated intensity-modulated radiotherapy for localized prostate cancer.

    Science.gov (United States)

    Wang, Lora S; Murphy, Colin T; Ruth, Karen; Zaorsky, Nicholas G; Smaldone, Marc C; Sobczak, Mark L; Kutikov, Alexander; Viterbo, Rosalia; Horwitz, Eric M

    2015-09-01

    Previous publications have demonstrated conflicting results regarding body mass index (BMI) and prostate cancer (CaP) outcomes after definitive radiotherapy (RT) before the dose escalation era. The goal of the current study was to determine whether increasing BMI was associated with outcomes in men with localized CaP who were treated with dose-escalated RT. The authors identified patients with localized (T1b-T4N0M0) CaP who were treated with definitive intensity-modulated RT and image-guided RT from 2001 through 2010. BMI was analyzed as a continuous variable. Adjusting for confounders, multivariable competing risk and Cox proportional hazards regression models were used to assess the association between BMI and the risk of biochemical failure (BF), distant metastases (DM), cause-specific mortality (CSM), and overall mortality. Of the 1442 patients identified, approximately 20% had a BMI prostate-specific antigen level (P = .018). On multivariable analysis, increasing BMI was associated with an increased risk of BF (hazard ratio [HR], 1.03; 95% confidence interval [95% CI], 1.00-1.07 [P = .042]), DM (HR, 1.07; 95% CI, 1.02-1.11 [P = .004]), CSM (HR, 1.15; 95% CI, 1.07-1.23 [PCancer Society.

  16. Optimizing Collimator Margins for Isotoxically Dose-Escalated Conformal Radiation Therapy of Non-Small Cell Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Warren, Samantha, E-mail: Samantha.warren@oncology.ox.ac.uk [Department of Oncology, Gray Institute of Radiation Oncology and Biology, University of Oxford, Oxford (United Kingdom); Oxford Cancer Centre, Oxford University Hospitals, Oxford (United Kingdom); Panettieri, Vanessa [William Buckland Radiotherapy Centre, Alfred Hospital, Commercial Road, Melbourne (Australia); Panakis, Niki; Bates, Nicholas [Oxford Cancer Centre, Oxford University Hospitals, Oxford (United Kingdom); Lester, Jason F. [Velindre Cancer Centre, Velindre Road, Whitchurch, Cardiff (United Kingdom); Jain, Pooja [Clatterbridge Cancer Centre, Clatterbridge Road, Wirral (United Kingdom); Landau, David B. [Department of Radiotherapy, Guy' s and St. Thomas' NHS Foundation Trust, London (United Kingdom); Nahum, Alan E.; Mayles, W. Philip M. [Clatterbridge Cancer Centre, Clatterbridge Road, Wirral (United Kingdom); Fenwick, John D. [Department of Oncology, Gray Institute of Radiation Oncology and Biology, University of Oxford, Oxford (United Kingdom); Oxford Cancer Centre, Oxford University Hospitals, Oxford (United Kingdom)

    2014-04-01

    Purpose: Isotoxic dose escalation schedules such as IDEAL-CRT [isotoxic dose escalation and acceleration in lung cancer chemoradiation therapy] (ISRCTN12155469) individualize doses prescribed to lung tumors, generating a fixed modeled risk of radiation pneumonitis. Because the beam penumbra is broadened in lung, the choice of collimator margin is an important element of the optimization of isotoxic conformal radiation therapy for lung cancer. Methods and Materials: Twelve patients with stage I-III non-small cell lung cancer (NSCLC) were replanned retrospectively using a range of collimator margins. For each plan, the prescribed dose was calculated according to the IDEAL-CRT isotoxic prescription method, and the absolute dose (D{sub 99}) delivered to 99% of the planning target volume (PTV) was determined. Results: Reducing the multileaf collimator margin from the widely used 7 mm to a value of 2 mm produced gains of 2.1 to 15.6 Gy in absolute PTV D{sub 99}, with a mean gain ± 1 standard error of the mean of 6.2 ± 1.1 Gy (2-sided P<.001). Conclusions: For NSCLC patients treated with conformal radiation therapy and an isotoxic dose prescription, absolute doses in the PTV may be increased by using smaller collimator margins, reductions in relative coverage being offset by increases in prescribed dose.

  17. Dextromethorphan/quinidine pharmacotherapy in patients with treatment resistant depression: A proof of concept clinical trial.

    Science.gov (United States)

    Murrough, James W; Wade, Elizabeth; Sayed, Sehrish; Ahle, Gabriella; Kiraly, Drew D; Welch, Alison; Collins, Katherine A; Soleimani, Laili; Iosifescu, Dan V; Charney, Dennis S

    2017-08-15

    At least one-third of patients with major depressive disorder (MDD) have treatment-resistant depression (TRD), defined as lack of response to two or more adequate antidepressant trials. For these patients, novel antidepressant treatments are urgently needed. The current study is a phase IIa open label clinical trial examining the efficacy and tolerability of a combination of dextromethorphan (DM) and the CYP2D6 enzyme inhibitor quinidine (Q) in patients with TRD. Dextromethorphan acts as an antagonist at the glutamate N-methyl-d-aspartate (NMDA) receptor, in addition to other pharmacodynamics properties that include activity at sigma-1 receptors. Twenty patients with unipolar TRD who completed informed consent and met all eligibility criteria we enrolled in an open-label study of DM/Q up to 45/10mg by mouth administered every 12h over the course of a 10-week period, and constitute the intention to treat (ITT) sample. Six patients discontinued prior to study completion. There was no treatment-emergent suicidal ideation, psychotomimetic or dissociative symptoms. Montgomery-Asberg Depression Rating Scale (MADRS) score was reduced from baseline to the 10-week primary outcome (mean change: -13.0±11.5, t19=5.0, pproof-of-concept design. Herein we report acceptable tolerability and preliminary efficacy of DM/Q up to 45/10mg administered every 12h in patients with TRD. Future larger placebo controlled randomized trials in this population are warranted. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Dose Escalation and Healthcare Resource Use among Ulcerative Colitis Patients Treated with Adalimumab in English Hospitals: An Analysis of Real-World Data.

    Directory of Open Access Journals (Sweden)

    Christopher M Black

    Full Text Available To describe the real-world use of adalimumab for maintenance treatment of ulcerative colitis (UC and associated healthcare costs in English hospitals.Retrospective cohort study.Analysis of NHS Hospital Episode Statistics linked with pharmacy dispensing data in English hospitals.Adult UC patients receiving ≥240mg during adalimumab treatment induction, subsequently maintained on adalimumab.Frequency and pattern of adalimumab use and dose escalation during maintenance treatment and associated healthcare costs (prescriptions and hospital visits.191 UC patients completed adalimumab treatment induction. 83 (43.46% dose escalated during maintenance treatment by ≥100% (equivalent to weekly dosing (median time to dose escalation: 139 days. 56 patients (67.47% subsequently de-escalated by ≥50% (median time to dose de-escalation: 21 days. Mean all-cause healthcare costs for all patients ≤12 months of index were £13,892. Dose escalators incurred greater mean healthcare costs than non-escalators ≤12 months of index (£14,596 vs. £13,351. Prescriptions accounted for 96.49% of UC-related healthcare costs (£11,090 of £11,494 in all patients.Within the cohort, 43.46% of UC patients escalated their adalimumab dose by ≥100% and incurred greater costs than non-escalators. The apparent underestimation of adalimumab dose escalation in previous studies may have resulted in underestimated costs in healthcare systems.

  19. Prospective evaluation of a hydrogel spacer for rectal separation in dose-escalated intensity-modulated radiotherapy for clinically localized prostate cancer

    Directory of Open Access Journals (Sweden)

    Eckert Franziska

    2013-01-01

    Full Text Available Abstract Background As dose-escalation in prostate cancer radiotherapy improves cure rates, a major concern is rectal toxicity. We prospectively assessed an innovative approach of hydrogel injection between prostate and rectum to reduce the radiation dose to the rectum and thus side effects in dose-escalated prostate radiotherapy. Methods Acute toxicity and planning parameters were prospectively evaluated in patients with T1-2 N0 M0 prostate cancer receiving dose-escalated radiotherapy after injection of a hydrogel spacer. Before and after hydrogel injection, we performed MRI scans for anatomical assessment of rectal separation. Radiotherapy was planned and administered to 78 Gy in 39 fractions. Results From eleven patients scheduled for spacer injection the procedure could be performed in ten. In one patient hydrodissection of the Denonvillier space was not possible. Radiation treatment planning showed low rectal doses despite dose-escalation to the target. In accordance with this, acute rectal toxicity was mild without grade 2 events and there was complete resolution within four to twelve weeks. Conclusions This prospective study suggests that hydrogel injection is feasible and may prevent rectal toxicity in dose-escalated radiotherapy of prostate cancer. Further evaluation is necessary including the definition of patients who might benefit from this approach. Trial registration: German Clinical Trials Register DRKS00003273.

  20. An Evaluation of a Factor Xa-Based Clotting Time Test for Enoxaparin: A Proof-of-Concept Study.

    Science.gov (United States)

    Ng, Deborah P J; Duffull, Stephen B; Faed, James M; Isbister, Geoffrey K; Gulati, Abhishek

    2017-01-01

    A well-accepted test for monitoring anticoagulation by enoxaparin is not currently available. As inadequate dosing may result in thrombosis or bleeding, a clinical need exists for a suitable test. Previous in silico and in vitro studies have identified factor Xa as an appropriate activating agent, and the phospholipid Actin FS as a cofactor for a Xa clotting time (TenaCT) test. A proof-of-concept study was designed to (1) explore the reproducibility of the TenaCT test and (2) explore factors that could affect the performance of the test. In vitro clotting time tests were carried out using plasma from 20 healthy volunteers. The effect of enoxaparin was determined at concentrations of 0.25, 0.5, and 1.0 IU/mL. Clotting times for the volunteers were significantly prolonged with increasing enoxaparin concentrations. Clotting times were significantly shortened for frozen plasma samples. No significant differences in prolongation of clotting times were observed between male and female volunteers or between the 2 evaluated age groups. The clotting times were consistent between 2 separate occasions. The TenaCT test was able to distinguish between the subtherapeutic and therapeutic concentrations of enoxaparin. Plasma should not be frozen prior to performing the test, without defining a frozen plasma reference range. This study provided proof-of-concept for a Xa-based test that can detect enoxaparin dose effects, but additional studies are needed to further develop the test.

  1. Vasodilation and Exercise Capacity in Patients with End-Stage Renal Disease: A Prospective Proof-of-Concept Study.

    Science.gov (United States)

    Habedank, Dirk; Schefold, Joerg C; Bernhardt, Carolin; Karhausen, Tim; Doehner, Wolfram; Anker, Stefan D; Reinke, Petra

    2016-11-01

    Previous data have pointed to the fact that vascular function is significantly impaired in patients with end-stage renal disease (ESRD). We aimed to better characterise vasodilation and exercise capacity in both ESRD and chronic heart failure (CHF) patients. A total of 30 ESRD patients (23 male; mean age 45.7 ± 9.9 years) were included in a prospective proof-of-concept study at a tertiary care academic centre. The patients underwent forearm venous plethysmography with post-ischaemic peak blood flow (PF) and flow-dependent flow (FDF) testing as well as cardiopulmonary exercise testing during the morning of the day following the last haemodialysis. After matching for age, gender, and body mass index, the data were compared to 30 patients with CHF and 20 age-matched healthy controls. PF in ESRD patients was reduced when compared to that in CHF patients (12.5 ± 4.2 vs. 15.6 ± 6.9 ml/100 ml/min; p = 0.048) and healthy controls (26.4 ± 9.3 ml/100 ml/min; p proof-of-concept study, exercise capacity was relatively preserved, while vasodilative capacity was substantially impaired in ESRD patients. Additional studies are warranted to examine the underlying mechanisms and potential clinical implications of our findings.

  2. Dose Escalation of Total Marrow Irradiation With Concurrent Chemotherapy in Patients With Advanced Acute Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation

    Energy Technology Data Exchange (ETDEWEB)

    Wong, Jeffrey Y.C., E-mail: jwong@coh.org [Department of Radiation Oncology, City of Hope National Medical Center, Duarte, California (United States); Forman, Stephen; Somlo, George [Department of Hematology/Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California (United States); Rosenthal, Joseph [Department of Hematology/Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California (United States); Department of Pediatrics, City of Hope National Medical Center, Duarte, California (United States); Liu An; Schultheiss, Timothy; Radany, Eric [Department of Radiation Oncology, City of Hope National Medical Center, Duarte, California (United States); Palmer, Joycelynne [Department of Biostatistics, City of Hope National Medical Center, Duarte, California (United States); Stein, Anthony [Department of Hematology/Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California (United States)

    2013-01-01

    Purpose: We have demonstrated that toxicities are acceptable with total marrow irradiation (TMI) at 16 Gy without chemotherapy or TMI at 12 Gy and the reduced intensity regimen of fludarabine/melphalan in patients undergoing hematopoietic cell transplantation (HCT). This article reports results of a study of TMI combined with higher intensity chemotherapy regimens in 2 phase I trials in patients with advanced acute myelogenous leukemia or acute lymphoblastic leukemia (AML/ALL) who would do poorly on standard intent-to-cure HCT regimens. Methods and Materials: Trial 1 consisted of TMI on Days -10 to -6, etoposide (VP16) on Day -5 (60 mg/kg), and cyclophosphamide (CY) on Day -3 (100 mg/kg). TMI dose was 12 (n=3 patients), 13.5 (n=3 patients), and 15 (n=6 patients) Gy at 1.5 Gy twice daily. Trial 2 consisted of busulfan (BU) on Days -12 to -8 (800 {mu}M min), TMI on Days -8 to -4, and VP16 on Day -3 (30 mg/kg). TMI dose was 12 (n=18) and 13.5 (n=2) Gy at 1.5 Gy twice daily. Results: Trial 1 had 12 patients with a median age of 33 years. Six patients had induction failures (IF), and 6 had first relapses (1RL), 9 with leukemia blast involvement of bone marrow ranging from 10%-98%, 5 with circulating blasts (24%-85%), and 2 with chloromas. No dose-limiting toxicities were observed. Eleven patients achieved complete remission at Day 30. With a median follow-up of 14.75 months, 5 patients remained in complete remission from 13.5-37.7 months. Trial 2 had 20 patients with a median age of 41 years. Thirteen patients had IF, and 5 had 1RL, 2 in second relapse, 19 with marrow blasts (3%-100%) and 13 with peripheral blasts (6%-63%). Grade 4 dose-limiting toxicities were seen at 13.5 Gy (stomatitis and hepatotoxicity). Stomatitis was the most frequent toxicity in both trials. Conclusions: TMI dose escalation to 15 Gy is possible when combined with CY/VP16 and is associated with acceptable toxicities and encouraging outcomes. TMI dose escalation is not possible with BU/VP16 due to

  3. Pelvic nodal dose escalation with prostate hypofractionation using conformal avoidance defined (H-CAD) intensity modulated radiation therapy

    Energy Technology Data Exchange (ETDEWEB)

    Hong, Theodore S.; Tome, Wolfgang A.; Jaradat, Hazim; Raisbeck, Bridget M.; Ritter, Mark A. [Univ. of Wisconsin Medical School, Madison, WI (United States). Dept. of Human Oncology

    2006-09-15

    The management of prostate cancer patients with a significant risk of pelvic lymph node involvement is controversial. Both whole pelvis radiotherapy and dose escalation to the prostate have been linked to improved outcome in such patients, but it is unclear whether conventional whole pelvis doses of only 45-50 Gy are optimal for ultimate nodal control. The purpose of this study is to examine the dosimetric and clinical feasibility of combining prostate dose escalation via hypofractionation with conformal avoidance-based IMRT (H-CAD) dose escalation to the pelvic lymph nodes. One conformal avoidance and one conventional plan were generated for each of eight patients. Conformal avoidance-based IMRT plans were generated that specifically excluded bowel, rectum, and bladder. The prostate and lower seminal vesicles (PTV 70) were planned to receive 70 Gy in 2.5 Gy/fraction while the pelvic lymph nodes (PTV 56) were to concurrently receive 56 Gy in 2 Gy/fraction. The volume of small bowel receiving >45 Gy was restricted to 300 ml or less. These conformal avoidance plans were delivered using helical tomotherapy or LINAC-based IMRT with daily imaging localization. All patients received neoadjuvant and concurrent androgen deprivation with a planned total of two years. The conventional, sequential plans created for comparison purposes for all patients consisted of a conventional 4-field pelvic box prescribed to 50.4 Gy (1.8 Gy/fraction) followed by an IMRT boost to the prostate of 25.2 Gy (1.8 Gy/fraction) yielding a final prostate dose of 75.6 Gy. For all plans, the prescription dose was to cover the target structure. Equivalent uniform dose (EUD) analyses were performed on all targets and dose-volume histograms (DVH) were displayed in terms of both physical and normalized total dose (NTD), i.e. dose in 2 Gy fraction equivalents. H-CAD IMRT plans were created for and delivered to all eight patients. Analysis of the H-CAD plans demonstrates prescription dose coverage of >95

  4. Dose-Escalated Hypofractionated Intensity-Modulated Radiotherapy in High-Risk Carcinoma of the Prostate: Outcome and Late Toxicity

    Directory of Open Access Journals (Sweden)

    David Thomson

    2012-01-01

    Results. Median followup was 84 months. Five-year overall survival (OS was 83% and biochemical progression-free survival (bPFS was 50% for 57 Gy. Five-year OS was 75% and bPFS 58% for 60 Gy. At 7 years, toxicity by RTOG criteria was acceptable with no grade 3 or above toxicity. Compared with baseline, there was no significant change in urinary symptoms at 2 or 7 years. Bowel symptoms were stable between 2 and 7 years. All patients continued to have significant sexual dysfunction. Conclusion. In high-risk prostate cancer, dose-escalated hypofractionated radiotherapy using IMRT results in encouraging outcomes and acceptable late toxicity.

  5. A Phase I Dose Escalation Study of Hypofractionated IMRT Field-in-Field Boost for Newly Diagnosed Glioblastoma Multiforme

    Energy Technology Data Exchange (ETDEWEB)

    Monjazeb, Arta M., E-mail: arta.monjazeb@ucdmc.ucdavis.edu [U.C. Davis School of Medicine, Department of Radiation Oncology, Sacramento, CA (United States); Ayala, Deandra; Jensen, Courtney [Radiation Oncology, Wake Forest University Health Sciences, Winston-Salem, NC (United States); Case, L. Douglas [Biostatistical Sciences, Wake Forest University Health Sciences, Winston-Salem, NC (United States); Bourland, J. Daniel; Ellis, Thomas L. [Neurosurgery, Wake Forest University Health Sciences, Winston-Salem, NC (United States); McMullen, Kevin P.; Chan, Michael D. [Radiation Oncology, Wake Forest University Health Sciences, Winston-Salem, NC (United States); Tatter, Stephen B. [Neurosurgery, Wake Forest University Health Sciences, Winston-Salem, NC (United States); Lesser, Glen J. [Hematology Oncology, Wake Forest University Health Sciences, Winston-Salem, NC (United States); Shaw, Edward G. [Radiation Oncology, Wake Forest University Health Sciences, Winston-Salem, NC (United States)

    2012-02-01

    Objectives: To describe the results of a Phase I dose escalation trial for newly diagnosed glioblastoma multiforme (GBM) using a hypofractionated concurrent intensity-modulated radiotherapy (IMRT) boost. Methods: Twenty-one patients were enrolled between April 1999 and August 2003. Radiotherapy consisted of daily fractions of 1.8 Gy with a concurrent boost of 0.7 Gy (total 2.5 Gy daily) to a total dose of 70, 75, or 80 Gy. Concurrent chemotherapy was not permitted. Seven patients were enrolled at each dose and dose limiting toxicities were defined as irreversible Grade 3 or any Grade 4-5 acute neurotoxicity attributable to radiotherapy. Results: All patients experienced Grade 1 or 2 acute toxicities. Acutely, 8 patients experienced Grade 3 and 1 patient experienced Grade 3 and 4 toxicities. Of these, only two reversible cases of otitis media were attributable to radiotherapy. No dose-limiting toxicities were encountered. Only 2 patients experienced Grade 3 delayed toxicity and there was no delayed Grade 4 toxicity. Eleven patients requiring repeat resection or biopsy were found to have viable tumor and radiation changes with no cases of radionecrosis alone. Median overall and progression-free survival for this cohort were 13.6 and 6.5 months, respectively. One- and 2-year survival rates were 57% and 19%. At recurrence, 15 patients received chemotherapy, 9 underwent resection, and 5 received radiotherapy. Conclusions: Using a hypofractionated concurrent IMRT boost, we were able to safely treat patients to 80 Gy without any dose-limiting toxicity. Given that local failure still remains the predominant pattern for GBM patients, a trial of dose escalation with IMRT and temozolomide is warranted.

  6. Safety and immunogenicity of the PRAME cancer immunotherapeutic in metastatic melanoma: results of a phase I dose escalation study

    Science.gov (United States)

    Gutzmer, R; Rivoltini, L; Levchenko, E; Testori, A; Utikal, J; Ascierto, P A; Demidov, L; Grob, J J; Ridolfi, R; Schadendorf, D; Queirolo, P; Santoro, A; Loquai, C; Dreno, B; Hauschild, A; Schultz, E; Lesimple, T P; Vanhoutte, N; Salaun, B; Gillet, M; Jarnjak, S; De Sousa Alves, P M; Louahed, J; Brichard, V G; Lehmann, F F

    2016-01-01

    Purpose The PRAME tumour antigen is expressed in several tumour types but in few normal adult tissues. A dose-escalation phase I/II study (NCT01149343) assessed the safety, immunogenicity and clinical activity of the PRAME immunotherapeutic (recombinant PRAME protein (recPRAME) with the AS15 immunostimulant) in patients with advanced melanoma. Here, we report the phase I dose-escalation study segment. Patients and methods Patients with stage IV PRAME-positive melanoma were enrolled to 3 consecutive cohorts to receive up to 24 intramuscular injections of the PRAME immunotherapeutic. The RecPRAME dose was 20, 100 or 500 µg in cohorts 1, 2 and 3, respectively, with a fixed dose of AS15. Adverse events (AEs), including predefined dose-limiting toxicity (DLT) and the anti-PRAME humoral response (ELISA), were coprimary end points. Cellular immune responses were evaluated using in vitro assays. Results 66 patients were treated (20, 24 and 22 in the respective cohorts). AEs considered by the investigator to be causally related were mostly grade 1 or 2 injection site symptoms, fatigue, chills, fever and headache. Two DLTs (grade 3 brain oedema and proteinuria) were recorded in two patients in two cohorts (cohorts 2 and 3). All patients had detectable anti-PRAME antibodies after four immunisations. Percentages of patients with predefined PRAME-specific-CD4+T-cell responses after four immunisations were similar in each cohort. No CD8+ T-cell responses were detected. Conclusions The PRAME immunotherapeutic had an acceptable safety profile and induced similar anti-PRAME-specific humoral and cellular immune responses in all cohorts. As per protocol, the phase II study segment was initiated to further evaluate the 500 µg PRAME immunotherapeutic dose. Trial registration number NCT01149343, Results. PMID:27843625

  7. Stereotactic Body Radiation Therapy for Prostate Cancer: Review of Experience of a Multicenter Phase I/II Dose Escalation Study

    Directory of Open Access Journals (Sweden)

    D. Nathan W. Kim

    2014-11-01

    Full Text Available Introduction: Stereotactic body radiation therapy (SBRT is an area of active investigation for treatment of prostate cancer. In our phase I dose escalation study maximum tolerated dose was not reached, and subsequently phase II study has been completed. The purpose of this article is to review our experiences of dose escalated SBRT for localized prostate cancer. Methods and Materials: Patients enrolled to phase I/II study from 2006-2011 were reviewed. Prescription dose groups were 45, 47.5 and 50 Gray (Gy in 5 fractions over 2.5 weeks. Toxicity and quality of life questionnaire data were collected and analyzed. Descriptive statistics were obtained in the form of means, medians, and ranges for the continuous variables, and frequencies and percentages for the categoric variables. Results: 91 patients were enrolled from five institutions. Median follow up for PSA evaluation was 42 months. PSA control remains at 99%. While the maximum tolerated dose was not reached in the phase I study, excess high grade rectal toxicity (10.6% was noted in the phase II study. The 13 patients treated to 50 Gy in the phase I study that did not have high grade rectal toxicity, in retrospect met these parameters and have not had further events on longer follow up. Conclusion: PSA control rate, even for patients with intermediate risk, is thus far excellent at these dose levels. This study provides a platform for exploration of SBRT based clinical trials aimed at optimizing outcome for intermediate and high risk patients. High grade toxicities specifically related to the rectum were observed in a small but meaningful minority at the highest dose level. Dose constraints based on physiologic parameters have been defined to mitigate this risk, and strategies to minimize rectal exposure to such doses are being explored.

  8. Phase 1 Study of Dose Escalation in Hypofractionated Proton Beam Therapy for Non-Small Cell Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Gomez, Daniel R., E-mail: dgomez@mdanderson.org [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Gillin, Michael [Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Liao, Zhongxing [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Wei, Caimiao [Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Lin, Steven H.; Swanick, Cameron; Alvarado, Tina; Komaki, Ritsuko; Cox, James D.; Chang, Joe Y. [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States)

    2013-07-15

    Background: Many patients with locally advanced non-small cell lung cancer (NSCLC) cannot undergo concurrent chemotherapy because of comorbidities or poor performance status. Hypofractionated radiation regimens, if tolerable, may provide an option to these patients for effective local control. Methods and Materials: Twenty-five patients were enrolled in a phase 1 dose-escalation trial of proton beam therapy (PBT) from September 2010 through July 2012. Eligible patients had histologically documented lung cancer, thymic tumors, carcinoid tumors, or metastatic thyroid tumors. Concurrent chemotherapy was not allowed, but concurrent treatment with biologic agents was. The dose-escalation schema comprised 15 fractions of 3 Gy(relative biological effectiveness [RBE])/fraction, 3.5 Gy(RBE)/fraction, or 4 Gy(RBE)/fraction. Dose constraints were derived from biologically equivalent doses of standard fractionated treatment. Results: The median follow-up time for patients alive at the time of analysis was 13 months (range, 8-28 months). Fifteen patients received treatment to hilar or mediastinal lymph nodes. Two patients experienced dose-limiting toxicity possibly related to treatment; 1 received 3.5-Gy(RBE) fractions and experienced an in-field tracheoesophageal fistula 9 months after PBT and 1 month after bevacizumab. The other patient received 4-Gy(RBE) fractions and was hospitalized for bacterial pneumonia/radiation pneumonitis 4 months after PBT. Conclusion: Hypofractionated PBT to the thorax delivered over 3 weeks was well tolerated even with significant doses to the lungs and mediastinal structures. Phase 2/3 trials are needed to compare the efficacy of this technique with standard treatment for locally advanced NSCLC.

  9. Rapid quantification of Staphylococcus aureus from endotracheal aspirates of ventilated patients: a proof-of-concept study.

    Science.gov (United States)

    Lacroix, Morgane; Barraud, Olivier; Clavel, Marc; Filiputti, Delphine; Prudent, Sandrine; François, Bruno; Ploy, Marie Cécile; Jestin, Marie-Astrid; Rodrigue, Marc; Pachot, Alexandre; Yugueros-Marcos, Javier; Moucadel, Virginie

    2015-10-01

    Major concern for intubated patients is ventilator-associated pneumonia (VAP). Early detection of VAP and its causative microorganism(s) is a key challenge for clinicians. Diagnosis is based on clinical, radiological, and microbiological elements, the latter being provided 24-48h after sampling. According to practices, clinicians can sample endotracheal aspirates (ETAs) so as to check for patient colonization or perform ETA in case of VAP suspicion. In this proof-of-concept study, we report the evaluation of a semiautomated molecular method to rapidly quantify Staphylococcus aureus, one of the most involved microorganisms in VAP, directly from raw ETA samples. After evaluation using artificial ETA samples, our method was applied on 40 clinical ETA samples. All S. aureus-positive samples were successfully detected and quantified. Our method can provide an efficient sample preparation protocol for all raw ETA samples, combined with an accurate quantification of the bacterial load, in less than 3h 30min.

  10. Catalytic conversion of light alkanes-proof-of-concept stage -- Phase 6. Final report, February 1--October 31, 1994

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1994-12-31

    During the course of the first three years of the Cooperative Agreement, the authors uncovered a family of metal perhaloporphyrin complexes which had unprecedented activity for the selective air-oxidation of light alkanes to alcohols. The reactivity of light hydrocarbon substrates with air or oxygen was in the order: isobutane > propane > ethane > methane, in accord with their homolytic bond dissociation energies. Isobutane was so reactive that the proof-of-concept stage of a process for producing tert-butyl alcohol from isobutane was begun (Phase 5). It was proposed that as more active catalytic systems were developed (Phases 4, 6), propane, then ethane and finally methane oxidations will move into this stage (Phases 7 through 9). As of this writing, however, the program has been terminated during the later stages of Phase 5 and 6 so that further work is not anticipated. 72 refs.

  11. Construction of Extended 3D Field of Views of the Internal Bladder Wall Surface: A Proof of Concept

    Science.gov (United States)

    Ben-Hamadou, Achraf; Daul, Christian; Soussen, Charles

    2016-09-01

    3D extended field of views (FOVs) of the internal bladder wall facilitate lesion diagnosis, patient follow-up and treatment traceability. In this paper, we propose a 3D image mosaicing algorithm guided by 2D cystoscopic video-image registration for obtaining textured FOV mosaics. In this feasibility study, the registration makes use of data from a 3D cystoscope prototype providing, in addition to each small FOV image, some 3D points located on the surface. This proof of concept shows that textured surfaces can be constructed with minimally modified cystoscopes. The potential of the method is demonstrated on numerical and real phantoms reproducing various surface shapes. Pig and human bladder textures are superimposed on phantoms with known shape and dimensions. These data allow for quantitative assessment of the 3D mosaicing algorithm based on the registration of images simulating bladder textures.

  12. Fuzzy logic inference-based Pavement Friction Management and real-time slippery warning systems: A proof of concept study.

    Science.gov (United States)

    Najafi, Shahriar; Flintsch, Gerardo W; Khaleghian, Seyedmeysam

    2016-05-01

    Minimizing roadway crashes and fatalities is one of the primary objectives of highway engineers, and can be achieved in part through appropriate maintenance practices. Maintaining an appropriate level of friction is a crucial maintenance practice, due to the effect it has on roadway safety. This paper presents a fuzzy logic inference system that predicts the rate of vehicle crashes based on traffic level, speed limit, and surface friction. Mamdani and Sugeno fuzzy controllers were used to develop the model. The application of the proposed fuzzy control system in a real-time slippery road warning system is demonstrated as a proof of concept. The results of this study provide a decision support model for highway agencies to monitor their network's friction and make appropriate judgments to correct deficiencies based on crash risk. Furthermore, this model can be implemented in the connected vehicle environment to warn drivers of potentially slippery locations.

  13. Teaching geriatrics using an innovative, individual-centered educational game: students and educators win. A proof-of-concept study.

    Science.gov (United States)

    van de Pol, Marjolein H J; Lagro, Joep; Fluit, Lia R M G; Lagro-Janssen, Toine L M; Olde Rikkert, Marcel G M

    2014-10-01

    Given the increasingly aging population, nearly every doctor will encounter elderly adults who present with multiple complex comorbidities that can challenge even experienced physicians. This may explain why many medical students do not have a positive attitude toward elderly adults and find the complexity of their problems overwhelming. It was hypothesized that a recently developed medical school geriatrics course, based on the game GeriatriX and designed specifically to address the complexities associated with decision-making in geriatrics, can have a positive effect on attitudes toward geriatrics and on perceived knowledge of geriatrics. The effects of this game-based course were evaluated as a proof of concept. The assessment was based on the Aging Semantic Differential (ASD) and a validated self-perceived knowledge scale of geriatric topics. The usability of (and satisfaction with) GeriatriX was also assessed using a 5-point Likert scale. After completion of the course, the ASD changed significantly in the geriatrics course group (n = 29; P = .02) but not in a control group that took a neuroscience course (n = 24; P = .30). Moreover, the geriatrics course group had a significant increase in self-perceived knowledge for 12 of the 18 topics (P = .002), whereas in the control group self-perceived knowledge increased significantly for one topic only (sensory impairment) (P = .04). Finally, the geriatrics students reported enjoying GeriatriX. This proof-of-concept study clearly supports the hypothesis that a 4-week course using a modern educational approach such as GeriatriX can improve students' self-perceived knowledge of geriatrics and their attitudes toward elderly adults. © 2014, Copyright the Authors Journal compilation © 2014, The American Geriatrics Society.

  14. Supercritical CO2 Foaming of Thermoplastic Materials Derived from Maize: Proof-of-Concept Use in Mammalian Cell Culture Applications

    Science.gov (United States)

    Trujillo-de Santiago, Grissel; Portales-Cabrera, Cynthia Guadalupe; Portillo-Lara, Roberto; Araiz-Hernández, Diana; Del Barone, Maria Cristina; García-López, Erika; Rojas-de Gante, Cecilia; de los Angeles De Santiago-Miramontes, María; Segoviano-Ramírez, Juan Carlos; García-Lara, Silverio; Rodríguez-González, Ciro Ángel; Alvarez, Mario Moisés; Di Maio, Ernesto; Iannace, Salvatore

    2015-01-01

    Background Foams are high porosity and low density materials. In nature, they are a common architecture. Some of their relevant technological applications include heat and sound insulation, lightweight materials, and tissue engineering scaffolds. Foams derived from natural polymers are particularly attractive for tissue culture due to their biodegradability and bio-compatibility. Here, the foaming potential of an extensive list of materials was assayed, including slabs elaborated from whole flour, the starch component only, or the protein fraction only of maize seeds. Methodology/Principal Findings We used supercritical CO2 to produce foams from thermoplasticized maize derived materials. Polyethylene-glycol, sorbitol/glycerol, or urea/formamide were used as plasticizers. We report expansion ratios, porosities, average pore sizes, pore morphologies, and pore size distributions for these materials. High porosity foams were obtained from zein thermoplasticized with polyethylene glycol, and from starch thermoplasticized with urea/formamide. Zein foams had a higher porosity than starch foams (88% and 85%, respectively) and a narrower and more evenly distributed pore size. Starch foams exhibited a wider span of pore sizes and a larger average pore size than zein (208.84 vs. 55.43 μm2, respectively). Proof-of-concept cell culture experiments confirmed that mouse fibroblasts (NIH 3T3) and two different prostate cancer cell lines (22RV1, DU145) attached to and proliferated on zein foams. Conclusions/Significance We conducted screening and proof-of-concept experiments on the fabrication of foams from cereal-based bioplastics. We propose that a key indicator of foamability is the strain at break of the materials to be foamed (as calculated from stress vs. strain rate curves). Zein foams exhibit attractive properties (average pore size, pore size distribution, and porosity) for cell culture applications; we were able to establish and sustain mammalian cell cultures on zein

  15. Supercritical CO2 foaming of thermoplastic materials derived from maize: proof-of-concept use in mammalian cell culture applications.

    Directory of Open Access Journals (Sweden)

    Grissel Trujillo-de Santiago

    Full Text Available Foams are high porosity and low density materials. In nature, they are a common architecture. Some of their relevant technological applications include heat and sound insulation, lightweight materials, and tissue engineering scaffolds. Foams derived from natural polymers are particularly attractive for tissue culture due to their biodegradability and bio-compatibility. Here, the foaming potential of an extensive list of materials was assayed, including slabs elaborated from whole flour, the starch component only, or the protein fraction only of maize seeds.We used supercritical CO2 to produce foams from thermoplasticized maize derived materials. Polyethylene-glycol, sorbitol/glycerol, or urea/formamide were used as plasticizers. We report expansion ratios, porosities, average pore sizes, pore morphologies, and pore size distributions for these materials. High porosity foams were obtained from zein thermoplasticized with polyethylene glycol, and from starch thermoplasticized with urea/formamide. Zein foams had a higher porosity than starch foams (88% and 85%, respectively and a narrower and more evenly distributed pore size. Starch foams exhibited a wider span of pore sizes and a larger average pore size than zein (208.84 vs. 55.43 μm2, respectively. Proof-of-concept cell culture experiments confirmed that mouse fibroblasts (NIH 3T3 and two different prostate cancer cell lines (22RV1, DU145 attached to and proliferated on zein foams.We conducted screening and proof-of-concept experiments on the fabrication of foams from cereal-based bioplastics. We propose that a key indicator of foamability is the strain at break of the materials to be foamed (as calculated from stress vs. strain rate curves. Zein foams exhibit attractive properties (average pore size, pore size distribution, and porosity for cell culture applications; we were able to establish and sustain mammalian cell cultures on zein foams for extended time periods.

  16. Protecting an island nation from extreme pandemic threats: Proof-of-concept around border closure as an intervention.

    Science.gov (United States)

    Boyd, Matt; Baker, Michael G; Mansoor, Osman D; Kvizhinadze, Giorgi; Wilson, Nick

    2017-01-01

    Countries are well advised to prepare for future pandemic risks (e.g., pandemic influenza, novel emerging agents or synthetic bioweapons). These preparations do not typically include planning for complete border closure. Even though border closure may not be instituted in time, and can fail, there might still plausible chances of success for well organized island nations. To estimate costs and benefits of complete border closure in response to new pandemic threats, at an initial proof-of-concept level. New Zealand was used as a case-study for an island country. An Excel spreadsheet model was developed to estimate costs and benefits. Case-study specific epidemiological data was sourced from past influenza pandemics. Country-specific healthcare cost data, valuation of life, and lost tourism revenue were imputed (with lost trade also in scenario analyses). For a new pandemic equivalent to the 1918 influenza pandemic (albeit with half the mortality rate, "Scenario A"), it was estimated that successful border closure for 26 weeks provided a net societal benefit (e.g., of NZ$11.0 billion, USD$7.3 billion). Even in the face of a complete end to trade, a net benefit was estimated for scenarios where the mortality rate was high (e.g., at 10 times the mortality impact of "Scenario A", or 2.75% of the country's population dying) giving a net benefit of NZ$54 billion (USD$36 billion). But for some other pandemic scenarios where trade ceased, border closure resulted in a net negative societal value (e.g., for "Scenario A" times three for 26 weeks of border closure-but not for only 12 weeks of closure when it would still be beneficial). This "proof-of-concept" work indicates that more detailed cost-benefit analysis of border closure in very severe pandemic situations for some island nations is probably warranted, as this course of action might sometimes be worthwhile from a societal perspective.

  17. Virtual reality exposure therapy as treatment for pain catastrophizing in fibromyalgia patients: proof-of-concept study (Study Protocol).

    Science.gov (United States)

    Morris, Linzette D; Grimmer-Somers, Karen A; Spottiswoode, Bruce; Louw, Quinette A

    2011-04-30

    Albeit exercise is currently advocated as one of the most effective management strategies for fibromyalgia syndrome (FMS); the implementation of exercise as a FMS treatment in reality is significantly hampered by patients' poor compliance. The inference that pain catastrophizing is a key predictor of poor compliance in FMS patients, justifies considering the alteration of pain catastrophizing in improving compliance towards exercises in FMS patients. The aim of this study is to provide proof-of-concept for the development and testing of a novel virtual reality exposure therapy (VRET) program as treatment for exercise-related pain catastrophizing in FMS patients. Two interlinked experimental studies will be conducted. Study 1 aims to objectively ascertain if neurophysiological changes occur in the functional brain areas associated with pain catastrophizing, when catastrophizing FMS subjects are exposed to visuals of exercise activities. Study 2 aims to ascertain the preliminary efficacy and feasibility of exposure to visuals of exercise activities as a treatment for exercise-related pain catastrophizing in FMS subjects. Twenty subjects will be selected from a group of FMS patients attending the Tygerberg Hospital in Cape Town, South Africa and randomly allocated to either the VRET (intervention) group or waiting list (control) group. Baseline neurophysiological activity for subjects will be collected in study 1 using functional magnetic resonance imaging (fMRI). In study 2, clinical improvement in pain catastrophizing will be measured using fMRI (objective) and the pain catastrophizing scale (subjective). The premise is if exposing FMS patients to visuals of various exercise activities trigger the functional brain areas associated with pain catastrophizing; then as a treatment, repeated exposure to visuals of the exercise activities using a VRET program could possibly decrease exercise-related pain catastrophizing in FMS patients. Proof-of-concept will either be

  18. A proof-of-concept implementation of a unit-based advanced practice registered nurse (APRN) role: structural empowerment, role clarity and team effectiveness.

    Science.gov (United States)

    Feistritzer, Nancye R; Jones, Pam O

    2014-03-01

    The quest for decreased cost of care and improved outcomes has created the need for highly effective clinical roles and teams. This article describes the role of a unit-based advanced practice registered nurse (APRN) within a proof-of-concept implementation of a new care delivery model, the Vanderbilt Anticipatory Care Team. Role clarity is central to both structural empowerment of the APRN and team effectiveness. A modified PeaceHealth Team Development Measure tool measured baseline role clarity as a component of overall team effectiveness. A role description for the unit-based APRN based on a comprehensive assessment of the proof-of-concept unit is provided.

  19. Prognostic Significance of Carbohydrate Antigen 19-9 in Unresectable Locally Advanced Pancreatic Cancer Treated With Dose-Escalated Intensity Modulated Radiation Therapy and Concurrent Full-Dose Gemcitabine: Analysis of a Prospective Phase 1/2 Dose Escalation Study

    Energy Technology Data Exchange (ETDEWEB)

    Vainshtein, Jeffrey M., E-mail: jvainsh@med.umich.edu [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Schipper, Matthew [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Zalupski, Mark M. [Division of Hematology Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan (United States); Lawrence, Theodore S. [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Abrams, Ross [Department of Radiation Oncology, Rush Medical Center, Chicago, Illinois (United States); Francis, Isaac R. [Department of Radiology, University of Michigan, Ann Arbor, Michigan (United States); Khan, Gazala [Division of Hematology Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan (United States); Leslie, William [Division of Hematology Oncology, Department of Internal Medicine, Rush Medical Center, Chicago, Illinois (United States); Ben-Josef, Edgar [Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania (United States)

    2013-05-01

    Purpose: Although established in the postresection setting, the prognostic value of carbohydrate antigen 19-9 (CA19-9) in unresectable locally advanced pancreatic cancer (LAPC) is less clear. We examined the prognostic utility of CA19-9 in patients with unresectable LAPC treated on a prospective trial of intensity modulated radiation therapy (IMRT) dose escalation with concurrent gemcitabine. Methods and Materials: Forty-six patients with unresectable LAPC were treated at the University of Michigan on a phase 1/2 trial of IMRT dose escalation with concurrent gemcitabine. CA19-9 was obtained at baseline and during routine follow-up. Cox models were used to assess the effect of baseline factors on freedom from local progression (FFLP), distant progression (FFDP), progression-free survival (PFS), and overall survival (OS). Stepwise forward regression was used to build multivariate predictive models for each endpoint. Results: Thirty-eight patients were eligible for the present analysis. On univariate analysis, baseline CA19-9 and age predicted OS, CA19-9 at baseline and 3 months predicted PFS, gross tumor volume (GTV) and black race predicted FFLP, and CA19-9 at 3 months predicted FFDP. On stepwise multivariate regression modeling, baseline CA19-9, age, and female sex predicted OS; baseline CA19-9 and female sex predicted both PFS and FFDP; and GTV predicted FFLP. Patients with baseline CA19-9 ≤90 U/mL had improved OS (median 23.0 vs 11.1 months, HR 2.88, P<.01) and PFS (14.4 vs 7.0 months, HR 3.61, P=.001). CA19-9 progression over 90 U/mL was prognostic for both OS (HR 3.65, P=.001) and PFS (HR 3.04, P=.001), and it was a stronger predictor of death than either local progression (HR 1.46, P=.42) or distant progression (HR 3.31, P=.004). Conclusions: In patients with unresectable LAPC undergoing definitive chemoradiation therapy, baseline CA19-9 was independently prognostic even after established prognostic factors were controlled for, whereas CA19-9 progression

  20. Exploring the Feasibility of Dose Escalation Positron Emission Tomography-Positive Disease with Intensity-Modulated Radiation Therapy and the Effects on Normal Tissue Structures for Thoracic Malignancies

    Energy Technology Data Exchange (ETDEWEB)

    Turner, Lehendrick M., E-mail: lehendrickt@yahoo.com [University of Texas M. D. Anderson Cancer Center School of Health Professions, Medical Dosimetry Program, Houston, TX (United States); Howard, Joshua A.; Dehghanpour, Pouya; Barrett, Renee D. [University of Texas M. D. Anderson Cancer Center School of Health Professions, Medical Dosimetry Program, Houston, TX (United States); Rebueno, Neal; Palmer, Matthew [Department of Radiation Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX (United States); Vedam, Sastry [Department of Radiation Physics, University of Texas M. D. Anderson Cancer Center, Houston, TX (United States); Klopp, Ann; Komaki, Ritsuko; Welsh, James W. [Department of Radiation Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX (United States)

    2011-01-01

    The pattern of failure is one of the major causes of mortality among thoracic patients. Studies have shown a correlation between local control and dose. Intensity-modulated radiation therapy (IMRT) has resulted in conformal dose distributions while limiting dose to normal tissue. However, thoracic malignancies treated with IMRT to highly conformal doses up to 70 Gy still have been found to fail. Thus, the need for dose escalation through simultaneous integrated boost (SIB) may prove effective in minimizing reoccurrences. For our study, 28 thoracic IMRT plans were reoptimized via dose escalation to the gross tumor volume (GTV) and planning target volume (PTV) of 79.2 Gy and 68.4 Gy, respectively. Reoccurrences in surrounding regions of microscopic disease are rare therefore, dose-escalating regional nodes (outside GTV) were not included. Hence, the need to edit GTV margins was acceptable for our retrospective study. A median dose escalation of approximately 15 Gy (64.8-79.2 Gy) via IMRT using SIB was deemed achievable with minimal percent differences received by critical structures compared with the original treatment plan. The target's mean doses were significantly increased based on p-value analysis, while the normal tissue structures were not significantly changed.

  1. Isotoxic dose escalation in the treatment of lung cancer by means of heterogeneous dose distributions in the presence of respiratory motion

    DEFF Research Database (Denmark)

    Baker, Mariwan; Nielsen, Morten; Hansen, Olfred;

    2011-01-01

    To test, in the presence of intrafractional respiration movement, a margin recipe valid for a homogeneous and conformal dose distribution and to test whether the use of smaller margins combined with heterogeneous dose distributions allows an isotoxic dose escalation when respiratory motion is con...

  2. Adaptation requirements due to anatomical changes in free-breathing and deep-inspiration breath-hold for standard and dose-escalated radiotherapy of lung cancer patients

    DEFF Research Database (Denmark)

    Sibolt, Patrik; Ottosson, Wiviann; Sjöström, David;

    2015-01-01

    Background. Radiotherapy of lung cancer patients is subject to uncertainties related to heterogeneities, anatomical changes and breathing motion. Use of deep-inspiration breath-hold (DIBH) can reduce the treated volume, potentially enabling dose-escalated (DE) treatments. This study was designed...

  3. A Phase I-II dose escalation study of fixed-dose rate gemcitabine, oxaliplatin and capecitabine every two weeks in advanced cholangiocarcinomas

    DEFF Research Database (Denmark)

    Lassen, Ulrik; Jensen, Lars Henrik; Sorensen, Morten;

    2011-01-01

    ) and capecitabine (C), and evaluate the safety and efficacy of this regimen in patients with advanced cholangiocarcinoma (CC). METHODS: In the Phase I part of the study a dose-escalation schedule of FDR G, O and C, administered every two weeks, was performed in patients with solid tumours and no other treatments...

  4. Double blind placebo controlled exposure to molds

    DEFF Research Database (Denmark)

    Meyer, H W; Jensen, K A; Nielsen, K F

    2005-01-01

    with a positive histamine release test to Penicillium chrysogenum were exposed double- blinded to either placebo, approximately 600,000 spores/m3 air of P. chrysogenum or approximately 350,000 spores/m3 of Trichoderma harzianum for 6 min on three separate days. A statistically significant rise in symptoms from...... mucous membranes appeared from the 9-graded symptom scale after exposure to T. harzianum or placebo. Dichotomizing the data, whether the participants experienced at least a two-step rise on the symptom scale or not, gave borderline increase in mucous membrane symptoms after exposure to P. chrysogenum...... to placebo in eight sensitive school employees. However, a statistical type II error cannot be excluded because of the small sample size. PRACTICAL IMPLICATIONS: In this double blind, placebo controlled study of mold exposure changes in symptoms, objective measurements and blood samples were small and mostly...

  5. Lack of benefit for the addition of androgen deprivation therapy to dose-escalated radiotherapy in the treatment of intermediate- and high-risk prostate cancer.

    LENUS (Irish Health Repository)

    Krauss, Daniel

    2012-02-01

    PURPOSE: Assessment of androgen deprivation therapy (ADT) benefits for prostate cancer treated with dose-escalated radiotherapy (RT). METHODS AND MATERIALS: From 1991 to 2004, 1,044 patients with intermediate- (n = 782) or high-risk (n = 262) prostate cancer were treated with dose-escalated RT at William Beaumont Hospital. Patients received external-beam RT (EBRT) alone, brachytherapy (high or low dose rate), or high dose rate brachytherapy plus pelvic EBRT. Intermediate-risk patients had Gleason score 7, prostate-specific antigen (PSA) 10.0-19.9 ng\\/mL, or Stage T2b-T2c. High-risk patients had Gleason score 8-10, PSA >\\/=20, or Stage T3. Patients were additionally divided specifically by Gleason score, presence of palpable disease, and PSA level to further define subgroups benefitting from ADT. RESULTS: Median follow-up was 5 years; 420 patients received ADT + dose-escalated RT, and 624 received dose-escalated RT alone. For all patients, no advantages in any clinical endpoints at 8 years were associated with ADT administration. No differences in any endpoints were associated with ADT administration based on intermediate- vs. high-risk group or RT modality when analyzed separately. Patients with palpable disease plus Gleason >\\/=8 demonstrated improved clinical failure rates and a trend toward improved survival with ADT. Intermediate-risk patients treated with brachytherapy alone had improved biochemical control when ADT was given. CONCLUSION: Benefits of ADT in the setting of dose-escalated RT remain poorly defined. This question must continue to be addressed in prospective study.

  6. Safety and efficacy of flexible-dose fesoterodine in British subjects with overactive bladder: insights into factors associated with dose escalation.

    Science.gov (United States)

    Cardozo, Linda; Hall, Timothy; Ryan, John; Ebel Bitoun, Caty; Kausar, Imran; Darekar, Amanda; Wagg, Adrian

    2012-11-01

    This study evaluated the efficacy and safety of flexible-dose fesoterodine and factors associated with dose escalation in subjects with overactive bladder (OAB). In this 12-week, open-label study, 331 adults with OAB symptoms for ≥3 months, ≥8 micturitions and ≥3 urgency episodes per 24 h and who reported at least "some moderate" bladder-related problems were treated with fesoterodine 4 mg once daily for 4 weeks, with the option to escalate to 8 mg for the remaining 8 weeks based on discussion of efficacy and tolerability with the investigator. Factors influencing dose escalation were identified using stepwise logistic regression. Efficacy was assessed via 3-day bladder diaries and patient-reported outcomes. Of the subjects, 59 % dose escalated at week 4; 93 % of escalators cited insufficient clinical response. The decision to escalate was most often made by the subject (alone or with the investigator). Improvements from baseline were observed in diary and patient-reported outcomes at weeks 4 and 12. Smaller improvements in micturition frequency and worse bladder-related problems at week 4 were significantly associated with increased likelihood of dose escalation; baseline micturition frequency, age, sex, body mass index, antimuscarinic-associated adverse events and OAB symptom duration were not. Non-escalators had greater improvement from baseline to week 4 than escalators; by week 12, improvement was similar among escalators and non-escalators. Fesoterodine was well tolerated. Treatment with flexible-dose fesoterodine improved bladder diary and patient-reported outcomes. Lower clinical response was related to dose escalation; after escalation, response in escalators approached that of non-escalators.

  7. SU-E-T-183: Feasibility of Extreme Dose Escalation for Glioblastoma Multiforme Using 4π Radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Nguyen, D; Rwigema, J; Yu, V; Kaprealian, T; Kupelian, P; Selch, M; Low, D; Sheng, K [Department of Radiation Oncology, UCLA, Los Angeles, CA (United States)

    2014-06-01

    Purpose: GBM recurrence primarily occurs inside or near the high-dose radiation field of original tumor site requiring greater than 100 Gy to significantly improve local control. We utilize 4π non-coplanar radiotherapy to test the feasibility of planning target volume (PTV) margin expansions or extreme dose escalations without incurring additional radiation toxicities. Methods: 11 GBM patients treated with VMAT to a prescription dose of 59.4 Gy or 60 Gy were replanned with 4π. Original VMAT plans were created with 2 to 4 coplanar or non-coplanar arcs using 3 mm hi-res MLC. The 4π optimization, using 5 mm MLC, selected and inverse optimized 30 beams from a candidate pool of 1162 beams evenly distributed through 4π steradians. 4π plans were first compared to clinical plans using the same prescription dose. Two more studies were then performed to respectively escalate the GTV and PTV doses to 100 Gy, followed by a fourth plan expanding the PTV by 5 mm and maintaining the prescription dose. Results: The standard 4π plan significantly reduced (p<0.01) max and mean doses to critical structures by a range of 47.0–98.4% and 61.0–99.2%, respectively. The high dose PTV/high dose GTV/expanded PTV studies showed a reduction (p<0.05) or unchanged* (p>0.05) maximum dose of 72.1%/86.7%/77.1% (chiasm), 7.2%*/27.7%*/30.7% (brainstem), 39.8%*/84.2%/51.9%* (spinal cord), 69.0%/87.0%/66.9% (L eye), 76.2%/88.1%/84.1% (R eye), 95.0%/98.6%/97.5% (L lens), 93.9%/98.8%/97.6% (R lens), 74.3%/88.5%/72.4% (L optical nerve), 80.4%/91.3%/75.7% (R optical nerve), 64.8%/84.2%/44.9%* (L cochlea), and 85.2%/93.0%/78.0% (R cochlea), respectively. V30 and V36 for both brain and (brain - PTV) were reduced for all cases except the high dose PTV plan. PTV dose coverage increased for all 4π plans. Conclusion: Extreme dose escalation or further margin expansion is achievable using 4π, maintaining or reducing OAR doses. This study indicates that clinical trials employing 4π delivery using

  8. Phase I Trial of Pelvic Nodal Dose Escalation With Hypofractionated IMRT for High-Risk Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Adkison, Jarrod B.; McHaffie, Derek R.; Bentzen, Soren M.; Patel, Rakesh R.; Khuntia, Deepak [Department of Human Oncology, University of Wisconsin Carbone Cancer Center, School of Medicine and Public Health, Madison, WI (United States); Petereit, Daniel G. [Department of Radiation Oncology, John T. Vucurevich Regional Cancer Care Institute, Rapid City Regional Hospital, Rapid City, SD (United States); Hong, Theodore S.; Tome, Wolfgang [Department of Human Oncology, University of Wisconsin Carbone Cancer Center, School of Medicine and Public Health, Madison, WI (United States); Ritter, Mark A., E-mail: ritter@humonc.wisc.edu [Department of Human Oncology, University of Wisconsin Carbone Cancer Center, School of Medicine and Public Health, Madison, WI (United States)

    2012-01-01

    Purpose: Toxicity concerns have limited pelvic nodal prescriptions to doses that may be suboptimal for controlling microscopic disease. In a prospective trial, we tested whether image-guided intensity-modulated radiation therapy (IMRT) can safely deliver escalated nodal doses while treating the prostate with hypofractionated radiotherapy in 5 Vulgar-Fraction-One-Half weeks. Methods and Materials: Pelvic nodal and prostatic image-guided IMRT was delivered to 53 National Comprehensive Cancer Network (NCCN) high-risk patients to a nodal dose of 56 Gy in 2-Gy fractions with concomitant treatment of the prostate to 70 Gy in 28 fractions of 2.5 Gy, and 50 of 53 patients received androgen deprivation for a median duration of 12 months. Results: The median follow-up time was 25.4 months (range, 4.2-57.2). No early Grade 3 Radiation Therapy Oncology Group or Common Terminology Criteria for Adverse Events v.3.0 genitourinary (GU) or gastrointestinal (GI) toxicities were seen. The cumulative actuarial incidence of Grade 2 early GU toxicity (primarily alpha blocker initiation) was 38%. The rate was 32% for Grade 2 early GI toxicity. None of the dose-volume descriptors correlated with GU toxicity, and only the volume of bowel receiving {>=}30 Gy correlated with early GI toxicity (p = 0.029). Maximum late Grades 1, 2, and 3 GU toxicities were seen in 30%, 25%, and 2% of patients, respectively. Maximum late Grades 1 and 2 GI toxicities were seen in 30% and 8% (rectal bleeding requiring cautery) of patients, respectively. The estimated 3-year biochemical control (nadir + 2) was 81.2 {+-} 6.6%. No patient manifested pelvic nodal failure, whereas 2 experienced paraaortic nodal failure outside the field. The six other clinical failures were distant only. Conclusions: Pelvic IMRT nodal dose escalation to 56 Gy was delivered concurrently with 70 Gy of hypofractionated prostate radiotherapy in a convenient, resource-efficient, and well-tolerated 28-fraction schedule. Pelvic nodal dose

  9. Trigeminal Neuralgia Treated With Stereotactic Radiosurgery: The Effect of Dose Escalation on Pain Control and Treatment Outcomes.

    Science.gov (United States)

    Kotecha, Rupesh; Kotecha, Ritesh; Modugula, Sujith; Murphy, Erin S; Jones, Mark; Kotecha, Rajesh; Reddy, Chandana A; Suh, John H; Barnett, Gene H; Neyman, Gennady; Machado, Andre; Nagel, Sean; Chao, Samuel T

    2016-09-01

    To analyze the effect of dose escalation on treatment outcome in patients undergoing stereotactic radiosurgery (SRS) for trigeminal neuralgia (TN). A retrospective review was performed of 870 patients who underwent SRS for a diagnosis of TN from 2 institutions. Patients were typically treated using a single 4-mm isocenter placed at the trigeminal nerve dorsal root entry zone. Patients were divided into groups based on treatment doses: ≤82 Gy (352 patients), 83 to 86 Gy (85 patients), and ≥90 Gy (433 patients). Pain response was classified using a categorical scoring system, with fair or poor pain control representing treatment failure. Treatment-related facial numbness was classified using the Barrow Neurological Institute scale. Log-rank tests were performed to test differences in time to pain failure or development of facial numbness for patients treated with different doses. Median age at first pain onset was 63 years, median age at time of SRS was 71 years, and median follow-up was 36.5 months from the time of SRS. A majority of patients (827, 95%) were clinically diagnosed with typical TN. The 4-year rate of excellent to good pain relief was 87% (95% confidence interval 84%-90%). The 4-year rate of pain response was 79%, 82%, and 92% in patients treated to ≤82 Gy, 83 to 86 Gy, and ≥90 Gy, respectively. Patients treated to doses ≤82 Gy had an increased risk of pain failure after SRS, compared with patients treated to ≥90 Gy (hazard ratio 2.0, P=.0007). Rates of treatment-related facial numbness were similar among patients treated to doses ≥83 Gy. Nine patients (1%) were diagnosed with anesthesia dolorosa. Dose escalation for TN to doses >82 Gy is associated with an improvement in response to treatment and duration of pain relief. Patients treated at these doses, however, should be counseled about the increased risk of treatment-related facial numbness. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Exploring Normalized Systems Potential for Dutch MoD’s Agility: A Proof of Concept on Flexibility, Time-to-market, Productivity and Quality

    NARCIS (Netherlands)

    Op 't Land, M.; Krouwel, M.R.; Van Dipten, E.G.; Verelst, J.

    2011-01-01

    Both the Command and Control Support Centre (C2SC) of the Dutch Ministry of Defense, and Capgemini are constantly exploring better ways of building and maintaining information systems which ef- fectively support strategy and operations of an enterprise. In a Proof of Concept conducted in March and A

  11. 68Ga- and 177Lu-Labeled PSMA I&T: Optimization of a PSMA-Targeted Theranostic Concept and First Proof-of-Concept Human Studies

    National Research Council Canada - National Science Library

    Weineisen, Martina; Schottelius, Margret; Simecek, Jakub; Baum, Richard P; Yildiz, Akin; Beykan, Seval; Kulkarni, Harshad R; Lassmann, Michael; Klette, Ingo; Eiber, Matthias; Schwaiger, Markus; Wester, Hans-Jürgen

    2015-01-01

    ...) in metastatic prostate cancer (PC), the goal of this study was the development, preclinical evaluation, and first proof-of-concept investigation of a PSMA inhibitor for imaging and therapy (PSMA I&T) for (68)Ga-based PET and (177...

  12. Exploring Normalized Systems Potential for Dutch MoD’s Agility: A Proof of Concept on Flexibility, Time-to-market, Productivity and Quality

    NARCIS (Netherlands)

    Op 't Land, M.; Krouwel, M.R.; Van Dipten, E.G.; Verelst, J.

    2011-01-01

    Both the Command and Control Support Centre (C2SC) of the Dutch Ministry of Defense, and Capgemini are constantly exploring better ways of building and maintaining information systems which ef- fectively support strategy and operations of an enterprise. In a Proof of Concept conducted in March and

  13. Exploring Normalized Systems Potential for Dutch MoD’s Agility: A Proof of Concept on Flexibility, Time-to-market, Productivity and Quality

    NARCIS (Netherlands)

    Op 't Land, M.; Krouwel, M.R.; Van Dipten, E.G.; Verelst, J.

    2011-01-01

    Both the Command and Control Support Centre (C2SC) of the Dutch Ministry of Defense, and Capgemini are constantly exploring better ways of building and maintaining information systems which ef- fectively support strategy and operations of an enterprise. In a Proof of Concept conducted in March and A

  14. Virtual reality exposure therapy as treatment for pain catastrophizing in fibromyalgia patients: proof-of-concept study (Study Protocol

    Directory of Open Access Journals (Sweden)

    Spottiswoode Bruce

    2011-04-01

    Full Text Available Abstract Background Albeit exercise is currently advocated as one of the most effective management strategies for fibromyalgia syndrome (FMS; the implementation of exercise as a FMS treatment in reality is significantly hampered by patients' poor compliance. The inference that pain catastrophizing is a key predictor of poor compliance in FMS patients, justifies considering the alteration of pain catastrophizing in improving compliance towards exercises in FMS patients. The aim of this study is to provide proof-of-concept for the development and testing of a novel virtual reality exposure therapy (VRET program as treatment for exercise-related pain catastrophizing in FMS patients. Methods Two interlinked experimental studies will be conducted. Study 1 aims to objectively ascertain if neurophysiological changes occur in the functional brain areas associated with pain catastrophizing, when catastrophizing FMS subjects are exposed to visuals of exercise activities. Study 2 aims to ascertain the preliminary efficacy and feasibility of exposure to visuals of exercise activities as a treatment for exercise-related pain catastrophizing in FMS subjects. Twenty subjects will be selected from a group of FMS patients attending the Tygerberg Hospital in Cape Town, South Africa and randomly allocated to either the VRET (intervention group or waiting list (control group. Baseline neurophysiological activity for subjects will be collected in study 1 using functional magnetic resonance imaging (fMRI. In study 2, clinical improvement in pain catastrophizing will be measured using fMRI (objective and the pain catastrophizing scale (subjective. Discussion The premise is if exposing FMS patients to visuals of various exercise activities trigger the functional brain areas associated with pain catastrophizing; then as a treatment, repeated exposure to visuals of the exercise activities using a VRET program could possibly decrease exercise-related pain catastrophizing

  15. Development of a lozenge for oral transmucosal delivery of trans-resveratrol in humans: proof of concept.

    Directory of Open Access Journals (Sweden)

    Otis L Blanchard

    Full Text Available Resveratrol provides multiple physiologic benefits which promote healthspan in various model species and clinical trials support continued exploration of resveratrol treatment in humans. However, there remains concern regarding low bioavailability and wide inter-individual differences in absorption and metabolism in humans, which suggests a great need to develop novel methods for resveratrol delivery. We hypothesized that oral transmucosal delivery, using a lozenge composed of a resveratrol-excipient matrix, would allow resveratrol to be absorbed rapidly into the bloodstream. We pursued proof of concept through two experiments. In the first experiment, the solubility of trans-resveratrol (tRES in water and 2.0 M solutions of dextrose, fructose, ribose, sucrose, and xylitol was determined using HPLC. Independent t-tests with a Bonferroni correction were used to compare the solubility of tRES in each of the solutions to that in water. tRES was significantly more soluble in the ribose solution (p = 0.0013 than in the other four solutions. Given the enhanced solubility of tRES in a ribose solution, a resveratrol-ribose matrix was developed into a lozenge suitable for human consumption. Lozenges were prepared, each containing 146±5.5 mg tRES per 2000 mg of lozenge mass. Two healthy human participants consumed one of the prepared lozenges following an overnight fast. Venipuncture was performed immediately before and 15, 30, 45, and 60 minutes following lozenge administration. Maximal plasma concentrations (Cmax for tRES alone (i.e., resveratrol metabolites not included were 325 and 332 ng⋅mL(-1 for the two participants at 15 minute post-administration for both individuals. These results suggest a resveratrol-ribose matrix lozenge can achieve greater Cmax and enter the bloodstream faster than previously reported dosage forms for gastrointestinal absorption. While this study is limited by small sample size and only one method of resveratrol

  16. Gut hormone release and appetite regulation in healthy non-obese participants following oligofructose intake. A dose-escalation study.

    Science.gov (United States)

    Pedersen, Camilla; Lefevre, Solenne; Peters, Véronique; Patterson, Michael; Ghatei, Mohammad A; Morgan, Linda M; Frost, Gary S

    2013-07-01

    Prevention of weight gain in adults is a major public health target. Animal experiments have consistently demonstrated a relationship between fermentable carbohydrate intake, such as oligofructose, anorectic gut hormones, and appetite suppression and body weight control. This study was designed to determine the dose of oligofructose which would augment the release of anorectic gut hormones and reduce appetite consistently in non-obese humans. Twelve non-obese participants were recruited for a 5-week dose-escalation study. Following a 9-14-day run-in, participants increased their daily oligofructose intake every week from 15, 25, 35, 45, to 55 g daily. Subjective appetite and side effects were monitored daily. Three-day food diaries were completed every week. Appetite study sessions explored the acute effects of 0, 15, 35, and 55 g oligofructose on appetite-related hormones, glycaemia, subjective appetite, and energy intake. In the home environment, oligofructose suppressed hunger, but did not affect energy intake. Oligofructose dose-dependently increased peptide YY, decreased pancreatic polypeptide and tended to decrease ghrelin, but did not significantly affect appetite profile, energy intake, glucose, insulin, or glucagon-like peptide 1 concentrations during appetite study sessions. In conclusion, oligofructose supplementation at ≥ 35 g/day increased peptide YY and suppressed pancreatic polypeptide and hunger; however, energy intake did not change significantly.

  17. Imatinib dose escalation versus sunitinib as a second line treatment in KIT exon 11 mutated GIST: a retrospective analysis.

    Science.gov (United States)

    Vincenzi, Bruno; Nannini, Margherita; Fumagalli, Elena; Bronte, Giuseppe; Frezza, Anna Maria; De Lisi, Delia; Spalato Ceruso, Mariella; Santini, Daniele; Badalamenti, Giuseppe; Pantaleo, Maria Abbondanza; Russo, Antonio; Dei Tos, Angelo Paolo; Casali, Paolo; Tonini, Giuseppe

    2016-10-25

    We retrospectively reviewed data from 123 patients (KIT exon 11 mutated) who received sunitinib or dose-escalated imatinib as second line.All patients progressed on imatinib (400 mg/die) and received a second line treatment with imatinib (800 mg/die) or sunitinib (50 mg/die 4 weeks on/2 off or 37.5 mg/day). Deletion versus other KIT 11 mutation was recorded, correlated with clinical benefits.64% received imatinib, 36% sunitinib. KIT exon 11 mutation was available in 94 patients. With a median follow-up of 61 months, median time to progression (TTP) in patients receiving sunitinib and imatinib was 10 (95% CI 9.7-10.9) and 5 months (95% CI 3.6-6.7) respectively (P = 0.012). No difference was found in overall survival (OS) (P = 0.883). In imatinib arm, KIT exon 11 deletions was associated with a shorter TTP (7 vs 17 months; P = 0.02), with a trend in OS (54 vs 71 months P = 0.063). No difference was found in patients treated with sunitinib (P = 0.370).A second line with sunitinib was associated with an improved TTP in KIT exon 11 mutated patients progressing on imatinib 400 mg/die. Deletions in exon 11 seemed to be correlated with worse outcome in patients receiving imatinib-based second line.

  18. Dose-Escalated Stereotactic Body Radiation Therapy for Prostate Cancer: Quality of Life Comparison of Two Prospective Trials

    Directory of Open Access Journals (Sweden)

    Harvey Charles Quon

    2016-08-01

    Full Text Available IntroductionThe optimal prostate stereotactic body radiation therapy (SBRT dose-fractionation scheme is controversial. This study compares long-term quality of life (QOL from two prospective trials of prostate SBRT to investigate the effect of increasing dose (NCT01578902 and NCT01146340.Material and MethodsPatients with localized prostate cancer received SBRT 35 or 40 Gy delivered in 5 fractions, once per week. QOL was measured using the Expanded Prostate Cancer Index Composite (EPIC at baseline and every 6 months. Fisher’s exact test and generalized estimating equations were used to analyze proportions of patients with clinically significant change and longitudinal changes in QOL.Results114 patients were included, 84 treated to 35 Gy and 30 treated to 40 Gy. Median QOL follow-up was 56 months (interquartile range [IQR] 46-60 and 38 months (IQR 32-42, respectively. The proportion of patients reporting clinically significant declines in average urinary, bowel, and sexual scores were not significantly different between dose levels, and were 20.5 vs. 24.1% (p=0.60, 26.8 vs. 41.4% (p=0.16, and 42.9 vs. 38.5% (p=0.82, respectively. Similarly, longitudinal analysis did not identify significant differences in QOL between treatment groups.ConclusionDose-escalated prostate SBRT from 35 to 40 Gy in 5 fractions was not associated with significant decline in long-term QOL.

  19. Acute and late toxicity in prostate cancer patients treated by dose escalated intensity modulated radiation therapy and organ tracking

    Directory of Open Access Journals (Sweden)

    Behrensmeier Frank

    2008-10-01

    Full Text Available Abstract Background To report acute and late toxicity in prostate cancer patients treated by dose escalated intensity-modulated radiation therapy (IMRT and organ tracking. Methods From 06/2004 to 12/2005 39 men were treated by 80 Gy IMRT along with organ tracking. Median age was 69 years, risk of recurrence was low 18%, intermediate 21% and high in 61% patients. Hormone therapy (HT was received by 74% of patients. Toxicity was scored according to the CTC scale version 3.0. Median follow-up (FU was 29 months. Results Acute and maximal late grade 2 gastrointestinal (GI toxicity was 3% and 8%, late grade 2 GI toxicity dropped to 0% at the end of FU. No acute or late grade 3 GI toxicity was observed. Grade 2 and 3 pre-treatment genitourinary (GU morbidity (PGUM was 20% and 5%. Acute and maximal late grade 2 GU toxicity was 56% and 28% and late grade 2 GU toxicity decreased to 15% of patients at the end of FU. Acute and maximal late grade 3 GU toxicity was 8% and 3%, respectively. Decreased late ≥ grade 2 GU toxicity free survival was associated with higher age (P = .025, absence of HT (P = .016 and higher PGUM (P Discussion GI toxicity rates after IMRT and organ tracking are excellent, GU toxicity rates are strongly related to PGUM.

  20. Can we avoid dose escalation for intermediate-risk prostate cancer in the setting of short-course neoadjuvant androgen deprivation?

    Directory of Open Access Journals (Sweden)

    Shakespeare TP

    2016-03-01

    Full Text Available Thomas P Shakespeare,1,2 Shea W Wilcox,1 Noel J Aherne1,2 1Department of Radiation Oncology, North Coast Cancer Institute, 2Faculty of Medicine, Rural Clinical School, The University of New South Wales, Coffs Harbour, New South Wales, Australia Background: Both dose-escalated external beam radiotherapy (DE-EBRT and androgen deprivation therapy (ADT improve the outcomes in patients with intermediate-risk prostate cancer. Despite this, there are only few reports evaluating DE-EBRT for patients with intermediate-risk prostate cancer receiving neoadjuvant ADT, and virtually no studies investigating dose escalation >74 Gy in this setting. We aimed to determine whether DE-EBRT >74 Gy improved the outcomes for patients with intermediate-risk prostate cancer who received neoadjuvant ADT. Findings: In our institution, patients with intermediate-risk prostate cancer were treated with neoadjuvant ADT and DE-EBRT, with doses sequentially increasing from 74 Gy to 76 Gy and then to 78 Gy between 2006 and 2012. We identified 435 patients treated with DE-EBRT and ADT, with a median follow-up of 70 months. For the 74 Gy, 76 Gy, and 78 Gy groups, five-year biochemical disease-free survival rates were 95.0%, 97.8%, and 95.3%, respectively; metastasis-free survival rates were 99.1%, 100.0%, and 98.6%, respectively; and prostate cancer-specific survival rate was 100% for all three dose levels. There was no significant benefit for dose escalation either on univariate or multivariate analysis for any outcome. Conclusion: There was no benefit for DE-EBRT >74 Gy in our cohort of intermediate-risk prostate cancer patients treated with neoadjuvant ADT. Given the higher risks of toxicity associated with dose escalation, it may be feasible to omit dose escalation in this group of patients. Randomized studies evaluating dose de-escalation should be considered. Keywords: radiotherapy, IMRT, dose, dose escalation, dose de-escalation, androgen deprivation therapy

  1. Stem cell-based treatments against stroke: observations from human proof-of-concept studies and considerations regarding clinical applicability

    Directory of Open Access Journals (Sweden)

    Thorsten Roland Doeppner

    2014-10-01

    Full Text Available Ischemic stroke remains a heavy burden for industrialized countries. The only causal therapy is the recanalization of occluded vessels via thrombolysis, which due to a narrow time window still can be offered only to a minority of patients. Since the majority of patients continues to exhibit neurological deficits even following successful thrombolysis, restorative therapies are urgently needed that promote brain remodeling and repair once stroke injury has occurred. Due to their unique properties of action, stem cell-based strategies gained increasing interest during recent years. Using various stroke models in both rodents and primates, the transplantation of stem cells, namely of bone marrow derived mesenchymal stem cells (MSCs or neural progenitor cells (NPCs, has been shown to promote neurological recovery most likely via indirect bystander actions. In view of promising observations, clinical proof-of-concept studies are currently under way, in which effects of stem and precursor cells are evaluated in human stroke patients. In this review we summarize already published studies, which due to the broad experience in other medical contexts mostly employed bone marrow-derived MSCs by means of intravenous transplantation. With the overall number of clinical trials limited in number, only a fraction of these studies used non-treated control groups, and only single studies were adequately blinded. Despite these limitations, first promising results justify the need for more elaborate clinical trials in order to make stem cell transplantation a success for stroke treatment in the future.

  2. Catalytic conversion of light alkanes-proof-of-concept stage - Phase IV. Topical report, February 1, 1994--January 31, 1995

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1998-12-31

    This report details the research performed on Phase IV of the extended Cooperative Agreement. This Phase, entitled C{sub 1}-C{sub 4} Research, provides the research support which accompanies the C{sub 4} Proof-of-Concept Phase (Phase V) as the two major activities of the Cooperative Agreement during calendar 1993. It is the objective of this phase to understand the nature of the catalysts and catalytic activity of perhaloporphyrin complexes uncovered during Phases I-III in order that superior catalytic materials can be made and tested which meet commercial criteria for the oxidation of the C{sub 1}-C{sub 4} light alkane gases found in natural gas and other available hydrocarbon streams. During Phase IV, we have examined the physical and electronic structures of the very active perhaloporphyrin catalysts which we have developed, and have gained an understanding of the properties which make them active. This has led us to design and synthesize materials which are cheaper, more active, more robust and, in general superior for carrying out practical catalysis. Our early generation perhaloporphyrin catalysts, while exhibiting unprecedented catalytic activity, were far too expensive for use in converting natural gas or its C{sub 1}-C{sub 4} components.

  3. Virtual Reality-Based Attention Bias Modification Training for Social Anxiety: A Feasibility and Proof of Concept Study

    Directory of Open Access Journals (Sweden)

    Antoine eUrech

    2015-10-01

    Full Text Available Attention bias modification (ABM programs have been considered as a promising new approach for the treatment of various disorders, including social anxiety disorder (SAD. However, previous studies yielded ambiguous results regarding the efficacy of ABM in SAD. The present proof-of-concept study investigates the feasibility of a newly developed virtual reality (VR-based dot-probe training paradigm. It was designed to facilitate attentional disengagement from threatening stimuli in socially anxious individuals (N=15. The following outcomes were examined: (a self-reports of enjoyment, motivation, flow and presence, (b attentional bias for social stimuli, and (c social anxiety symptoms. Results showed that ABM training is associated with high scores in enjoyment, motivation, flow and presence. Furthermore, significant improvements in terms of attention bias and social anxiety symptoms were observed from pre- to follow-up assessment. The study suggests that VR is a feasible and presumably a promising new medium for ABM trainings. Controlled studies will need to be carried out.

  4. Proof of Concept: Matrix metalloproteinase inhibitor decreases inflammation and improves muscle insulin sensitivity in people with type 2 diabetes

    Directory of Open Access Journals (Sweden)

    Frankwich Karen

    2012-10-01

    Full Text Available Abstract Background Obesity is a state of subclinical inflammation resulting in loss of function of insulin receptors and decreased insulin sensitivity. Inhibition of the inflammatory enzymes, matrix metalloproteinases (MMPs, for 6 months in rodent models restores insulin receptor function and insulin sensitivity. Methods This 12-week double-blind, randomized, placebo (PL-controlled proof-of-concept study was performed to determine if the MMP inhibitor (MMPI, doxycycline, decreased global markers of inflammation and enhanced muscle insulin sensitivity in obese people with type 2 diabetes (DM2. The study included non-DM2 controls (n = 15, and DM2 subjects randomized to PL (n = 13 or doxycycline 100 mg twice daily (MMPI; n = 11. All participants were evaluated on Day 1; MMPI and PL groups were also evaluated after 84 days of treatment. Results There was a significant decrease in inflammatory markers C-reactive protein (P  Conclusions This study demonstrated short term treatment of people with diabetes with an MMPI resulted in decreased inflammation and improved insulin sensitivity. Larger, longer studies are warranted to determine if doxycycline can improve glucose control in people with diabetes. Trial Registration Clinicaltrials.gov NCT01375491

  5. Proof-of-concept Design and Development of an EN13606-based Electronic Health Care Record Service

    Science.gov (United States)

    Muñoz, Adolfo; Somolinos, Roberto; Pascual, Mario; Fragua, Juan A.; González, Miguel A.; Monteagudo, Jose Luis; Salvador, Carlos H.

    2007-01-01

    Objective The authors present an Electronic Healthcare Record (EHR) server, designed and developed as a proof of concept of the revised prEN13606:2005 European standard concerning EHR communications. Methods The development of the server includes five modules: the libraries for the management of the standard reference model, for the demographic package and for the data types; the permanent storage module, built on a relational database; two communication interfaces through which the clients can send information or make queries; the XML (eXtensible Markup Language) process module; and the tools for the validation of the extracts managed, implemented on a defined XML-Schema. Results The server was subjected to four phases of trials, the first three with ad hoc test data and processes to ensure that each of the modules complied with its specifications and that the interaction between them provided the expected functionalities. The fourth used real extracts generated by other research groups for the additional purpose of testing the validity of the standard in real-world scenarios. Conclusion The acceptable performance of the server has made it possible to include it as a middleware service in a platform for the out-of-hospital follow-up and monitoring of patients with chronic heart disease which, at the present time, supports pilot projects and clinical trials for the evaluation of eHealth services. PMID:17068357

  6. Multivariate Analysis As a Support for Diagnostic Flowcharts in Allergic Bronchopulmonary Aspergillosis: A Proof-of-Concept Study

    Directory of Open Access Journals (Sweden)

    Joana Vitte

    2017-08-01

    Full Text Available Molecular-based allergy diagnosis yields multiple biomarker datasets. The classical diagnostic score for allergic bronchopulmonary aspergillosis (ABPA, a severe disease usually occurring in asthmatic patients and people with cystic fibrosis, comprises succinct immunological criteria formulated in 1977: total IgE, anti-Aspergillus fumigatus (Af IgE, anti-Af “precipitins,” and anti-Af IgG. Progress achieved over the last four decades led to multiple IgE and IgG(4 Af biomarkers available with quantitative, standardized, molecular-level reports. These newly available biomarkers have not been included in the current diagnostic criteria, either individually or in algorithms, despite persistent underdiagnosis of ABPA. Large numbers of individual biomarkers may hinder their use in clinical practice. Conversely, multivariate analysis using new tools may bring about a better chance of less diagnostic mistakes. We report here a proof-of-concept work consisting of a three-step multivariate analysis of Af IgE, IgG, and IgG4 biomarkers through a combination of principal component analysis, hierarchical ascendant classification, and classification and regression tree multivariate analysis. The resulting diagnostic algorithms might show the way for novel criteria and improved diagnostic efficiency in Af-sensitized patients at risk for ABPA.

  7. Using Expectancy Value Theory as a Framework to Reduce Student Resistance to Active Learning: A Proof of Concept.

    Science.gov (United States)

    Cooper, Katelyn M; Ashley, Michael; Brownell, Sara E

    2017-01-01

    There has been a national movement to transition college science courses from passive lectures to active learning environments. Active learning has been shown to be a more effective way for students to learn, yet there is concern that some students are resistant to active learning approaches. Although there is much discussion about student resistance to active learning, few studies have explored this topic. Furthermore, a limited number of studies have applied theoretical frameworks to student engagement in active learning. We propose using a theoretical lens of expectancy value theory to understand student resistance to active learning. In this study, we examined student perceptions of active learning after participating in 40 hours of active learning. We used the principal components of expectancy value theory to probe student experience in active learning: student perceived self-efficacy in active learning, value of active learning, and potential cost of participating in active learning. We found that students showed positive changes in the components of expectancy value theory and reported high levels of engagement in active learning, which provide proof of concept that expectancy value theory can be used to boost student perceptions of active learning and their engagement in active learning classrooms. From these findings, we have built a theoretical framework of expectancy value theory applied to active learning.

  8. Using Drainage Slots in Permeable Paving Blocks to Delay the Effects of Clogging: Proof of Concept Study

    Directory of Open Access Journals (Sweden)

    Terry Lucke

    2014-09-01

    Full Text Available Permeable interlocking concrete pavements (PICP are specifically designed to remove sediment and other pollutants from stormwater runoff. Over time, this can lead to clogging of the PICP system. Previous research has shown that much of the clogging occurs on the bedding aggregate directly below the paving joints, while the remainder of the aggregate is unaffected. This paper describes a proof of concept study to delay the effects of clogging by making more efficient use of the bedding aggregate used in PICP systems. Lateral drainage slots were cut into the underside of PICP blocks to allow sediment-laden stormwater to access, and be filtered by, a greater surface area of bedding aggregate. Eight different slot designs were trialed in the study to determine which of the slot designs made the most efficient use of the bedding aggregate to filter the sediment from the stormwater. The study results demonstrated that the eight drainage slot designs deposited between 25% and 366% more sediment (by weight beneath the pavers than the control pavement. The results of the study suggest that PICP systems with drainage slots cast into their bases would take much longer to clog than unmodified pavers, thereby proving the concept of this study.

  9. Early-life metal exposure and schizophrenia: A proof-of-concept study using novel tooth-matrix biomarkers

    Science.gov (United States)

    Modabbernia, A.; Velthorst, E.; Gennings, C.; De Haan, L.; Austin, C.; Sutterland, A.; Mollon, J.; Frangou, S.; Wright, R.; Arora, M.; Reichenberg, A.

    2016-01-01

    Background Despite evidence for the effects of metals on neurodevelopment, the long-term effects on mental health remain unclear due to methodological limitations. Our objective was to determine the feasibility of studying metal exposure during critical neurodevelopmental periods and to explore the association between early-life metal exposure and adult schizophrenia. Methods We analyzed childhood-shed teeth from nine individuals with schizophrenia and five healthy controls. We investigated the association between exposure to lead (Pb2+), manganese (Mn2+), cadmium (Cd2+), copper (Cu2+), magnesium (Mg2+), and zinc (Zn2+), and schizophrenia, psychotic experiences, and intelligence quotient (IQ). We reconstructed the dose and timing of early-life metal exposures using laser ablation inductively coupled plasma mass spectrometry. Results We found higher early-life Pb2+ exposure among patients with schizophrenia than controls. The differences in log Mn2+ and log Cu2+ changed relatively linearly over time to postnatal negative values. There was a positive correlation between early-life Pb2+ levels and psychotic experiences in adulthood. Moreover, we found a negative correlation between Pb2+ levels and adult IQ. Conclusions In our proof-of-concept study, using tooth-matrix biomarker that provides direct measurement of exposure in the fetus and newborn, we provide support for the role of metal exposure during critical neurodevelopmental periods in psychosis. PMID:27311101

  10. Inhibiting avian influenza virus shedding using a novel RNAi antiviral vector technology: proof of concept in an avian cell model.

    Science.gov (United States)

    Linke, Lyndsey M; Wilusz, Jeffrey; Pabilonia, Kristy L; Fruehauf, Johannes; Magnuson, Roberta; Olea-Popelka, Francisco; Triantis, Joni; Landolt, Gabriele; Salman, Mo

    2016-03-01

    Influenza A viruses pose significant health and economic threats to humans and animals. Outbreaks of avian influenza virus (AIV) are a liability to the poultry industry and increase the risk for transmission to humans. There are limitations to using the AIV vaccine in poultry, creating barriers to controlling outbreaks and a need for alternative effective control measures. Application of RNA interference (RNAi) techniques hold potential; however, the delivery of RNAi-mediating agents is a well-known obstacle to harnessing its clinical application. We introduce a novel antiviral approach using bacterial vectors that target avian mucosal epithelial cells and deliver (small interfering RNA) siRNAs against two AIV genes, nucleoprotein (NP) and polymerase acidic protein (PA). Using a red fluorescent reporter, we first demonstrated vector delivery and intracellular expression in avian epithelial cells. Subsequently, we demonstrated significant reductions in AIV shedding when applying these anti-AIV vectors prophylactically. These antiviral vectors provided up to a 10,000-fold reduction in viral titers shed, demonstrating in vitro proof-of-concept for using these novel anti-AIV vectors to inhibit AIV shedding. Our results indicate this siRNA vector technology could represent a scalable and clinically applicable antiviral technology for avian and human influenza and a prototype for RNAi-based vectors against other viruses.

  11. Semi-empirical models for chlorine activation and ozone depletion in the Antarctic stratosphere: proof of concept

    Science.gov (United States)

    Huck, P. E.; Bodeker, G. E.; Kremser, S.; McDonald, A. J.; Rex, M.; Struthers, H.

    2013-03-01

    Two semi-empirical models were developed for the Antarctic stratosphere to relate the shift of species within total chlorine (Cly = HCl + ClONO2 + HOCl + 2 × Cl2 + 2×Cl2O2 + ClO + Cl) into the active forms (here: ClOx = 2×Cl2O2 + ClO), and to relate the rate of ozone destruction to ClOx. These two models provide a fast and computationally inexpensive way to describe the inter- and intra-annual evolution of ClOx and ozone mass deficit (OMD) in the Antarctic spring. The models are based on the underlying physics/chemistry of the system and capture the key chemical and physical processes in the Antarctic stratosphere that determine the interaction between climate change and Antarctic ozone depletion. They were developed considering bulk effects of chemical mechanisms for the duration of the Antarctic vortex period and quantities averaged over the vortex area. The model equations were regressed against observations of daytime ClO and OMD providing a set of empirical fit coefficients. Both semi-empirical models are able to explain much of the intra- and inter-annual variability observed in daily ClOx and OMD time series. This proof-of-concept paper outlines the semi-empirical approach to describing the evolution of Antarctic chlorine activation and ozone depletion.

  12. Semi-empirical models for chlorine activation and ozone depletion in the Antarctic stratosphere: proof of concept

    Directory of Open Access Journals (Sweden)

    P. E. Huck

    2013-03-01

    Full Text Available Two semi-empirical models were developed for the Antarctic stratosphere to relate the shift of species within total chlorine (Cly = HCl + ClONO2 + HOCl + 2 × Cl2 + 2×Cl2O2 + ClO + Cl into the active forms (here: ClOx = 2×Cl2O2 + ClO, and to relate the rate of ozone destruction to ClOx. These two models provide a fast and computationally inexpensive way to describe the inter- and intra-annual evolution of ClOx and ozone mass deficit (OMD in the Antarctic spring. The models are based on the underlying physics/chemistry of the system and capture the key chemical and physical processes in the Antarctic stratosphere that determine the interaction between climate change and Antarctic ozone depletion. They were developed considering bulk effects of chemical mechanisms for the duration of the Antarctic vortex period and quantities averaged over the vortex area. The model equations were regressed against observations of daytime ClO and OMD providing a set of empirical fit coefficients. Both semi-empirical models are able to explain much of the intra- and inter-annual variability observed in daily ClOx and OMD time series. This proof-of-concept paper outlines the semi-empirical approach to describing the evolution of Antarctic chlorine activation and ozone depletion.

  13. Ordered mesoporous silica to enhance the bioavailability of poorly water-soluble drugs: Proof of concept in man.

    Science.gov (United States)

    Bukara, Katarina; Schueller, Laurent; Rosier, Jan; Martens, Mark A; Daems, Tinne; Verheyden, Loes; Eelen, Siemon; Van Speybroeck, Michiel; Libanati, Cristian; Martens, Johan A; Van Den Mooter, Guy; Frérart, Françoise; Jolling, Koen; De Gieter, Marjan; Bugarski, Branko; Kiekens, Filip

    2016-11-01

    Formulating poorly water soluble drugs using ordered mesoporous silica materials is an emerging approach to tackle solubility-related bioavailability problems. The current study was conducted to assess the bioavailability-enhancing potential of ordered mesoporous silica in man. In this open-label, randomized, two-way cross-over study, 12 overnight fasted healthy volunteers received a single dose of fenofibrate formulated with ordered mesoporous silica or a marketed product based on micronized fenofibrate. Plasma concentrations of fenofibric acid, the pharmacologically active metabolite of fenofibrate, were monitored up to 96h post-dose. The rate (Cmax/dose increased by 77%; tmax reduced by 0.75h) and extent of absorption (AUC0-24h/dose increased by 54%) of fenofibrate were significantly enhanced following administration of the ordered mesoporous silica based formulation. The results of this study serve as a proof of concept in man for this novel formulation approach. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. Knowledge management in secondary pharmaceutical manufacturing by mining of data historians-A proof-of-concept study.

    Science.gov (United States)

    Meneghetti, Natascia; Facco, Pierantonio; Bezzo, Fabrizio; Himawan, Chrismono; Zomer, Simeone; Barolo, Massimiliano

    2016-05-30

    In this proof-of-concept study, a methodology is proposed to systematically analyze large data historians of secondary pharmaceutical manufacturing systems using data mining techniques. The objective is to develop an approach enabling to automatically retrieve operation-relevant information that can assist the management in the periodic review of a manufactory system. The proposed methodology allows one to automatically perform three tasks: the identification of single batches within the entire data-sequence of the historical dataset, the identification of distinct operating phases within each batch, and the characterization of a batch with respect to an assigned multivariate set of operating characteristics. The approach is tested on a six-month dataset of a commercial-scale granulation/drying system, where several millions of data entries are recorded. The quality of results and the generality of the approach indicate that there is a strong potential for extending the method to even larger historical datasets and to different operations, thus making it an advanced PAT tool that can assist the implementation of continual improvement paradigms within a quality-by-design framework.

  15. A label-free detector for liquid chromatography systems using mm-wave technology: First proof of concept.

    Science.gov (United States)

    Zhang, Y; Declerck, S; Mangelings, D; He, G; Matvejev, V; Vander Heyden, Y; Stiens, J

    2017-08-08

    The development of millimeter-wave (mm-wave) technology has enabled the study of bio-molecular interactions by means of electromagnetic waves with frequencies between 30 and 300GHz. In this study, an attempt has been made to exploit the possibility of mm-wave technology as alternative detection technique for liquid chromatographic (LC) systems. The goal is to design and fabricate a label-free mm-wave detector that is compatible with LC systems. As proof-of-concept experiments, the UV absorbing compounds praziquantel and trans-stilbene-oxide as well as a non-UV absorbing compound sorbitol are injected in an open capillary as well as a capillary with stationary phase and measured by both mm-wave and UV detectors. The in-house developed mm-wave detector is capable of detecting all compounds without the need for labelling. Although the detection limit of such detector still needs to be verified and occasionally improved in the future, it already shows great potential as an additional detection technique for LC systems. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Metformin and Melatonin in Adrenocortical Carcinoma: Morphoproteomics and Biomedical Analytics Provide Proof of Concept in a Case Study.

    Science.gov (United States)

    Brown, Robert E; Buryanek, Jamie; McGuire, Mary F

    2017-08-01

    Metformin has been proposed as a novel anti-cancer drug for adrenocortical carcinoma (ACC) based upon Poli's recent preclinical studies that 1. "in vitro" metformin modulates the ACC cell model H295R and 2. "in vivo" metformin inhibits tumor growth in a xenograft model as confirmed by a significant reduction of Ki67 [1]. Here we report on our prior clinical case study that provides proof of concept for Poli's studies. We were requested to perform morphoproteomic analysis to further define the biology of, and raise targeted therapeutic options, for a case of post-treatment and chemoresistant ACC metastatic to the liver and the lung. Profiling the patient's ACC from the liver resulted in the recommendation of metformin as a maintenance therapy, which was supported by biomedical data analysis. The patient remains on maintenance therapy with metformin and melatonin and is free of disease some 7 years post diagnosis, thus underscoring the recommendation for clinical trials employing these therapeutic agents. © 2017 by the Association of Clinical Scientists, Inc.

  17. A novel topical agent in the treatment of seborrheic keratoses: A proof of concept study by clinical and dermoscopic evaluation.

    Science.gov (United States)

    Lacarrubba, Francesco; Nasca, Maria Rita; Verzì, Anna Elisa; Micali, Giuseppe

    2017-08-10

    In this proof of concept study, 50 lesions from 15 patients with multiple seborrheic keratoses (SKs) were treated with a novel aqueous solution containing nitric acid, zinc and copper salts, and organic acids (acetic, lactic, and oxalic acid). Treatment consisted in the application of an amount of the solution sufficient to obtain a whitening/yellowish reaction. Application of the nitric-zinc solution was performed every other week until clinical and dermoscopic clearance or crust formation, for a maximum of 4 applications. Efficacy evaluation was performed at 8 weeks (T1) and 6 months (T2). All subjects, who reported no or minimal discomfort during and after the application of the solution, completed the study. At T1, a complete clinical and dermoscopic resolution was observed in 37 lesions after an average of 3 applications/lesion (range 2-4). A partial response, with minimal persistent residual spots, was detected in the remaining 13 lesions. All patients with complete clearance showed no relapses at a 6-month follow-up (T2). The positive preliminary results indicate that this novel solution may represent a promising alternative option for SKs especially in patients not keen or eligible to undergo invasive tissue-destructive procedures. © 2017 Wiley Periodicals, Inc.

  18. Non-Invasive Intra-cardiac Pressure Measurements Using Subharmonic-Aided Pressure Estimation: Proof of Concept in Humans.

    Science.gov (United States)

    Dave, Jaydev K; Kulkarni, Sushmita V; Pangaonkar, Purva P; Stanczak, Maria; McDonald, Maureen E; Cohen, Ira S; Mehrotra, Praveen; Savage, Michael P; Walinsky, Paul; Ruggiero, Nicholas J; Fischman, David L; Ogilby, David; VanWhy, Carolyn; Lombardi, Matthew; Forsberg, Flemming

    2017-08-11

    This study evaluated the feasibility of employing non-invasive intra-cardiac pressure estimation using subharmonic signals from ultrasound contrast agents in humans. This institutional review board-approved proof-of-concept study included 15 consenting patients scheduled for left and right heart catheterization. During the catheterization procedure, Definity was infused intra-venously at 4-10 mL/min. Ultrasound scanning was performed with a Sonix RP using pulse inversion, three incident acoustic output levels and 2.5-MHz transmit frequency. Radiofrequency data were processed and subharmonic amplitudes were compared with the pressure catheter data. The correlation coefficient between subharmonic signals and pressure catheter data ranged from -0.3 to -0.9. For acquisitions with optimum acoustic output, pressure errors between the subharmonic technique and catheter were as low as 2.6 mmHg. However, automatically determining optimum acoustic output during scanning for each patient remains to be addressed before clinical applicability can be decided. Copyright © 2017 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

  19. Multivariate Analysis As a Support for Diagnostic Flowcharts in Allergic Bronchopulmonary Aspergillosis: A Proof-of-Concept Study.

    Science.gov (United States)

    Vitte, Joana; Ranque, Stéphane; Carsin, Ania; Gomez, Carine; Romain, Thomas; Cassagne, Carole; Gouitaa, Marion; Baravalle-Einaudi, Mélisande; Bel, Nathalie Stremler-Le; Reynaud-Gaubert, Martine; Dubus, Jean-Christophe; Mège, Jean-Louis; Gaudart, Jean

    2017-01-01

    Molecular-based allergy diagnosis yields multiple biomarker datasets. The classical diagnostic score for allergic bronchopulmonary aspergillosis (ABPA), a severe disease usually occurring in asthmatic patients and people with cystic fibrosis, comprises succinct immunological criteria formulated in 1977: total IgE, anti-Aspergillus fumigatus (Af) IgE, anti-Af "precipitins," and anti-Af IgG. Progress achieved over the last four decades led to multiple IgE and IgG(4) Af biomarkers available with quantitative, standardized, molecular-level reports. These newly available biomarkers have not been included in the current diagnostic criteria, either individually or in algorithms, despite persistent underdiagnosis of ABPA. Large numbers of individual biomarkers may hinder their use in clinical practice. Conversely, multivariate analysis using new tools may bring about a better chance of less diagnostic mistakes. We report here a proof-of-concept work consisting of a three-step multivariate analysis of Af IgE, IgG, and IgG4 biomarkers through a combination of principal component analysis, hierarchical ascendant classification, and classification and regression tree multivariate analysis. The resulting diagnostic algorithms might show the way for novel criteria and improved diagnostic efficiency in Af-sensitized patients at risk for ABPA.

  20. Design trade-off and proof of concept for LOUPE, the Lunar Observatory for Unresolved Polarimetry of Earth.

    Science.gov (United States)

    Hoeijmakers, H J; Arts, M L J; Snik, F; Keller, C U; Kuiper, J M

    2016-09-19

    We provide a proof of the technical feasibility of LOUPE, the first integral-field snapshot spectropolarimeter, designed to monitor the reflected flux and polarization spectrum of Earth. These are to be used as benchmark data for the retrieval of biomarkers and atmospheric and surface characteristics from future direct observations of exoplanets. We perform a design trade-off for an implementation in which LOUPE performs snapshot integral-field spectropolarimetry at visible wavelengths. We used off-the-shelf optics to construct a polarization modulator, in which polarization information is encoded into the spectrum as a wavelength-dependent modulation, while spatial resolution is maintained using a micro-lens array. The performance of this design concept is validated in a laboratory setup. Our proof-of-concept is capable of measuring a grid of 50 × 50 polarization spectra between 610 and 780 nm of a mock target planet - proving the merit of this design. The measurements are affected by systematic noise on the percent level, and we discuss how to mitigate this in future iterations. We conclude that LOUPE can be small and robust while meeting the science goals of this particular space application, and note the many potential applications that may benefit from our concept for doing snapshot integral-field spectropolarimetry.

  1. Polymeric microcapsules with switchable mechanical properties for self-healing concrete: synthesis, characterisation and proof of concept

    Science.gov (United States)

    Kanellopoulos, A.; Giannaros, P.; Palmer, D.; Kerr, A.; Al-Tabbaa, A.

    2017-04-01

    Microcapsules, with sodium silicate solution as core, were produced using complex coacervation in a double, oil-in-water-in oil, emulsion system. The shell material was a gelatin-acacia gum crosslinked coacervate and the produced microcapsules had diameters ranging from 300 to 700 μm. The shell material designed with switchable mechanical properties. When it is hydrated exhibits soft and ‘rubbery’ behaviour and, when dried, transitions to a stiff and ‘glassy’ material. The microcapsules survived drying and rehydrating cycles and preserved their structural integrity when exposed to highly alkaline solutions that mimic the pH environment of concrete. Microscopy revealed that the shell thickness of the microcapsules varies across their perimeter from 5 to 20 μm. Thermal analysis showed that the produced microcapsules were very stable up to 190 °C. Proof of concept investigation has demonstrated that the microcapsules successfully survive and function when exposed to a cement-based matrix. Observations showed that the microcapsules survive mixing with cement and rupture successfully upon crack formation releasing the encapsulated sodium silicate solution.

  2. Targeting pain catastrophization in patients with fibromyalgia using virtual reality exposure therapy: a proof-of-concept study.

    Science.gov (United States)

    Morris, Linzette Deidrè; Louw, Quinette Abegail; Grimmer, Karen Anne; Meintjes, Ernesta

    2015-11-01

    [Purpose] Pain catastrophizing is a key predictor of poor compliance to exercises among patients with fibromyalgia syndrome. Alteration of pain catastrophizing in this group is thus warranted. This study aimed to provide proof-of-concept of a novel virtual reality exposure therapy program as treatment for exercise-related pain catastrophizing in patients with fibromyalgia syndrome. [Subjects and Methods] An exploratory, case-controlled study was conducted (fibromyalgia syndrome group and matched control group). Functional magnetic resonance imaging was used to acquire neural correlates. The functional magnetic resonance imaging task consisted of two stimuli: active (exercise activity visuals) and passive (relaxing visuals). Structural images and blood-oxygenation-level-dependent contrasts were acquired for the conditions and compared within subjects/groups and between groups. Statistic images were thresholded using corrected clusters (determined by Z>2.3; level of significance: 0.05). [Results] Thirteen fibromyalgia syndrome subjects and nine healthy matched controls were included. The right inferior frontal gyrus, right middle frontal gyrus, right posterior cerebellum, left thalamus, and left supramarginal gyrus were activated in the fibromyalgia syndrome subjects. [Conclusion] The study results provide preliminary proof indicating that exposing patients with fibromyalgia syndrome to visuals of exercises elicits neurophysiological changes in functional brain areas associated with pain catastrophization and add to the current body of knowledge regarding the possibility of objectively identifying cognitive behavioral strategies like pain catastrophization.

  3. Virtual Reality-Based Attention Bias Modification Training for Social Anxiety: A Feasibility and Proof of Concept Study.

    Science.gov (United States)

    Urech, Antoine; Krieger, Tobias; Chesham, Alvin; Mast, Fred W; Berger, Thomas

    2015-01-01

    Attention bias modification (ABM) programs have been considered as a promising new approach for the treatment of various disorders, including social anxiety disorder (SAD). However, previous studies yielded ambiguous results regarding the efficacy of ABM in SAD. The present proof-of-concept study investigates the feasibility of a newly developed virtual reality (VR)-based dot-probe training paradigm. It was designed to facilitate attentional disengagement from threatening stimuli in socially anxious individuals (N = 15). The following outcomes were examined: (a) self-reports of enjoyment, motivation, flow, and presence; (b) attentional bias for social stimuli; and (c) social anxiety symptoms. Results showed that ABM training is associated with high scores in enjoyment, motivation, flow, and presence. Furthermore, significant improvements in terms of attention bias and social anxiety symptoms were observed from pre- to follow-up assessment. The study suggests that VR is a feasible and presumably a promising new medium for ABM trainings. Controlled studies will need to be carried out.

  4. Proof of Concept

    DEFF Research Database (Denmark)

    Margheritini, Lucia; Parmeggiani, Stefano; Kofoed, Jens Peter

    it is needed. In the following paragraphs, the desk study on the WEBAP concept is presented in terms of overtopping flow rates for different configurations. Investigations on different drafts, slope angles and crest levels have been completed. Calculations on the pipe discharge have been made in order......The Wave Energized Baltic Aeration Pump (WEBAP) is a concept that proposes to find a solution to the low level of oxygenation of the Baltic Sea by bringing the surface sea water to the depth where the oxygen is needed. It proposes to do so by using the rich in oxygen overtopping water collected...... in a reservoir floating on the sea. The stored water, after overtopping the ramp leading to the reservoir, will be at a higher level than mean water level and therefore will have a potential energy. This potential energy is indeed used to pump down to the sea bed the oxygenated water right there where...

  5. POTENTIAL APPLICATIONS OF IMAGE-GUIDED RADIOTHERAPY FOR RADIATION DOSE ESCALATION IN PATIENTS WITH EARLY STAGE HIGH-RISK PROSTATE CANCER

    Directory of Open Access Journals (Sweden)

    Nam Phong Nguyen

    2015-02-01

    Full Text Available Patients with early stage high-risk prostate cancer (PSA >20, Gleason score >7 are at high risk of recurrence following prostate cancer irradiation. Radiation dose escalation to the prostate may improve biochemical free survival for these patients. However, high rectal and bladder dose with conventional three-dimensional conformal radiotherapy (3D-CRT may lead to excessive gastrointestinal and genitourinary toxicity. Image-guided radiotherapy (IGRT, by virtue of combining the steep dose gradient of intensity-modulated radiotherapy (IMRT and daily pretreatment imaging, may allow for radiation dose escalation and decreased treatment morbidity. Reduced treatment time is feasible with hypofractionated IGRT and it may improve patient quality of life.

  6. Phase I trial of dose-escalating metronomic temozolomide plus bevacizumab and bortezomib for patients with recurrent glioblastoma.

    Science.gov (United States)

    McCracken, D Jay; Celano, Emma C; Voloschin, Alfredo D; Read, William L; Olson, Jeffrey J

    2016-10-01

    The average survival time for patients with recurrent glioblastoma is between 5 and 9 months. Phase I and II trials have shown a modest survival benefit with combination temozolomide and other chemotherapeutics. We conducted a phase I trial of dose-escalating temozolomide with bevacizumab and the proteasome inhibitor bortezomib for patients with recurrent disease. Three groups of three patients were scheduled to receive daily doses of temozolomide at 25, 50, and 75 mg/m(2). Fixed doses of bortezomib and bevacizumab were given at standard intervals. Patients were monitored for dose-limiting toxicities (DLT) to determine the maximum-tolerated dose (MTD) of temozolomide with this regimen. No DLT were seen in the first two groups (25 and 50 mg/m(2) temozolomide). One patient in the 75 mg/m(2) group experienced a grade 4 elevation of ALT and three more patients were accrued for a total of six patients at that dose level. No other DLT occurred, thus making 75 mg/m(2) the MTD. Progression-free survival was 3.27 months for all patients and mean overall survival was 20.75 months. The MTD of temozolomide was 75 mg/m(2) in combination with bevacizumab and bortezomib for recurrent glioblastoma. Only one patient experienced a severe (Grade 4) elevation of ALT. This study will provide the framework for further studies to elicit effectiveness and better determine a safety profile for this drug combination.

  7. Long-term tolerance and outcomes for dose escalation in early salvage post-prostatectomy radiation therapy

    Energy Technology Data Exchange (ETDEWEB)

    Safdieh, Joseph; Schwartz, David; Weiner, Joseph; Weiss, Jeffrey P.; Madeb, Isaac; Rotman, Marvin; Schreiber, David [Dept.of Veteran Affairs, New York Harbor Healthcare System, Brooklyn (United States); Rineer, Justin [University of Florida Health Cancer Center, Orlando (United States)

    2014-09-15

    To study the long-term outcomes and tolerance in our patients who received dose escalated radiotherapy in the early salvage post-prostatectomy setting. The medical records of 54 consecutive patients who underwent radical prostatectomy subsequently followed by salvage radiation therapy (SRT) to the prostate bed between 2003-2010 were analyzed. Patients included were required to have a pre-radiation prostate specific antigen level (PSA) of 2 ng/mL or less. The median SRT dose was 70.2 Gy. Biochemical failure after salvage radiation was defined as a PSA level >0.2 ng/mL. Biochemical control and survival endpoints were analyzed using the Kaplan-Meier method. Univariate and multivariate Cox regression analysis were used to identify the potential impact of confounding factors on outcomes. The median pre-SRT PSA was 0.45 ng/mL and the median follow-up time was 71 months. The 4- and 7-year actuarial biochemical control rates were 75.7% and 63.2%, respectively. The actuarial 4- and 7-year distant metastasis-free survival was 93.7% and 87.0%, respectively, and the actuarial 7-year prostate cancer specific survival was 94.9%. Grade 3 late genitourinary toxicity developed in 14 patients (25.9%), while grade 4 late genitourinary toxicity developed in 2 patients (3.7%). Grade 3 late gastrointestinal toxicity developed in 1 patient (1.9%), and grade 4 late gastrointestinal toxicity developed in 1 patient (1.9%). In this series with long-term follow-up, early SRT provided outcomes and toxicity profiles similar to those reported from the three major randomized trials studying adjuvant radiation therapy.

  8. A Phase I Clinical and Pharmacology Study Using Amifostine as a Radioprotector in Dose-escalated Whole Liver Radiation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Feng, Mary, E-mail: maryfeng@umich.edu [Department of Radiation Oncology, School of Medicine, University of Michigan, Ann Arbor, Michigan (United States); Smith, David E. [Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan (United States); Normolle, Daniel P. [Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Knol, James A. [Department of Surgery, School of Medicine, University of Michigan, Ann Arbor, Michigan (United States); Pan, Charlie C.; Ben-Josef, Edgar [Department of Radiation Oncology, School of Medicine, University of Michigan, Ann Arbor, Michigan (United States); Lu Zheng; Feng, Meihua R.; Chen Jun [Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan (United States); Ensminger, William [Department of Internal Medicine, School of Medicine, University of Michigan, Ann Arbor, Michigan (United States); Lawrence, Theodore S. [Department of Radiation Oncology, School of Medicine, University of Michigan, Ann Arbor, Michigan (United States)

    2012-08-01

    Purpose: Diffuse intrahepatic tumors are difficult to control. Whole-liver radiotherapy has been limited by toxicity, most notably radiation-induced liver disease. Amifostine is a prodrug free-radical scavenger that selectively protects normal tissues and, in a preclinical model of intrahepatic cancer, systemic amifostine reduced normal liver radiation damage without compromising tumor effect. We hypothesized that amifostine would permit escalation of whole-liver radiation dose to potentially control microscopic disease. We also aimed to characterize the pharmacokinetics of amifostine and its active metabolite WR-1065 to optimize timing of radiotherapy. Methods and Materials: We conducted a radiation dose-escalation trial for patients with diffuse, intrahepatic cancer treated with whole-liver radiation and intravenous amifostine. Radiation dose was assigned using the time-to-event continual reassessment method. A companion pharmacokinetic study was performed. Results: Twenty-three patients were treated, with a maximum dose of 40 Gy. Using a logistical regression model, compared with our previously treated patients, amifostine increased liver tolerance by 3.3 {+-} 1.1 Gy (p = 0.007) (approximately 10%) with similar response rates. Peak concentrations of WR-1065 were 25 {mu}M with an elimination half-life of 1.5 h; these levels are consistent with radioprotective effects of amifostine in patients. Conclusion: These findings demonstrate for the first time that amifostine is a normal liver radioprotector. They further suggest that it may be useful to combine amifostine with fractionated or stereotactic body radiation therapy for patients with focal intrahepatic cancer.

  9. Dosimetric Feasibility of Dose Escalation Using SBRT Boost for Stage III Non-Small Cell Lung Cancer

    Science.gov (United States)

    Hepel, Jaroslaw T.; Peter, Justin; Hiatt, Jessica R.; Patel, Salil; Osibanjo, Oluwademilade; Safran, Howard; Curran, Bruce; DiPetrillo, Thomas

    2012-01-01

    Purpose: Standard chemoradiation therapy for stage III non-small cell lung cancer (NSCLCa) results in suboptimal outcomes with a high rate of local failure and poor overall survival. We hypothesize that dose escalation using stereotactic body radiotherapy (SBRT) boost could improve upon these results. We present here a study evaluating the dosimetric feasibility of such an approach. Methods: Anonymized CT data sets from five randomly selected patients with stage III NSCLCa undergoing definitive chemoradiation therapy in our department with disease volumes appropriate for SBRT boost were selected. Three-dimensional conformal radiation therapy (3D-CRT) plans to 50.4 Gy in 28 fractions were generated follow by SBRT plans to two dose levels, 16 Gy in two fractions and 28 Gy in two fractions. SBRT plans and total composite (3D-CRT and SBRT) were optimized and evaluated for target coverage and dose to critical structures; lung, esophagus, cord, and heart. Results: All five plans met predetermined target coverage and normal tissue dose constraints. PTV V95 was equal to or greater than 95% in all cases. The cumulative lung V20 and V5 of the combined 3D-CRT and SBRT plans were less than or equal to 30 and 55%, respectively. The 5 cc esophageal dose was less than 12 Gy for all low and high dose SBRT plans. The cumulative dose to the esophagus was also acceptable with less than 10% of the esophagus receiving doses in excess of 50 Gy. The cumulative spinal cord dose was less than 33 Gy and heart V25 was less than 5%. Conclusion: The combination of chemoradiation to 50.4 Gy followed by SBRT boost to gross disease at the primary tumor and involved regional lymph nodes is feasible with respect to normal tissue dose constraints in this dosimetric pilot study. A phase I/II trial to evaluate the clinical safety and efficacy of this approach is being undertaken. PMID:23057009

  10. SU-E-T-500: Dose Escalation Strategy for Lung Cancer Patients Using a Biologically- Guided Target Definition

    Energy Technology Data Exchange (ETDEWEB)

    Shusharina, N; Khan, F; Choi, N; Sharp, G [Massachusetts General Hospital, Boston, MA (United States)

    2014-06-01

    Purpose: Dose escalation strategy for lung cancer patients can lead to late symptoms such as pneumonitis and cardiac injury. We propose a strategy to increase radiation dose for improving local tumor control while simultaneously striving to minimize the injury of organs at risk (OAR). Our strategy is based on defining a small, biologically-guided target volume for receiving additional radiation dose. Methods: 106 patients with lung cancer treated with radiotherapy were selected for patients diagnosed with stage II and III disease. Previous research has shown that 50% of the maximum SUV threshold in FDG-PET imaging is appropriate for delineation of the most aggressive part of a tumor. After PET- and CT-derived targets were contoured, an IMRT treatment plan was designed to deliver 60 Gy to the GTV as delineated on a 4D CT (Plan 1). A second plan was designed with additional dose of 18 Gy to the PET-derived volume (Plan 2). A composite plan was generated by the addition of Plan 1 and Plan 2. Results: Plan 1 was compared to the composite plan and increases in OAR dose were assessed. For seven patients on average, lung V5 was increased by 1.4% and V20 by 4.2% for ipsilateral lung and by 13.5% and 7% for contralateral lung. For total lung, V5 and V20 were increased by 4.5% and 4.8% respectively. Mean lung dose was increased by 9.7% for the total lung. The maximum dose to the spinal cord increased by 16% on average. For the heart, V20 increased by 4.2% and V40 by 5.2%. Conclusion: It seems feasible that an additional 18 Gy of radiation dose can be delivered to FDG PET-derived subvolume of the CT-based GTV of the primary tumor without significant increase in total dose to the critical organs such as lungs, spinal cord and heart.

  11. A phase I dose-escalation study of lenalidomide in combination with gemcitabine in patients with advanced pancreatic cancer.

    Directory of Open Access Journals (Sweden)

    Gustav J Ullenhag

    Full Text Available Lenalidomide have both immunomodulatory and anti-angiogenic properties which could confer anti-cancer effects. The aim of this study was to assess the feasibility of combining lenalidomide with the standard treatment gemcitabine in pancreatic cancer patients with advanced disease.Eligible patients had locally advanced or metastatic adenocarcinoma of the pancreas. Patients received lenalidomide days 1-21 orally and gemcitabine 1000 mg/m2 intravenously (days 1, 8 and 15, each 28 day cycle. Three cohorts of lenalidomide were examined (Cohort I = 15 mg, Cohort II = 20 mg and Cohort III = 25 mg daily. The maximum tolerated dose (MTD of lenalidomide given in combination with gemcitabine was defined as the highest dose level at which no more than one out of four (25% subjects experiences a dose-limiting toxicity (DLT. Patients should also be able to receive daily low molecular weight heparin (LMWH (e.g. dalteparin 5000 IU s.c. daily as a prophylactic anticoagulant for venous thromboembolic events (VTEs. Twelve patients (n = 4, n = 3 and n = 5 in cohort I, II and III, respectively were enrolled in this study.Median duration of treatment was 11 weeks (range 1-66, and median number of treatment cycles were three (range 1-14. The only DLT was a cardiac failure grade 3 in cohort III. Frequent treatment-related adverse events (AEs (all grades included neutropenia, leucopenia and fatigue (83% each, but there was no febrile neutropenia; thrombocytopenia (75%; dermatological toxicity (75%; diarrhea and nausea (42% each; and neuropathy (42%.This phase I study demonstrates the feasibility of the combination of lenalidomide and gemcitabine as first-line treatment in patients with advanced pancreatic cancer. The tolerability profile demonstrated in the dose escalation schedule of lenalidomide suggests the dosing of lenalidomide to be 25 mg daily on days 1-21 with standard dosing of gemcitabine and merits further evaluation in a phase II trial.ClinicalTrials.gov NCT

  12. A planning study of radiotherapy dose escalation of PET-active tumour volumes in non-small cell lung cancer patients

    Energy Technology Data Exchange (ETDEWEB)

    Sloth Moeller, Ditte; Hoffmann, Lone (Dept. of Medical Physics, Aarhus Univ. Hospital, Aarhus (Denmark)), e-mail: dittmoel@rm.dk; Khalil, Azza Ahmed; Marquard Knap, Marianne (Dept. of Oncology, Aarhus Univ. Hospital, Aarhus (Denmark)); Muren, Ludvig Paul (Dept. of Medical Physics, Aarhus Univ. Hospital, Aarhus (Denmark); Dept. of Oncology, Aarhus Univ. Hospital, Aarhus (Denmark))

    2011-08-15

    Background. Patients with non-small cell lung cancer (NSCLC) have poor prognosis partly because of high local failure rates. Escalating the dose to the tumour may decrease the local failure rates and thereby, improve overall survival, but the risk of complications will limit the possibility to dose-escalate a broad range of patients. Escalating only PET-active areas of the tumour may increase the potential for reaching high doses for a variety of tumour sizes and locations. Material and methods. Ten patients were randomly chosen for a dose escalation planning study. A planning target volume (PTV) was defined on the mid-ventilation scan of a four-dimensional computed tomography (4D-CT) scan and a boost planning target volume (PTV-boost) was defined based on a positron emission tomography computed tomography (PET-CT) scan. Treatment plans were created aiming to reach the highest achievable of 74 Gy, 78 Gy or 82 Gy in 2 Gy per fraction prescribed to the PTV-boost without compromising normal tissue constraints and with the PTV prescribed in all cases a biological equivalent dose in 2 Gy fractions of 66 Gy. Results. Nine of ten patients could be escalated to the highest dose level (82 Gy), while one patient was limited by the oesophagus dose constraint and could only reach 74 Gy. Four patients could be dose-escalated above 82 Gy without compromising normal tissue constraints. Conclusion. Dose-escalating only the PET-active areas of lung tumours to doses of 82 Gy while respecting normal tissue constraints is feasible, also in a series of unselected patients including cases with relatively large tumours

  13. Treatment of Non-alcoholic Fatty Liver Disease with Curcumin: A Randomized Placebo-controlled Trial.

    Science.gov (United States)

    Rahmani, Sepideh; Asgary, Sedigheh; Askari, Gholamreza; Keshvari, Mahtab; Hatamipour, Mahdi; Feizi, Awat; Sahebkar, Amirhossein

    2016-09-01

    Non-alcoholic fatty liver disease (NAFLD) is a global health problem. Although many aspects of NAFLD pathogenesis have been understood, there is a paucity of effective treatments to be used as the second line when lifestyle modification is insufficient. Curcumin, a natural polyphenol from turmeric, has been shown to be effective against development of hepatic steatosis and its progression to steatohepatitis, yet these beneficial effects have not been explored in clinical practice. The aim of this study is to investigate the effects of curcumin on hepatic fat content as well as biochemical and anthropometric features of patients with NAFLD. In this randomized double-blind placebo-controlled trial, patients with ultrasonographic evidence of NAFLD were randomly assigned to receive an amorphous dispersion curcumin formulation (500 mg/day equivalent to 70-mg curcumin) or matched placebo for a period of 8 weeks. Liver fat content (assessed through ultrasonography), glycemic and lipid profile, transaminase levels, and anthropometric indices were evaluated at baseline and at the end of follow-up period. The clinical trial protocol was registered under the Iranian Registry of Clinical Trials ID: IRCT2014110511763N18. Compared with placebo, curcumin was associated with a significant reduction in liver fat content (78.9% improvement in the curcumin vs 27.5% improvement in the placebo group). There were also significant reductions in body mass index and serum levels of total cholesterol, low-density lipoprotein cholesterol, triglycerides, aspartate aminotransferase, alanine aminotransferase, glucose, and glycated hemoglobin compared with the placebo group. Curcumin was safe and well tolerated during the course of trial. Findings of the present proof-of-concept trial suggested improvement of different features of NAFLD after a short-term supplementation with curcumin. Copyright © 2016 John Wiley & Sons, Ltd.

  14. Acute side effects after dose-escalation treatment of prostate cancer using the new urethral catheter BeamCath{sup R} technique

    Energy Technology Data Exchange (ETDEWEB)

    Fransson, Per; Loefroth, P.O.; Franzen, L.; Henriksson, Roger; Bergstroem, P.; Widmark, A. [Umeaa Univ. (Sweden). Dept. of Oncology

    2001-11-01

    Acute side effects after dose-escalated radiotherapy for prostate cancer with different treatment techniques were evaluated, using a daily diary recorded by the patients. Dose escalation was performed using the urethral catheter BeamCath{sup R} (registered trade mark name) technique. Side effects were evaluated in 267 patients by means of a daily diary during the treatment and at 3-months' follow-up. The patients' evaluations were compared with those of patients treated with conventional or conformal techniques. Looser stools were reported in the conventional (placebo) and 76 Gy groups at 3-months' follow-up compared with at week 1. No other obvious increase in rectal or bladder morbidity was seen in the 76 Gy group. The catheter did not increase the urinary frequency in comparison to the other groups. The reported urgency and starting problems at the beginning of treatment seemed to improve in all groups at 3-months' follow-up. External beam radiotherapy dose escalation using the BeamCath{sup R} technique did not result in a dose-dependent increase in acute side effects.

  15. Hydrological modelling in a "big data" era: a proof of concept of hydrological models as web services

    Science.gov (United States)

    Buytaert, Wouter; Vitolo, Claudia

    2013-04-01

    Dealing with the massive increase in global data availability of all sorts is increasingly being known as "big data" science. Indeed, largely leveraged by the internet, a new resource of data sets emerges that are so large and heterogeneous that they become awkward to work with. New algorithms, methods and models are needed to filter such data to find trends, test hypotheses, make predictions and quantify uncertainties. As a considerable share of the data relate to environmental processes (e.g., satellite images, distributed sensor networks), this evolution provides exciting challenges for environmental sciences, and hydrology in particular. Web-enabled models are a promising approach to process large and distributed data sets, and to provide tailored products for a variety of end-users. It will also allow hydrological models to be used as building blocks in larger earth system simulation systems. However, in order to do so we need to reconsider the ways that hydrological models are built, results are made available, and uncertainties are quantified. We present the results of an experimental proof of concept of a hydrological modelling web-service to process heterogeneous hydrological data sets. The hydrological model itself consists of a set of conceptual model routines implemented with on a common platform. This framework is linked to global and local data sets through web standards provided by the Open Geospatial Consortium, as well as to a web interface that enables an end-user to request stream flow simulations from a self-defined location. In essence, the proof-of-concept can be seen as an implementation of the "Models of Everywhere" concept introduced by Beven in 2007. Although the setup is operational and effectively simulates stream flow, we identify several bottlenecks for optimal hydrological simulation in a web-context. The major challenges we identify are related to (1) model selection; (2) uncertainty quantification, and (3) user interaction and

  16. Investigations on hydrogen isotope ratios of endogenous urinary steroids: reference-population-based thresholds and proof-of-concept.

    Science.gov (United States)

    Piper, Thomas; Thomas, Andreas; Thevis, Mario; Saugy, Martial

    2012-09-01

    Carbon isotope ratio (CIR) analysis has been routinely and successfully used in sports drug testing for many years to uncover the misuse of endogenous steroids. One limitation of the method is the availability of steroid preparations exhibiting CIRs equal to endogenous steroids. To overcome this problem, hydrogen isotope ratios (HIR) of endogenous urinary steroids were investigated as a potential complement; results obtained from a reference population of 67 individuals are presented herein. An established sample preparation method was modified and improved to enable separate measurements of each analyte of interest where possible. From the fraction of glucuronidated steroids; pregnanediol, 16-androstenol, 11-ketoetiocholanolone, androsterone (A), etiocholanolone (E), dehydroepiandrosterone (D), 5α- and 5β-androstanediol, testosterone and epitestosterone were included. In addition, sulfate conjugates of A, E, D, epiandrosterone and 17α- and 17β-androstenediol were considered and analyzed after acidic solvolysis. The obtained results enabled the calculation of the first reference-population-based thresholds for HIR of urinary steroids that can readily be applied to routine doping control samples. Proof-of-concept was accomplished by investigating urine specimens collected after a single oral application of testosterone-undecanoate. The HIR of most testosterone metabolites were found to be significantly influenced by the exogenous steroid beyond the established threshold values. Additionally, one regular doping control sample with an extraordinary testosterone/epitestosterone ratio of 100 without suspicious CIR was subjected to the complementary methodology of HIR analysis. The HIR data eventually provided evidence for the exogenous origin of urinary testosterone metabolites. Despite further investigations on HIR being advisable to corroborate the presented reference-population-based thresholds, the developed method proved to be a new tool supporting modern

  17. Direct liquefaction proof-of-concept program: POC bench option run 01 (227-90). Final report

    Energy Technology Data Exchange (ETDEWEB)

    Comolli, A.G.; Pradhan, V.R.; Lee, T.L.K.; Karolkiewicz, W.F.; Popper, G.

    1996-05-01

    This report presents the results of bench-scale work, Bench Run PB-01, conducted under the DOE Proof of Concept-Bench Option Program in direct coal liquefaction at Hydrocarbon Technologies, Inc. in Lawrenceville, New Jersey. The Bench Run PB-01 was the first of nine runs planned under the POC Bench Option Contract between the US DOE and Hydrocarbon Technologies, Inc. The primary goal of this bench run was to evaluate the most successful of the process improvements concepts, evolving out of the earlier CMSL Project, for conventional direct liquefaction as well as coprocessing of a sub-bituminous Black Thunder mine coal with waste organics such as waste plastics and heavy resid. The interstage separation of light ends and gases was indeed found to reduce the overall light gas-make from the liquefaction process. The organic waste feeds such as mixed plastics and vacuum resid, employed during Bench Run PB-01, in combined processing with coal, resulted in making the overall process more hydrogen efficient by virtue of reducing the light gas make and also decreasing the hydrogen consumption from the process, while at the same time improving the yields and quality of the distillate products. A definite synergy was found during the combined processing of coal with mixtures of vacuum resid and mixed waste plastics. The application of an all dispersed catalyst conversion reactor resulted in higher feed throughput at equivalent process performance, but also necessitated the use of an in-line hydrotreater for improving the quality of IBP-400{degrees}C distillate products. The combination of HTI`s iron gel catalyst and Molyvan-A was found very effective in achieving high levels of process performance; although, in recycled form, these catalysts were not as effective as the freshly added precursors.

  18. Noninvasive referencing of intraocular tumors for external beam radiation therapy using optical coherence tomography: A proof of concept

    Energy Technology Data Exchange (ETDEWEB)

    Rüegsegger, Michael B.; Steiner, Patrick; Kowal, Jens H., E-mail: jens.kowal@artorg.unibe.ch [ARTORG Center for Biomedical Engineering Research, University of Bern, Bern 3010 (Switzerland); Geiser, Dominik [Berne University of Applied Sciences, HuCE OptoLab, 2501 (Switzerland); Pica, Alessia; Aebersold, Daniel M. [Department of Radiation Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3010 (Switzerland)

    2014-08-15

    Purpose: External beam radiation therapy is currently considered the most common treatment modality for intraocular tumors. Localization of the tumor and efficient compensation of tumor misalignment with respect to the radiation beam are crucial. According to the state of the art procedure, localization of the target volume is indirectly performed by the invasive surgical implantation of radiopaque clips or is limited to positioning the head using stereoscopic radiographies. This work represents a proof-of-concept for direct and noninvasive tumor referencing based on anterior eye topography acquired using optical coherence tomography (OCT). Methods: A prototype of a head-mounted device has been developed for automatic monitoring of tumor position and orientation in the isocentric reference frame for LINAC based treatment of intraocular tumors. Noninvasive tumor referencing is performed with six degrees of freedom based on anterior eye topography acquired using OCT and registration of a statistical eye model. The proposed prototype was tested based on enucleated pig eyes and registration accuracy was measured by comparison of the resulting transformation with tilt and torsion angles manually induced using a custom-made test bench. Results: Validation based on 12 enucleated pig eyes revealed an overall average registration error of 0.26 ± 0.08° in 87 ± 0.7 ms for tilting and 0.52 ± 0.03° in 94 ± 1.4 ms for torsion. Furthermore, dependency of sampling density on mean registration error was quantitatively assessed. Conclusions: The tumor referencing method presented in combination with the statistical eye model introduced in the past has the potential to enable noninvasive treatment and may improve quality, efficacy, and flexibility of external beam radiotherapy of intraocular tumors.

  19. Quantitative Tracking of Salmonella Enteritidis Transmission Routes Using Barcode-Tagged Isogenic Strains in Chickens: Proof-of-Concept Study

    Science.gov (United States)

    Yang, Yichao; Ricke, Steven C.; Tellez, Guillermo; Kwon, Young Min

    2017-01-01

    Salmonella is an important foodborne bacterial pathogen, however, a fundamental understanding on Salmonella transmission routes within a poultry flock remains unclear. In this study, a series of barcode-tagged strains were constructed by inserting six random nucleotides into a functionally neutral region on the chromosome of S. Enteritidis as a tool for quantitative tracking of Salmonella transmission in chickens. Six distinct barcode-tagged strains were used for infection or contamination at either low dose (103 CFUs; three strains) or high dose (105 CFUs; three strains) in three independent experiments (Experiment 1 oral gavage; Experiment 2 contaminated feed; Experiment 3 contaminated water). For all chick experiments, cecal and foot-wash samples were collected from a subset of the chickens at days 7 or/and 14, from which genomic DNA was extracted and used to amplify the barcode regions. After the resulting PCR amplicons were pooled and analyzed by MiSeq sequencing, a total of approximately 1.5 million reads containing the barcode sequences were analyzed to determine the relative frequency of every barcode-tagged strain in each sample. In Experiment 1, the high dose of oral infection was correlated with greater dominance of the strains in the ceca of the respective seeder chickens and also in the contact chickens yet at lesser degrees. When chicks were exposed to contaminated feed (Experiment 2) or water (Experiment 3), there were no clear patterns of the barcode-tagged strains in relation to the dosage, except that the strains introduced at low dose required a longer time to colonize the ceca with contaminated feed. Most foot-wash samples contained only one to three strains for the majority of the samples, suggesting potential existence of an unknown mechanism(s) for strain exclusion. These results demonstrated the proof of concept of using barcode tagged to investigate transmission dynamics of Salmonella in chickens in a quantitative manner. PMID:28261587

  20. Integrating health education and physical activity programming for cardiovascular health promotion among female inmates: A proof of concept study.

    Science.gov (United States)

    Nair, Uma S; Jordan, Jeremy S; Funk, Daniel; Gavin, Kristin; Tibbetts, Erica; Collins, Bradley N

    2016-05-01

    Female inmate populations in the United States tend to be overweight, physically inactive, experience high stress, and have a history of nicotine and other drug dependence. Thus, they bear an elevated risk of cardiovascular (CV) disease than the general population. However, few evidence-based health interventions exist for this population. This study will test proof of concept, feasibility, and potential efficacy of a multiple health behavior change intervention that integrates CV-health promotion education delivered during a physical activity (PA) program (indoor cycling) tailored to this population. This study uses a quasi-experimental 2-group design with two measurement time-points: baseline and 8-week end of treatment. N=120 incarcerated women (18-59years of age) who are medically cleared for participation in PA will be enrolled. Indoor cycling instructors will be trained to deliver five health education topics over an 8-week period during twice-weekly cycling classes. Topics match the American Heart Association recommendations for CV health: (a) nutrition, (b) PA promotion, (c) weight management, (d) stress management, and (e) smoking cessation and relapse prevention. Modes of intervention include instructor advice, written materials and audio/video clips reviewed during class. CV-related and mental health measures will be assessed at both time-points. Results will guide a full scale efficacy study. Future research in this area has potential to impact the health of female inmates, a high-risk population. Moreover, this multiple health behavior change intervention model represents a community approach to health promotion that could generalize to other underserved populations who may benefit most from similar intervention efforts.

  1. Chimeric proteins combining phosphatase and cellulose-binding activities: proof-of-concept and application in the hydrolysis of paraoxon.

    Science.gov (United States)

    Gonçalves, Larissa M; Chaimovich, Hernan; Cuccovia, Iolanda M; Marana, Sandro R

    2014-05-01

    Phosphatases for organophosphate degradation and carbohydrate-binding domains (CBMs) have potential biotechnological applications. As a proof-of-concept, a soluble chimeric protein that combines acid phosphatase (AppA) from Escherichia coli and a CBM from Xanthomonas axonopodis pv. citri (AppA-CBM) was produced in E.coli. AppACBM adsorbed in microcrystalline cellulose Avicel PH101 catalyzed the hydrolysis of p-nitrophenyl phosphate (PNPP). The binding to microcrystalline cellulose displayed saturation behavior with an apparent binding constant (Kb) of 22 ± 5 mg and a maximum binding (Bmax) of 1.500 ± 0.001 enzyme units. Binding was highest at pH 2.5 and decreased above pH 6.5, as previously observed for family 2 CBMs. The Km values for PNPP of AppA-CBM and native AppA were identical (2.7 mM). To demonstrate that this strategy for protein engineering has practical applications and is largely functional, even for phosphatases exhibiting diverse folds, a chimeric protein combining human paraoxonase 1 (hPON1) and the CBM was produced. Both PON1-CBM and hPON1 had identical Km values for paraoxon (1.3 mM). Additionally, hPON1 bound to microcrystalline cellulose with a Kb of 27 ± 3 mg, the same as that observed for AppA-CBM. These data show that the phosphatase domains are as functional in both of the chimeric proteins as they are in the native enzymes and that the CBM domain maintains the same cellulose affinity. Therefore, the engineering of chimeric proteins combining domains of phosphatases and CBMs is fully feasible, resulting in chimeric enzymes that exhibit potential for OP detoxification.

  2. Technical Note: Motion-perturbation method applied to dosimetry of dynamic MLC target tracking—A proof-of-concept

    Energy Technology Data Exchange (ETDEWEB)

    Feygelman, Vladimir, E-mail: vladimir.feygelman@moffitt.org; Tonner, Brian; Hunt, Dylan; Zhang, Geoffrey; Moros, Eduardo [Department of Radiation Oncology, Moffitt Cancer Center, Tampa, Florida 33612 (United States); Stambaugh, Cassandra [Department of Physics, University of South Florida, Tampa, Florida 33612 (United States); Nelms, Benjamin E. [Canis Lupus LLC, Merrimac, Wisconsin 53561 (United States)

    2015-11-15

    Purpose: Previous studies show that dose to a moving target can be estimated using 4D measurement-guided dose reconstruction based on a process called virtual motion simulation, or VMS. A potential extension of VMS is to estimate dose during dynamic multileaf collimator (MLC)-tracking treatments. The authors introduce a modified VMS method and quantify its performance as proof-of-concept for tracking applications. Methods: Direct measurements with a moving biplanar diode array were used to verify accuracy of the VMS dose estimates. A tracking environment for variably sized circular MLC apertures was simulated by sending preprogrammed control points to the MLC while simultaneously moving the accelerator treatment table. Sensitivity of the method to simulated tracking latency (0–700 ms) was also studied. Potential applicability of VMS to fast changing beam apertures was evaluated by modeling, based on the demonstrated dependence of the cumulative dose on the temporal dose gradient. Results: When physical and virtual latencies were matched, the agreement rates (2% global/2 mm gamma) between the VMS and the biplanar dosimeter were above 96%. When compared to their own reference dose (0 induced latency), the agreement rates for VMS and biplanar array track closely up to 200 ms of induced latency with 10% low-dose cutoff threshold and 300 ms with 50% cutoff. Time-resolved measurements suggest that even in the modulated beams, the error in the cumulative dose introduced by the 200 ms VMS time resolution is not likely to exceed 0.5%. Conclusions: Based on current results and prior benchmarks of VMS accuracy, the authors postulate that this approach should be applicable to any MLC-tracking treatments where leaf speeds do not exceed those of the current Varian accelerators.

  3. Proof-of-Concept of a Networked Validation Environment for Distributed Air/Ground NextGen Concepts

    Science.gov (United States)

    Grisham, James; Larson, Natalie; Nelson, Justin; Reed, Joshua; Suggs, Marvin; Underwood, Matthew; Papelis, Yiannis; Ballin, Mark G.

    2013-01-01

    The National Airspace System (NAS) must be improved to increase capacity, reduce flight delays, and minimize environmental impacts of air travel. NASA has been tasked with aiding the Federal Aviation Administration (FAA) in NAS modernization. Automatic Dependent Surveillance-Broadcast (ADS-B) is an enabling technology that is fundamental to realization of the Next Generation Air Transportation System (NextGen). Despite the 2020 FAA mandate requiring ADS-B Out equipage, airspace users are lacking incentives to equip with the requisite ADS-B avionics. A need exists to validate in flight tests advanced concepts of operation (ConOps) that rely on ADS-B and other data links without requiring costly equipage. A potential solution is presented in this paper. It is possible to emulate future data link capabilities using the existing in-flight Internet and reduced-cost test equipment. To establish proof-of-concept, a high-fidelity traffic operations simulation was modified to include a module that simulated Internet transmission of ADS-B messages. An advanced NASA ConOp, Flight Deck Interval Management (FIM), was used to evaluate technical feasibility. A preliminary assessment of the effects of latency and dropout rate on FIM was performed. Flight hardware that would be used by proposed test environment was connected to the simulation so that data transfer from aircraft systems to test equipment could be verified. The results indicate that the FIM ConOp, and therefore, many other advanced ConOps with equal or lesser response characteristics and data requirements, can be evaluated in flight using the proposed concept.

  4. Semi-empirical models for chlorine activation and ozone depletion in the Antarctic stratosphere: proof of concept

    Directory of Open Access Journals (Sweden)

    P. E. Huck

    2012-10-01

    Full Text Available Two semi-empirical models were developed for the Antarctic stratosphere to relate the shift of species within total chlorine (Cly = HCl + ClONO2 + HOCl + 2 × Cl2 + 2 × Cl2O2 + ClO + Cl into the active forms (here: ClOx = 2 × Cl2O2 + ClO, and to relate the rate of ozone destruction to ClOx. These two models provide a fast and computationally inexpensive way to describe the inter- and intra-annual evolution of ClOx and ozone mass deficit (OMD in the Antarctic spring. The models are based on the underlying physics/chemistry of the system and capture the key chemical and physical processes in the Antarctic stratosphere that determine the interaction between climate change and Antarctic ozone depletion. They were developed considering bulk effects of chemical mechanisms for the duration of the Antarctic vortex period and quantities averaged over the vortex area. The model equations were regressed against observations of daytime ClO and OMD providing a set of empirical fit coefficients. Both semi-empirical models are able to explain much of the intra- and inter-annual variability observed in daily ClOx and OMD time series. This proof-of-concept paper outlines the semi-empirical approach to describing the evolution of Antarctic chlorine activation and ozone depletion.

  5. Using ambulatory virtual environments for the assessment of functional gait impairment: a proof-of-concept study.

    Science.gov (United States)

    Gérin-Lajoie, Martin; Ciombor, Deborah McK; Warren, William H; Aaron, Roy K

    2010-04-01

    This study aimed to demonstrate the sensitivity of virtual reality (VR)/motion tracking to detect global functional gait impairment resulting from an emulated knee disability as a prelude to describing mobility changes following lower limb injury/treatment. Participants walked in a figure-8 around two virtual posts placed 6m apart while viewing the computer-generated environment in a helmet-mounted display. Three-dimensional position and orientation of the participant's head were tracked and used to update the virtual scenes, measure walking path and speed, and control task parameters with real-time feedback. Participants walked with/without an emulated lower extremity disability (splint preventing normal knee flexion). Participants performed the task at self-selected Natural (NAT) speed providing a baseline measure of their turning speed and area. Turning speed and area were then in turn maintained fixed (controlled speed, CS; controlled path, CP) while the other variable was measured as a gait impairment indicator. Different adaptive strategies were used to cope with the emulated deficit during the NAT scenario: maintaining turning speed while altering path geometry; decreasing turning speed while maintaining path geometry; and combining the previous two strategies. This resulted, on average, in decreased turning speeds and increased turning areas. The CS and CP manipulations respectively generated even greater turning areas and more consistent speed decreases. The three subtests acted as intertwined filters enabling the detection of functional gait impairment in all subjects regardless of their adaptive strategies. This proof-of-concept study demonstrated how VR/motion tracking technology can be used to detect and quantitatively characterize global functional mobility impairment.

  6. Technical Note: Motion-perturbation method applied to dosimetry of dynamic MLC target tracking--A proof-of-concept.

    Science.gov (United States)

    Feygelman, Vladimir; Tonner, Brian; Stambaugh, Cassandra; Hunt, Dylan; Zhang, Geoffrey; Moros, Eduardo; Nelms, Benjamin E

    2015-11-01

    Previous studies show that dose to a moving target can be estimated using 4D measurement-guided dose reconstruction based on a process called virtual motion simulation, or VMS. A potential extension of VMS is to estimate dose during dynamic multileaf collimator (MLC)-tracking treatments. The authors introduce a modified VMS method and quantify its performance as proof-of-concept for tracking applications. Direct measurements with a moving biplanar diode array were used to verify accuracy of the VMS dose estimates. A tracking environment for variably sized circular MLC apertures was simulated by sending preprogrammed control points to the MLC while simultaneously moving the accelerator treatment table. Sensitivity of the method to simulated tracking latency (0-700 ms) was also studied. Potential applicability of VMS to fast changing beam apertures was evaluated by modeling, based on the demonstrated dependence of the cumulative dose on the temporal dose gradient. When physical and virtual latencies were matched, the agreement rates (2% global/2 mm gamma) between the VMS and the biplanar dosimeter were above 96%. When compared to their own reference dose (0 induced latency), the agreement rates for VMS and biplanar array track closely up to 200 ms of induced latency with 10% low-dose cutoff threshold and 300 ms with 50% cutoff. Time-resolved measurements suggest that even in the modulated beams, the error in the cumulative dose introduced by the 200 ms VMS time resolution is not likely to exceed 0.5%. Based on current results and prior benchmarks of VMS accuracy, the authors postulate that this approach should be applicable to any MLC-tracking treatments where leaf speeds do not exceed those of the current Varian accelerators.

  7. Photodynamic Therapy treatment of onychomycosis with Aluminium-Phthalocyanine Chloride nanoemulsions: A proof of concept clinical trial.

    Science.gov (United States)

    Morgado, Luciano Ferreira; Trávolo, Ana Regina Franchi; Muehlmann, Luís Alexandre; Narcizo, Paulo Souza; Nunes, Rodrigo Barbosa; Pereira, Pedro Alencar Gomes; Py-Daniel, Karen Rapp; Jiang, Cheng-Shi; Gu, Jinsong; Azevedo, Ricardo Bentes; Longo, João Paulo Figueiró

    2017-08-01

    The conventional treatment of onychomycosis, a common fungal infection, consists in the use of local and systemic drugs for 4-6 months. This long protocol is often ineffective due to patient compliance, and usually promotes important collateral effects such as liver and kidney failure. As the alternative, Photodynamic Therapy (PDT) has been used as a noninvasive alternative local treatment for onychomycosis due to the reduction of systemic side effects, fact indicates their use for patients undergoing other systemic treatments. In the present article, we evaluated the effectiveness, as well as the safety of PDT mediated by Aluminium-Phthalocyanine Chloride, entrapped in nanoemulsions, as a drug carrier, to treat onychomycosis in a proof of concept clinical trial. To the date, this is the first published clinical trial that uses PDT mediated by nanomedicines to treat onychomycosis. As main results, we can highlight the safety of the clinical protocol and the antifungal effectiveness similar to the conventional treatments. We observed the (1) clinical cure of 60% of treated lesions; (2) the absence of local and systemic adverse effects; (3) from these clinically healed lesions, 40% were negative for fungal infection in laboratorial exams; and (4) nails that presented negative fungal culture were kept without fungal infection for at least four weeks. The innovation of this approach is the absence of collateral effects, due to the local therapeutically treatment, and the possibility to repeat the treatment without inducing fungal resistance, a fact that indicates this approach as a possible alternative protocol for onychomycosis management. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Selection of reliable biomarkers from PCR array analyses using relative distance computational model: methodology and proof-of-concept study.

    Directory of Open Access Journals (Sweden)

    Chunsheng Liu

    Full Text Available It is increasingly evident about the difficulty to monitor chemical exposure through biomarkers as almost all the biomarkers so far proposed are not specific for any individual chemical. In this proof-of-concept study, adult male zebrafish (Danio rerio were exposed to 5 or 25 µg/L 17β-estradiol (E2, 100 µg/L lindane, 5 nM 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or 15 mg/L arsenic for 96 h, and the expression profiles of 59 genes involved in 7 pathways plus 2 well characterized biomarker genes, vtg1 (vitellogenin1 and cyp1a1 (cytochrome P450 1A1, were examined. Relative distance (RD computational model was developed to screen favorable genes and generate appropriate gene sets for the differentiation of chemicals/concentrations selected. Our results demonstrated that the known biomarker genes were not always good candidates for the differentiation of pair of chemicals/concentrations, and other genes had higher potentials in some cases. Furthermore, the differentiation of 5 chemicals/concentrations examined were attainable using expression data of various gene sets, and the best combination was the set consisting of 50 genes; however, as few as two genes (e.g. vtg1 and hspa5 [heat shock protein 5] were sufficient to differentiate the five chemical/concentration groups in the present test. These observations suggest that multi-parameter arrays should be more reliable for biomonitoring of chemical exposure than traditional biomarkers, and the RD computational model provides an effective tool for the selection of parameters and generation of parameter sets.

  9. Selection of reliable biomarkers from PCR array analyses using relative distance computational model: methodology and proof-of-concept study.

    Science.gov (United States)

    Liu, Chunsheng; Xu, Hongyan; Lam, Siew Hong; Gong, Zhiyuan

    2013-01-01

    It is increasingly evident about the difficulty to monitor chemical exposure through biomarkers as almost all the biomarkers so far proposed are not specific for any individual chemical. In this proof-of-concept study, adult male zebrafish (Danio rerio) were exposed to 5 or 25 µg/L 17β-estradiol (E2), 100 µg/L lindane, 5 nM 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or 15 mg/L arsenic for 96 h, and the expression profiles of 59 genes involved in 7 pathways plus 2 well characterized biomarker genes, vtg1 (vitellogenin1) and cyp1a1 (cytochrome P450 1A1), were examined. Relative distance (RD) computational model was developed to screen favorable genes and generate appropriate gene sets for the differentiation of chemicals/concentrations selected. Our results demonstrated that the known biomarker genes were not always good candidates for the differentiation of pair of chemicals/concentrations, and other genes had higher potentials in some cases. Furthermore, the differentiation of 5 chemicals/concentrations examined were attainable using expression data of various gene sets, and the best combination was the set consisting of 50 genes; however, as few as two genes (e.g. vtg1 and hspa5 [heat shock protein 5]) were sufficient to differentiate the five chemical/concentration groups in the present test. These observations suggest that multi-parameter arrays should be more reliable for biomonitoring of chemical exposure than traditional biomarkers, and the RD computational model provides an effective tool for the selection of parameters and generation of parameter sets.

  10. Working with parents to treat anxiety-disordered children: A proof of concept RCT evaluating Fear-less Triple P.

    Science.gov (United States)

    Cobham, Vanessa E; Filus, Ania; Sanders, Matthew R

    2017-08-01

    Little is known about the efficacy of parent-only interventions and the maintenance of gains over time with anxiety-disordered children and adolescents. The current study aimed to evaluate the efficacy of a 6-session parent-focused intervention (Fear-less Triple P) in reducing children's anxiety symptomatology. The parents of 61 anxiety-disordered children (7-14 years) were randomly assigned to either the 6-session parent-only group CBT intervention or a wait-list control (WL) group. Diagnostic and questionnaire measures were administered at post-treatment; as well as 3-, 6- and 12 months following the completion of treatment. Families in the WL group were re-assessed after 6 weeks (the duration of the active intervention) and were then offered the intervention. The parent-only intervention produced superior outcomes for children on diagnostic and questionnaire measures. The percentages of children free of any anxiety diagnosis following the intervention were 38.7% (post-treatment); 58.6% (3-mth); 69.2% (6-mth); and 84% (12-mth). At the post-treatment assessment point, 3.4% of children in the WL group were free of any anxiety diagnosis. Mother and child questionnaire measures demonstrated gains from pre to post-treatment that were maintained over time. This proof of concept study suggests that the brief, parent-only intervention evaluated is an efficacious treatment approach for child anxiety disorders. A parent-only, group CBT intervention such as the one described here offers a cost-effective, low intensity alternative to traditional child-focused interventions. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Determining the adenoma detection rate and adenomas per colonoscopy by photography alone: proof-of-concept study.

    Science.gov (United States)

    Rex, Douglas K; Hardacker, Kyle; MacPhail, Margaret; Rahmani, Farrah; Vemulapalli, Krishna C; Kahi, Charles J

    2015-03-01

    The adenoma detection rate (ADR) and adenomas detected per colonoscopy (APC) are measures of the quality of mucosal inspection during colonoscopy. In a resect and discard policy, pathologic assessment for calculation of ADR and APC would not be available. The aim of this study was to determine whether ADR and APC calculation based on photography alone is adequate compared with the pathology-based gold standard. A prospective, observational, proof-of-concept study was performed in an academic endoscopy unit. High definition photographs of consecutive polyps were taken, and pathology was estimated by the colonoscopist. Among 121 consecutive patients aged ≥ 50 years who underwent colonoscopy, 268 polyps were removed from 97 patients. Photographs of consecutive polyps were reviewed by a second endoscopist. The resect and discard policy applied to lesions that were ≤ 5 mm in size. When only photographs of lesions that were ultimately proven to be adenomas were included, the reviewer assessed ADR and APC to be lower than that determined by pathology (absolute reductions of 6.6 % and 0.17, and relative reductions of 12.6 % and 13.1 % in ADR and APC, respectively). When all photographs were included for calculation of ADR and APC, the reviewer determined the ADR to be 3.3 % lower (absolute reduction) and the APC to be the same as the rates determined by pathology. In a simulated resect and discard strategy, a high-level detector can document adequate ADR and APC by photography alone. © Georg Thieme Verlag KG Stuttgart · New York.

  12. Accelerating the commercialization of university technologies for military healthcare applications: the role of the proof of concept process

    Science.gov (United States)

    Ochoa, Rosibel; DeLong, Hal; Kenyon, Jessica; Wilson, Eli

    2011-06-01

    The von Liebig Center for Entrepreneurism and Technology Advancement at UC San Diego (vonliebig.ucsd.edu) is focused on accelerating technology transfer and commercialization through programs and education on entrepreneurism. Technology Acceleration Projects (TAPs) that offer pre-venture grants and extensive mentoring on technology commercialization are a key component of its model which has been developed over the past ten years with the support of a grant from the von Liebig Foundation. In 2010, the von Liebig Entrepreneurism Center partnered with the U.S. Army Telemedicine and Advanced Technology Research Center (TATRC), to develop a regional model of Technology Acceleration Program initially focused on military research to be deployed across the nation to increase awareness of military medical needs and to accelerate the commercialization of novel technologies to treat the patient. Participants to these challenges are multi-disciplinary teams of graduate students and faculty in engineering, medicine and business representing universities and research institutes in a region, selected via a competitive process, who receive commercialization assistance and funding grants to support translation of their research discoveries into products or services. To validate this model, a pilot program focused on commercialization of wireless healthcare technologies targeting campuses in Southern California has been conducted with the additional support of Qualcomm, Inc. Three projects representing three different universities in Southern California were selected out of forty five applications from ten different universities and research institutes. Over the next twelve months, these teams will conduct proof of concept studies, technology development and preliminary market research to determine the commercial feasibility of their technologies. This first regional program will help build the needed tools and processes to adapt and replicate this model across other regions in the

  13. A proof-of-concept study on the combination of repetitive transcranial magnetic stimulation and relaxation techniques in chronic tinnitus.

    Science.gov (United States)

    Kreuzer, Peter M; Poeppl, Timm B; Bulla, Jan; Schlee, Winfried; Lehner, Astrid; Langguth, Berthold; Schecklmann, Martin

    2016-10-01

    Interference of ongoing neuronal activity and brain stimulation motivated this study to combine repetitive transcranial magnetic stimulation (rTMS) and relaxation techniques in tinnitus patients. Forty-two patients were enrolled in this one-arm proof-of-concept study to receive ten sessions of rTMS applied to the left dorsolateral prefrontal cortex and temporo-parietal cortex. During stimulation, patients listened to five different kinds of relaxation audios. Variables of interest were tinnitus questionnaires, tinnitus numeric rating scales, depressivity, and quality of life. Results were compared to results of historical control groups having received the same rTMS protocol (active control) and sham treatment (placebo) without relaxation techniques. Thirty-eight patients completed the treatment, drop-out rates and adverse events were low. Responder rates (reduction in tinnitus questionnaire (TQ) score ≥5 points 10 weeks after treatment) were 44.7 % in the study, 27.8 % in the active control group, and 21.7 % in the placebo group, differing between groups on a near significant level. For the tinnitus handicap inventory (THI), the main effect of group was not significant. However, linear mixed model analyses showed that the relaxation/rTMS group differed significantly from the active control group showing steeper negative THI trend for the relaxation/rTMS group indicating better amelioration over the course of the trial. Deepness of relaxation during rTMS and selection of active relaxation vs. passive listening to music predicted larger TQ. All remaining secondary outcomes turned out non-significant. This combined treatment proved to be a safe, feasible and promising approach to enhance rTMS treatment effects in chronic tinnitus.

  14. Mindfulness and Metta-based Trauma Therapy (MMTT): Initial Development and Proof-of-Concept of an Internet Resource.

    Science.gov (United States)

    Frewen, Paul; Rogers, Nicholas; Flodrowski, Les; Lanius, Ruth

    Trauma and stressor-related disorders, including post-traumatic stress disorder (PTSD) and related comorbid disorders such as anxiety, depression, and dissociative disorders, are difficult to treat. Mindfulness-based clinical interventions have proven efficacy for mental health treatment in face-to-face individual and group modalities, although the feasibility and efficacy of delivering these interventions via the internet has not been evaluated. The present research developed mindfulness and metta-based trauma therapy (MMTT) as an internet resource to support the practice of mindfulness and metta (lovingkindness) meditations for self-regulation and healing from trauma and stressor-related disorders. In the present "proof-of-concept" study, research participants (n = 177) recruited online practiced mindfulness and metta meditations and related therapeutic exercises available via the website and rated their perceived credibility as interventions for improving self-regulation and well-being and reducing PTSD symptoms, anxiety, depressive, and dissociative experiences, as well as their experienced ease, helpfulness, and informational value. Results suggest that, independent of level of self-reported current and past psychiatric history and PTSD symptoms, participants considered the MMTT website as a credible and helpful therapeutic intervention for improving self-regulation and well-being and reducing PTSD, anxiety, depression, and dissociation. Overall, participants considered guided and non-guided meditation practices more helpful than a journaling exercise, and participants with increased PTSD symptoms preferred metta (lovingkindness) meditations less than other participants. We conclude that MMTT should be piloted in clinical trials as an adjunctive intervention to evidence-based treatments for persons with mood, anxiety, and trauma and stressor-related disorders, as well as more generally as an online resource to support self-regulation and well

  15. Using peer observers to assess the quality of cancer multidisciplinary team meetings: a qualitative proof of concept study

    Science.gov (United States)

    Harris, Jenny; Green, James SA; Sevdalis, Nick; Taylor, Cath

    2014-01-01

    Background Multidisciplinary team (MDT) working is well established as the foundation for providing cancer services in the UK and elsewhere. A core activity is the weekly meeting (or case conference/tumor boards) where the treatment recommendations for individual patients are agreed. Evidence suggests that the quality of team working varies across cancer teams, and this may impact negatively on the decision-making process, and ultimately patient care. Feedback on performance by expert observers may improve performance, but can be resource-intensive to implement. This proof of concept study sought to: develop a structured observational assessment tool for use by peers (managers or clinicians from the local workforce) and explore its usability; assess the feasibility of the principle of observational assessment by peers; and explore the views of MDT members and observers about the utility of feedback from observational assessment. Methods For tool development, the content was informed by national clinical consensus recommendations for best practice in cancer MDTs and developed in collaboration with an expert steering group. It consisted of ten subdomains of team working observable in MDT meetings that were rated on a 10-point scale (very poor to very good). For observational assessment, a total of 19 peer observers used the tool (assessing performance in 20 cancer teams from four hospitals). For evaluation, telephone interviews with 64 team members and all peer observers were analyzed thematically. Results The tool was easy to use and areas for refinement were identified. Peer observers were identified and most indicated that undertaking observation was feasible. MDT members generally reported that observational assessment and feedback was useful, with the potential to facilitate improvements in team working. Conclusion This study suggests that observation and feedback by peers may provide a feasible and acceptable approach to enhance MDT performance. Further tool

  16. Ciclosporin A proof of concept study in patients with active, progressive HTLV-1 associated myelopathy/tropical spastic paraparesis.

    Directory of Open Access Journals (Sweden)

    Fabiola Martin

    Full Text Available INTRODUCTION: Patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP become progressively impaired, with chronic pain, immobility and bladder, bowel and sexual dysfunction. Tested antiretroviral therapies have not been effective and most patients are offered a short course of corticosteroids or interferon-α, physiotherapy and symptomatic management. Pathogenesis studies implicate activated T-lymphocytes and cytokines in tissue damage. We therefore tested the hypothesis that inhibition of T-cell activation with ciclosporin A would be safe and clinically beneficial in patients with early and/or clinically progressing HAM/TSP. MATERIALS AND METHODS: Open label, proof of concept, pilot study of 48 weeks therapy with the calcineurin antagonist, ciclosporin A (CsA, in seven patients with 'early' (50% deterioration in timed walk during the preceding three months HAM/TSP. Primary outcomes were incidence of clinical failure at 48 weeks and time to clinical failure. RESULTS: All patients completed 72 weeks study participation and five showed objective evidence of clinical improvement after 3 months treatment with CsA. Two patients exhibited clinical failure over 6.4 person-years of follow-up to week 48. One patient had a >2 point deterioration in IPEC (Insituto de Pesquisa Clinica Evandro Chagas disability score at weeks 8 and 12, and then stopped treatment. The other stopped treatment at week 4 because of headache and tremor and deterioration in timed walk, which occurred at week 45. Overall pain, mobility, spasticity and bladder function improved by 48 weeks. Two patients recommenced CsA during follow-up due to relapse. CONCLUSIONS: These data provide initial evidence that treatment with CsA is safe and may partially reverse the clinical deterioration seen in patients with early/progressive HAM/TSP. This trial supports further investigation of this agent's safety and effectiveness in larger, randomised controlled studies in

  17. Design of a complex virtual reality simulation to train finger motion for persons with hemiparesis: a proof of concept study.

    Science.gov (United States)

    Adamovich, Sergei V; Fluet, Gerard G; Mathai, Abraham; Qiu, Qinyin; Lewis, Jeffrey; Merians, Alma S

    2009-07-17

    Current neuroscience has identified rehabilitation approaches with the potential to stimulate adaptive changes in the brains of persons with hemiparesis. These approaches include, intensive task-oriented training, bimanual activities and balancing proximal and distal upper extremity interventions to reduce competition between these segments for neural territory. This paper describes the design and feasibility testing of a robotic/virtual environment system designed to train the hand and arm of persons with hemiparesis. The system employs a simulated piano that presents visual, auditory and tactile feedback comparable to an actual piano. Arm tracking allows patients to train both the arm and hand as a coordinated unit, emphasizing the integration of both transport and manipulation phases. The piano trainer includes songs and scales that can be performed with one or both hands. Adaptable haptic assistance is available for more involved subjects. An algorithm adjusts task difficulty in proportion to subject performance. A proof of concept study was performed on four subjects with upper extremity hemiparesis secondary to chronic stroke to establish: a) the safety and feasibility of this system and b) the concurrent validity of robotically measured kinematic and performance measures to behavioral measures of upper extremity function. None of the subjects experienced adverse events or responses during or after training. As a group, the subjects improved in both performance time and key press accuracy. Three of the four subjects demonstrated improvements in fractionation, the ability to move each finger individually. Two subjects improved their aggregate time on the Jebsen Test of Hand Function and three of the four subjects improved in Wolf Motor Function Test aggregate time. The system designed in this paper has proven to be safe and feasible for the training of hand function for persons with hemiparesis. It features a flexible design that allows for the use and further

  18. Hypofractionated Dose Escalated 3D Conformal Radiotherapy for Prostate Cancer: Outcomes from a Mono-Institutional Phase II Study.

    Science.gov (United States)

    Tramacere, Francesco; Arcangeli, Stefano; Pignatelli, Antonietta; Castagna, Roberta; Portaluri, Maurizio

    2015-05-01

    (bNED) was 83% for all patients. Our study confirms that 3D conformal radiotherapy (3DCRT) remains a safe and effective method to deliver a dose-escalated hypofractionated regimen for PCa patients in all risk classes with acceptable toxicity rates and optimal biochemical control. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  19. Limits of dose escalation in lung cancer: a dose-volume histogram analysis comparing coplanar and non-coplanar techniques

    Energy Technology Data Exchange (ETDEWEB)

    Derycke, S.; Van Duyse, B.; Schelfhout, J.; De Neve, W.

    1995-12-01

    To evaluate the feasibility of dose escalation in radiotherapy of inoperable lung cancer, a dose-volume histogram analysis was performed comparing standard coplanar (2D) with non-coplanar (3D) beam arrangements on a non-selected group of 20 patients planned by Sherouse`s GRATISTM 3D-planning system. Serial CT-scanning was performed and 2 Target Volumes (Tvs) were defined. Gross Tumor Volume (GTV) defined a high-dose Target Volume (TV-1). GTV plus location of node stations with > 10% probability of invasion (Minet et al.) defined an intermediate-dose Target Volume (TV-2). However, nodal regions which are incompatible with cure were excluded from TV-2. These are ATS-regions 1, 8, 9 and 14 all left and right as well as heterolateral regions. For 3D-planning, Beam`s Eye View selected (by an experienced planner) beam arrangements were optimised using Superdot, a method of target dose-gradient annihilation developed by Sherouse. A second 3D-planning was performed using 4 beam incidences with maximal angular separation. The linac`s isocenter for the optimal arrangement was located at the geometrical center of gravity of a tetraheder, the tetraheder`s comers being the consecutive positions of the virtual source. This ideal beam arrangement was approximated as close as possible, taking into account technical limitations (patient-couch-gantry collisions). Criteria for tolerance were met if no points inside the spinal cord exceeded 50 Gy and if at least 50% of the lung volume received less than 20Gy. If dose regions below 50 Gy were judged acceptable at TV-2, 2D- as well as 3D-plans allow safe escalation to 80 Gy at TV-1. When TV-2 needed to be encompassed by isodose surfaces exceeding 50Gy, 3D-plans were necessary to limit dose at the spinal cord below tolerance. For large TVs dose is limited by lung tolerance for 3D-plans. An analysis (including NTCP-TCP as cost functions) of rival 3D-plans is being performed.

  20. Dose escalation of the hypoxic cell sensitizer etanidazole combined with ifosfamide, carboplatin, etoposide, and autologous hematopoietic stem cell support.

    Science.gov (United States)

    Elias, A D; Wheeler, C; Ayash, L J; Schwartz, G; Ibrahim, J; Mills, L; McCauley, M; Coleman, N; Warren, D; Schnipper, L; Antman, K H; Teicher, B A; Frei, E

    1998-06-01

    Multiple mechanisms of drug resistance contribute to treatment failure. Although high-dose therapy attempts to overwhelm these defenses pharmacologically, this approach is only successful in a fraction of treated patients. Many drug resistance mechanisms are shared between malignant and normal cells, but the expression of various drug resistance mechanisms associated with hypoxia is largely confined to tumor tissue. Thus, reversal of this mechanism is likely to provide a therapeutic advantage to the host. This study was designed to define the dose-limiting toxicities and maximum tolerated dose of etanidazole when it is given concurrently with high-dose ifosfamide, carboplatin, and etoposide (ICE), with hematopoietic stem cell support. The maximum tolerated doses of high-dose ICE were administered concurrently with dose escalations of etanidazole, a hypoxic cell sensitizer. All agents were given by 96-h continuous i.v. infusion beginning on day -7. Mesna uroprotection was provided. Autologous marrow and cytokine mobilized peripheral blood progenitor cells were reinfused on day 0. Granulocyte colony-stimulating factor was administered following reinfusion until the granulocytes recovered to > 1000/microliter. Fifty-five adults with advanced malignancies were enrolled in cohorts of five to nine patients. Four dose levels of etanidazole between 3 and 5.5 g/m2/day (12, 16, 20, and 22 g/m2 total doses) and two doses of carboplatin (1600 and 1800 mg/m2 total doses) were evaluated. Seven patients died of organ toxicity (13%); two each from veno-occlusive disease of liver and sepsis; and one each from sudden death, renal failure, and refractory thrombocytopenic hemorrhage. Five deaths occurred at the top dose level. One additional patient suffered a witnessed cardiorespiratory arrest from ventricular fibrillation and was resuscitated. Dose-dependent and largely reversible peripheral neuropathy was observed consisting of two syndromes: severe cramping myalgic/neuralgic pain

  1. Vorinostat and Concurrent Stereotactic Radiosurgery for Non-Small Cell Lung Cancer Brain Metastases: A Phase 1 Dose Escalation Trial.

    Science.gov (United States)

    Choi, Clara Y H; Wakelee, Heather A; Neal, Joel W; Pinder-Schenck, Mary C; Yu, Hsiang-Hsuan Michael; Chang, Steven D; Adler, John R; Modlin, Leslie A; Harsh, Griffith R; Soltys, Scott G

    2017-09-01

    To determine the maximum tolerated dose (MTD) of vorinostat, a histone deacetylase inhibitor, given concurrently with stereotactic radiosurgery (SRS) to treat non-small cell lung cancer (NSCLC) brain metastases. Secondary objectives were to determine toxicity, local failure, distant intracranial failure, and overall survival rates. In this multicenter study, patients with 1 to 4 NSCLC brain metastases, each ≤2 cm, were enrolled in a phase 1, 3 + 3 dose escalation trial. Vorinostat dose levels were 200, 300, and 400 mg orally once daily for 14 days. Single-fraction SRS was delivered on day 3. A dose-limiting toxicity (DLT) was defined as any Common Terminology Criteria for Adverse Events version 3.0 grade 3 to 5 acute nonhematologic adverse event related to vorinostat or SRS occurring within 30 days. From 2009 to 2014, 17 patients were enrolled and 12 patients completed study treatment. Because no DLTs were observed, the MTD was established as 400 mg. Acute adverse events were reported by 10 patients (59%). Five patients discontinued vorinostat early and withdrew from the study. The most common reasons for withdrawal were dyspnea (n=2), nausea (n=1), and fatigue (n=2). With a median follow-up of 12 months (range, 1-64 months), Kaplan-Meier overall survival was 13 months. There were no local failures. One patient (8%) at the 400-mg dose level with a 2.0-cm metastasis developed histologically confirmed grade 4 radiation necrosis 2 months after SRS. The MTD of vorinostat with concurrent SRS was established as 400 mg. Although no DLTs were observed, 5 patients withdrew before completing the treatment course, a result that emphasizes the need for supportive care during vorinostat administration. There were no local failures. A larger, randomized trial may evaluate both the tolerability and potential local control benefit of vorinostat concurrent with SRS for brain metastases. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. A Proof of Concept Study to Detect Urease Producing Bacteria in Lungs Using Aerosolized 13C-Urea

    Science.gov (United States)

    Timmins, Graham; Davies, Lea; Heynekamp, Theresa; Harkins, Michelle; Sharp, Zachary D.; Kelly, H. William

    2016-01-01

    This is a “proof of concept” study to determine whether inhalation of 13C-urea can be safely used to detect the presence of urease producing bacteria in the airways of patients with cystic fibrosis (CF) by detecting 13CO2 in breath. This was a prospective, 2-part, open label, single-center, single-arm, single-administration, dose-escalation investigational device exemption trial. First, the safety of 20 and 50 mg inhaled 13C-urea was evaluated in 6 healthy adult participants. Then, 3 adult CF participants colonized with Pseudomonas aeruginosa were enrolled for each dose of inhaled 13C-urea. The safety of inhaled 13C-urea was assessed by spirometry and physical examination. 13C-urea was administered using a jet nebulizer, followed by serial spirometry (10 min and 30 min post inhalation) and collection of exhaled breath at 5, 10, and 15 min post inhalation. There was no clinical significant change in any of the spirometry values compared to baseline in healthy participants and CF patients. Mean of 13CO2/12CO2 delta over baseline (DOB) values in CF participants at 5, 10, and 15 min post inhalation was as follows: 20 mg dose 4‰ (2.2‰–4.9‰), 1‰ (1.0‰–1.4‰), and 1‰ (0.4‰–1.5‰); 50 mg dose: 10‰ (6.2‰–14.5‰), 3‰ (2.1‰–4.3‰), and 1.5‰ (0.6‰–2.3‰). Inhaled 13C-urea for detection of urease producing bacteria was safe, and preliminary data suggest that 13CO2/12CO2 DOB values may be higher in CF patients with P. aeruginosa at 5–10 min after inhalation of 13C-urea. A future direction is to investigate use of inhaled 13C-urea in young children who have difficulty producing sputum for culturing. PMID:27458537

  3. The ethics of placebo-controlled trials: methodological justifications.

    Science.gov (United States)

    Millum, Joseph; Grady, Christine

    2013-11-01

    The use of placebo controls in clinical trials remains controversial. Ethical analysis and international ethical guidance permit the use of placebo controls in randomized trials when scientifically indicated in four cases: (1) when there is no proven effective treatment for the condition under study; (2) when withholding treatment poses negligible risks to participants; (3) when there are compelling methodological reasons for using placebo, and withholding treatment does not pose a risk of serious harm to participants; and, more controversially, (4) when there are compelling methodological reasons for using placebo, and the research is intended to develop interventions that can be implemented in the population from which trial participants are drawn, and the trial does not require participants to forgo treatment they would otherwise receive. The concept of methodological reasons is essential to assessing the ethics of placebo controls in these controversial last two cases. This article sets out key considerations relevant to considering whether methodological reasons for a placebo control are compelling.

  4. A Phase Ib dose-escalation study to evaluate safety and tolerability of the addition of the aminopeptidase inhibitor tosedostat (CHR-2797) to paclitaxel in patients with advanced solid tumours

    NARCIS (Netherlands)

    C.M.L. Herpen, C.M.L. (Carla); F.A.L.M. Eskens (Ferry); M.J.A. de Jonge (Maja); I. Desar; L. Hooftman (Leon); E. Bone (Elisabeth); J.N.H. Timmerbonte (Johanna); J. Verweij (Jaap)

    2010-01-01

    textabstractBackground: This Phase Ib dose-escalating study investigated safety, maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK) and clinical antitumour activity of tosedostat (CHR-2797), an orally bioavailable aminopeptidase inhibitor, in combination with

  5. A Phase Ib dose-escalation study to evaluate safety and tolerability of the addition of the aminopeptidase inhibitor tosedostat (CHR-2797) to paclitaxel in patients with advanced solid tumours

    NARCIS (Netherlands)

    C.M.L. Herpen, C.M.L. (Carla); F.A.L.M. Eskens (Ferry); M.J.A. de Jonge (Maja); I. Desar; L. Hooftman (Leon); E. Bone (Elisabeth); J.N.H. Timmerbonte (Johanna); J. Verweij (Jaap)

    2010-01-01

    textabstractBackground: This Phase Ib dose-escalating study investigated safety, maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK) and clinical antitumour activity of tosedostat (CHR-2797), an orally bioavailable aminopeptidase inhibitor, in combination with paclitaxe

  6. Risk assessment for job burnout with a mobile health web application using questionnaire data: a proof of concept study.

    Science.gov (United States)

    von Känel, Roland; van Nuffel, Marc; Fuchs, Walther J

    2016-01-01

    Job burnout has become a rampant epidemic in working societies, causing high productivity loss and healthcare costs. An easy accessible tool to detect clinically relevant risk may bear the potential to timely avert the dire sequelae of burnout. As a start, we performed a proof of concept study to test the utilization of a mobile health web application for a free and anonymous burnout risk assessment with established questionnaires. We designed a client-side javascript web application for users who filled out demographic and psychometric data forms over the internet. Users were recruited through social media, back links from hospital websites, and search engine optimization. Similar to population-based studies, we used the Maslach Burnout Inventory-General Survey (MBI-GS) to calculate a burnout risk index (BRIX). As additional mental health burden indices, users filled out the Perceived Stress Scale, Insomina Severity Index, and Profile of Mood States. Within six months, the MBI-GS was completed by 11,311 users (median age 33 years, 85 % women) of whom 20.0 % had no clinically relevant burnout risk, 54.7 % had mild-to-moderate risk, and 25.3 % had high risk. In the 2947 users completing all questionnaires, female sex (B = -0.03), cohabiting (B = -0.03), negative affect (B = 0.46), positive affect (B = -0.20), perceived stress (B = 0.18), and insomnia symptoms (B = 0.04) explained 56.2 % of the variance in the continuously scaled BRIX. The reliability was good to excellent for all psychometric scales. The weighting of the BRIX with mental health burden indices primarily modified the risk in users with mild-to-moderate burnout risk. A low-threshold web application can reliably assess the risk of job burnout. As the bulk of users had clinically relevant burnout scores, a web application may be useful to target employees at risk. The clinical value of the BRIX and its modification with coexistent/absent mental health burden awaits

  7. Using peer observers to assess the quality of cancer multidisciplinary team meetings: a qualitative proof of concept study

    Directory of Open Access Journals (Sweden)

    Harris J

    2014-08-01

    Full Text Available Jenny Harris,1 James SA Green,2,3 Nick Sevdalis,4 Cath Taylor1 1Florence Nightingale School of Nursing and Midwifery, King's College London, London, UK; 2Department of Urology, Whipps Cross University Hospital, London, UK; 3Department of Health and Social Care, London South Bank University, London, UK; 4Department of Surgery and Cancer, Imperial College London, London, UK Background: Multidisciplinary team (MDT working is well established as the foundation for providing cancer services in the UK and elsewhere. A core activity is the weekly meeting (or case conference/tumor boards where the treatment recommendations for individual patients are agreed. Evidence suggests that the quality of team working varies across cancer teams, and this may impact negatively on the decision-making process, and ultimately patient care. Feedback on performance by expert observers may improve performance, but can be resource-intensive to implement. This proof of concept study sought to: develop a structured observational assessment tool for use by peers (managers or clinicians from the local workforce and explore its usability; assess the feasibility of the principle of observational assessment by peers; and explore the views of MDT members and observers about the utility of feedback from observational assessment. Methods: For tool development, the content was informed by national clinical consensus recommendations for best practice in cancer MDTs and developed in collaboration with an expert steering group. It consisted of ten subdomains of team working observable in MDT meetings that were rated on a 10-point scale (very poor to very good. For observational assessment, a total of 19 peer observers used the tool (assessing performance in 20 cancer teams from four hospitals. For evaluation, telephone interviews with 64 team members and all peer observers were analyzed thematically. Results: The tool was easy to use and areas for refinement were identified. Peer

  8. mHealth medication and blood pressure self-management program in Hispanic hypertensives: a proof of concept trial

    Directory of Open Access Journals (Sweden)

    Sieverdes JC

    2013-10-01

    Full Text Available John C Sieverdes,1 Mathew Gregoski,1 Sachin Patel,1 Deborah Williamson,1 Brenda Brunner-Jackson,1 Judith Rundbaken,1 Eveline Treiber,1 Lydia Davidson,1 Frank A Treiber1,21Technology Applications Center for Healthful Lifestyles, College of Nursing, 2College of Medicine, Medical University of South Carolina, Charleston, SC, USAAbstract: Patient nonadherence to medication regimens and provider therapeutic inertia (failure to respond in timely manner to clinical data are two primary contributors to ineffective chronic disease management. This 3-month proof of concept trial used an iterative design approach guided by self-determination theory and the technology acceptance model to develop a culturally sensitive, patient-centered, and provider-centered mobile health medication and blood pressure self-management program. Cellular connected electronic medication trays provided reminder signals for patients to take medications and smartphone messaging reminded patients to take at-home blood pressures using a Bluetooth-enabled monitor. Providers were given bimonthly feedback. Motivational and reinforcement text and audio messages were sent based upon medication adherence rates and blood pressure levels. Ten Hispanics with uncontrolled essential hypertension were randomized to standard care and Smartphone Medication Adherence Stops Hypertension (SMASH intervention groups. Primary outcomes of provider and patient acceptability of the program were found to be high. Retention rates for the 3-month program were 100%, with mean ± standard deviation overall medication adherence for the SMASH group at 97.2% ± 2.8%, with all strongly believing the program helped them remember to take their medication. SMASH participants measured their blood pressure every 3 days 83.2% ± 6.0% of the time and completed 89.2% ± 19.06% of the expected readings. Nonparametric tests showed statistical significance for resting blood pressure changes between groups at months 2 (P = 0

  9. Efficacy of intravenous immunoglobulin monotherapy in patients with cutaneous lupus erythematosus: results of proof-of-concept study

    Directory of Open Access Journals (Sweden)

    Christa Ky

    2015-03-01

    Full Text Available Cutaneous lupus erythematosus (CLE is a chronic inflammatory autoimmune skin disease. Evidence-based therapy for CLE is lacking in the most part. Intravenous immunoglobulin (IVIg is being increasingly utilized as off-label therapy for a variety of autoimmune and inflammatory conditions, especially in dermatology. The usefulness of IVIg in CLE is not well established. The goal of the present study was to obtain the proof-of-concept evidence that IVIg can control acute CLE and thus replace current systemic immunosuppressive therapy that causes severe side effects and adverse reactions. Sixteen patients who tried and failed various systemic treatments for CLE were screened and consented to use IVIg as a monotherapy. The IVIg was administered at 500 mg/kg/day on 4 consecutive days up to a total of 2 g/kg/month for 3 months, and the subjects were monitored for additional 6 months off any drug for a possible relapse. The cumulative results revealed an overall improvement, as evinced by a decrease of both objective and subjective measures of disease activity. The most sensitive and specific objective and subjective instruments for assessment of the therapeutic effect of IVIg were CLASI-A (Cutaneous Lupus Erythematosus Disease Area and Severity Index measuring disease activity and Skindex-29 scores, respectively. The CLASI-A score dropped down from the initial value taken as 100%, and remained in the range of approximately 70% until the last visit. Three patients (18.8% had a temporary flare of CLE symptoms but recovered within a month from the relapse. No serious side effects and adverse reactions occurred. Thus, IVIg monotherapy in CLE allowed to achieve: i rapid and persistent decreased in disease activity; ii steady improvement of patients’ quality of life assessed by Skindex-29; iii low relapse rate; and iv mild nature and short duration of relapses. Since healing was maintained for months after IVIg treatment, it is possible that the IVIg

  10. Reconstruction of 3D Shapes of Opaque Cumulus Clouds from Airborne Multiangle Imaging: A Proof-of-Concept

    Science.gov (United States)

    Davis, A. B.; Bal, G.; Chen, J.

    2015-12-01

    Operational remote sensing of microphysical and optical cloud properties is invariably predicated on the assumption of plane-parallel slab geometry for the targeted cloud. The sole benefit of this often-questionable assumption about the cloud is that it leads to one-dimensional (1D) radiative transfer (RT)---a textbook, computationally tractable model. We present new results as evidence that, thanks to converging advances in 3D RT, inverse problem theory, algorithm implementation, and computer hardware, we are at the dawn of a new era in cloud remote sensing where we can finally go beyond the plane-parallel paradigm. Granted, the plane-parallel/1D RT assumption is reasonable for spatially extended stratiform cloud layers, as well as the smoothly distributed background aerosol layers. However, these 1D RT-friendly scenarios exclude cases that are critically important for climate physics. 1D RT---whence operational cloud remote sensing---fails catastrophically for cumuliform clouds that have fully 3D outer shapes and internal structures driven by shallow or deep convection. For these situations, the first order of business in a robust characterization by remote sensing is to abandon the slab geometry framework and determine the 3D geometry of the cloud, as a first step toward bone fide 3D cloud tomography. With this specific goal in mind, we deliver a proof-of-concept for an entirely new kind of remote sensing applicable to 3D clouds. It is based on highly simplified 3D RT and exploits multi-angular suites of cloud images at high spatial resolution. Airborne sensors like AirMSPI readily acquire such data. The key element of the reconstruction algorithm is a sophisticated solution of the nonlinear inverse problem via linearization of the forward model and an iteration scheme supported, where necessary, by adaptive regularization. Currently, the demo uses a 2D setting to show how either vertical profiles or horizontal slices of the cloud can be accurately reconstructed

  11. Ultra-high gradient channeling acceleration in nanostructures: Design/progress of proof-of-concept (POC) experiments

    Science.gov (United States)

    Shin, Y. M.; Green, A.; Lumpkin, A. H.; Thurman-Keup, R. M.; Shiltsev, V.; Zhang, X.; Farinella, D. M.-A.; Taborek, P.; Tajima, T.; Wheeler, J. A.; Mourou, G.

    2017-03-01

    A short bunch of relativistic particles, or a short-pulse laser, perturb the density state of conduction electrons in a solid crystal and excite wakefields along atomic lattices in a crystal. Under a coupling condition between a driver and plasma, the wakes, if excited, can accelerate channeling particles with TeV/m acceleration gradients [1], in principle, since the density of charge carriers (conduction electrons) in solids n0 = 1020 - 1023 cm-3 is significantly higher than what was considered above in gaseous plasma. Nanostructures have some advantages over crystals for channeling applications of high power beams. The de-channeling rate can be reduced and the beam acceptance increased by the large size of the channels. For beam-driven acceleration, a bunch length with a sufficient charge density would need to be in the range of the plasma wavelength to properly excite plasma wakefields, and channeled particle acceleration with the wakefields must occur before the ions in the lattices move beyond the restoring threshold. In the case of the excitation by short laser pulses, the dephasing length is appreciably increased with the larger channel, which enables channeled particles to gain sufficient amounts of energy. This paper describes simulation analyses on beam- and laser (X-ray)-driven accelerations in effective nanotube models obtained from the Vsim and EPOCH codes. Experimental setups to detect wakefields are also outlined with accelerator facilities at Fermilab and Northern Illinois University (NIU). In the FAST facility, the electron beamline was successfully commissioned at 50 MeV, and it is being upgraded toward higher energies for electron accelerator R&D. The 50 MeV injector beamline of the facility is used for X-ray crystal-channeling radiation with a diamond target. It has been proposed to utilize the same diamond crystal for a channeling acceleration proof-of-concept (POC). Another POC experiment is also designed for the NIU accelerator lab with time

  12. Design of a complex virtual reality simulation to train finger motion for persons with hemiparesis: a proof of concept study

    Directory of Open Access Journals (Sweden)

    Qiu Qinyin

    2009-07-01

    Full Text Available Abstract Background Current neuroscience has identified rehabilitation approaches with the potential to stimulate adaptive changes in the brains of persons with hemiparesis. These approaches include, intensive task-oriented training, bimanual activities and balancing proximal and distal upper extremity interventions to reduce competition between these segments for neural territory. Methods This paper describes the design and feasibility testing of a robotic/virtual environment system designed to train the hand and arm of persons with hemiparesis. The system employs a simulated piano that presents visual, auditory and tactile feedback comparable to an actual piano. Arm tracking allows patients to train both the arm and hand as a coordinated unit, emphasizing the integration of both transport and manipulation phases. The piano trainer includes songs and scales that can be performed with one or both hands. Adaptable haptic assistance is available for more involved subjects. An algorithm adjusts task difficulty in proportion to subject performance. A proof of concept study was performed on four subjects with upper extremity hemiparesis secondary to chronic stroke to establish: a the safety and feasibility of this system and b the concurrent validity of robotically measured kinematic and performance measures to behavioral measures of upper extremity function. Results None of the subjects experienced adverse events or responses during or after training. As a group, the subjects improved in both performance time and key press accuracy. Three of the four subjects demonstrated improvements in fractionation, the ability to move each finger individually. Two subjects improved their aggregate time on the Jebsen Test of Hand Function and three of the four subjects improved in Wolf Motor Function Test aggregate time. Conclusion The system designed in this paper has proven to be safe and feasible for the training of hand function for persons with hemiparesis

  13. Intensity modulated radiation therapy with simultaneous integrated boost based dose escalation on neoadjuvant chemoradiation therapy for locally advanced distal esophageal adenocarcinoma

    Institute of Scientific and Technical Information of China (English)

    Ming Zeng; Fernando N Aguila; Taral Patel; Mark Knapp; XueQiang Zhu; XiLin Chen; Phillip D Price

    2016-01-01

    AIM:To evaluate impact of radiation therapy dose escalation through intensity modulated radiation therapy with simultaneous integrated boost(IMRT-SIB).METHODS:We retrospectively reviewed the patients who underwent four-dimensional-based IMRT-SIBbased neoadjuvant chemoradiation protocol.During the concurrent chemoradiation therapy,radiation therapy was through IMRT-SIB delivered in 28 consecutive daily fractions with total radiation doses of 56 Gy to tumor and 5040 Gy dose-painted to clinical tumor volume,with a regimen at the discretion of the treating medical oncologist.This was followed by surgical tumor resection.We analyzed pathological completion response(p CR) rates its relationship with overall survival and event-freesurvival.RESULTS:Seventeen patients underwent dose escalation with the IMRT-SIB protocol between 2007 and 2014 and their records were available for analysis.Among the IMRT-SIB-treated patients,the toxicity appeared mild,the most common side effects were grade 1-3 esophagitis(46%) and pneumonitis(11.7%).There were no cardiac events.The Ro resection rate was 94%(n = 16),the p CR rate was 47%(n = 8),and the postoperative morbidity was zero.There was one mediastinal failure found,one patient had local failure at the anastomosis site,and the majority of failures were distant in the lung or bone.The 3-year diseasefree survival and overall survival rates were 41%(n = 7) and 53%(n = 9),respectively.CONCLUSION:The dose escalation through IMRT-SIB in the chemoradiation regimen seems responsible for down-staging the distal esophageal with well-tolerated complications.

  14. Dose escalation for patients with decreasing PSA during radiotherapy for elevated PSA after radical prostatectomy improves biochemical progression-free survival. Results of a retrospective study

    Energy Technology Data Exchange (ETDEWEB)

    Siegmann, Alessandra; Faehndrich, Julia; Lohm, Gunnar; Hinkelbein, Wolfgang [Charite Universitaetsmedizin, Berlin (Germany). Dept. of Radiation Oncology; Bottke, Dirk; Bartkowiak, Detlef; Wiegel, Thomas [University Hospital Ulm (Germany). Dept. of Radiation Oncology; Miller, Kurt [Charite Universitaetsmedizin, Berlin (Germany). Dept. of Urology

    2011-08-15

    The optimal dose for salvage radiotherapy (SRT) after radical prostatectomy (RP) is still not defined. It should be at least 66 Gy. In the present study, the suitability of PSA regression as a selection criterion for an SRT dose escalation to 70.2 Gy was examined. Between 1997 and 2007, 301 prostate cancer patients received SRT after RP at the Charite - University Medicine Berlin, Campus Benjamin Franklin. None of the patients had antihormone therapy prior to SRT. A total of 234 patients received 66.6 Gy. From 2002 on, 67 patients with a PSA decrease during SRT were irradiated with 70.2 Gy. The influence of this selection and dose escalation on freedom from biochemical progression (bNED) was analyzed. The median follow-up of the whole group was 30 months, the median pre-SRT PSA was 0.28 ng/ml. Of the patients, 27% (82/301) developed biochemical progression, 31% from the 66.6 Gy cohort (73/292) and 13% from the 70.2 Gy cohort (9/67) (p = 0.01). The calculated 2-years bNED was 74% for the whole group, 88% vs. 71% after 70.2 Gy and 66.6 Gy, respectively (p = 0.01). In a multivariate analysis, the total dose (p = 0.017), the re-achievement of an undetectable PSA after SRT (p = 0.005), and the infiltration of the seminal vesicles (p = 0.049) were independent parameters of bNED. Our analysis suggests that patient selection during SRT for a dose escalation to 70.2 Gy can improve the freedom from biochemical progression in patients with SRT after RP. (orig.)

  15. Mobile Health Medication Adherence and Blood Pressure Control in Renal Transplant Recipients: A Proof-of-Concept Randomized Controlled Trial.

    Science.gov (United States)

    McGillicuddy, John W; Gregoski, Mathew J; Weiland, Anna K; Rock, Rebecca A; Brunner-Jackson, Brenda M; Patel, Sachin K; Thomas, Beje S; Taber, David J; Chavin, Kenneth D; Baliga, Prabhakar K; Treiber, Frank A

    2013-09-04

    Mobile phone based programs for kidney transplant recipients are promising tools for improving long-term graft outcomes and better managing comorbidities (eg, hypertension, diabetes). These tools provide an easy to use self-management framework allowing optimal medication adherence that is guided by the patients' physiological data. This technology is also relatively inexpensive, has an intuitive interface, and provides the capability for real-time personalized feedback to help motivate patient self-efficacy. Automated summary reports of patients' adherence and blood pressure can easily be uploaded to providers' networks helping reduce clinical inertia by reducing regimen alteration time. The aim of this study was to assess the feasibility, acceptability, and preliminary outcomes of a prototype mobile health (mHealth) medication and blood pressure (BP) self-management system for kidney transplant patients with uncontrolled hypertension. A smartphone enabled medication adherence and BP self-management system was developed using a patient and provider centered design. The development framework utilized self-determination theory with iterative stages that were guided and refined based on patient/provider feedback. A 3-month proof-of-concept randomized controlled trial was conducted in 20 hypertensive kidney transplant patients identified as non-adherent to their current medication regimen based on a month long screening using an electronic medication tray. Participants randomized to the mHealth intervention had the reminder functions of their electronic medication tray enabled and received a bluetooth capable BP monitor and a smartphone that received and transmitted encrypted physiological data and delivered reminders to measure BP using text messaging. Controls received standard of care and their adherence continued to be monitored with the medication tray reminders turned off. Providers received weekly summary reports of patient medication adherence and BP readings

  16. [Placebo control and clinical trial of Chinese medicine].

    Science.gov (United States)

    Wu, Jing

    2010-10-01

    World Health Organization aims to develop safe, effective and practical traditional medicine. Traditional Chinese medicine (TCM) and other complementary and alternative medicine are being recognized in the whole world nowadays. However, the definite effect of Chinese medicine is still in need of scientific research proof. Placebo control is of equal importance to active control and blank control in clinical trial of TCM. This article briefly reviewed the importance of placebo control and commented on its present situation in clinical trial of TCM. This article also brought up the preliminary proposals of placebo application in TCM clinical trial. We should emphasize scientific placebo preparation and good design of placebo-controlled trial, which are directed by International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. A good clinical trial project will avoid unnecessary wastes and provide safe and effective treatment for people.

  17. A prospective study of differences in duodenum compared to remaining small bowel motion between radiation treatments: Implications for radiation dose escalation in carcinoma of the pancreas

    Directory of Open Access Journals (Sweden)

    Wahab Sasha H

    2006-09-01

    Full Text Available Abstract Purpose As a foundation for a dose escalation trial, we sought to characterize duodenal and non-duodenal small bowel organ motion between fractions of pancreatic radiation therapy. Patients and methods Nine patients (4 women, 5 men undergoing radiation therapy were enrolled in this prospective study. The patients had up to four weekly CT scans performed during their course of radiation therapy. Pancreas, duodenum and non-duodenal small bowel were then contoured for each CT scan. On the initial scan, a four-field plan was generated to fully cover the pancreas. This plan was registered to each subsequent CT scan. Dose-volume histogram (DVH analyses were performed for the duodenum, non-duodenal small bowel, large bowel, and pancreas. Results With significant individual variation, the volume of duodenum receiving at least 80% of the prescribed dose was consistently greater than the remaining small bowel. In the patient with the largest inter-fraction variation, the fractional volume of non-duodenal small bowel irradiated to at least the 80% isodose line ranged from 1% to 20%. In the patient with the largest inter-fraction variation, the fractional volume of duodenum irradiated to at least the 80% isodose line ranged from 30% to 100%. Conclusion The volume of small bowel irradiated during four-field pancreatic radiation therapy changes substantially between fractions. This suggests dose escalation may be possible. However, dose limits to the duodenum should be stricter than for other segments of small bowel.

  18. Peptide Nucleic Acid-Fluorescence In Situ Hybridization for Detection of Staphylococci From Endophthalmitis Isolates: A Proof-of-Concept Study.

    Science.gov (United States)

    Patel, Nimesh; Miller, Darlene; Relhan, Nidhi; Flynn, Harry W

    2017-08-01

    Rapid identification of pathogens causing endophthalmitis may improve treatment outcomes through early administration of species-specific medication. The current study reports a new molecular application of peptide nucleic acid-fluorescence in situ hybridization (PNA-FISH) with Staphylococcus-specific molecular PNA probes for the potential rapid detection of common pathogens causing endophthalmitis. An experimental study was designed to evaluate the proof of concept at the microbiology laboratory of the Bascom Palmer Eye Institute. Stored culture-positive staphylococci endophthalmitis isolates obtained from prior vitreous samples (n = 15), along with broth as negative controls (n = 5) were used. Inoculum was prepared to a final concentration of 1 × 105 colony-forming units/mL to ensure that the isolates were viable. Smears of samples were fixed and hybridized using QuickFISH protocol with probes for Staphylococcus. With PNA-FISH technique, Staphylococcus aureus was identified in 9 of 10 samples and coagulase-negative staphylococci were identified in 10 of 10 samples. Detection time was 20 minutes. This study serves a proof of concept using a new microbial detection system with FISH probes, and may have the potential for clinical use in the rapid and accurate identification of isolates from patients with endophthalmitis.

  19. In vivo effects of ketamine on glutamate-glutamine and gamma-aminobutyric acid in obsessive-compulsive disorder: Proof of concept.

    Science.gov (United States)

    Rodriguez, Carolyn I; Kegeles, Lawrence S; Levinson, Amanda; Ogden, R Todd; Mao, Xiangling; Milak, Matthew S; Vermes, Donna; Xie, Shan; Hunter, Liane; Flood, Pamela; Moore, Holly; Shungu, Dikoma C; Simpson, Helen B

    2015-08-30

    We previously reported the rapid and robust clinical effects of ketamine versus saline infusions in a proof-of-concept crossover trial in unmedicated adults with obsessive-compulsive disorder (OCD). This study examined the concurrent neurochemical effects of ketamine versus saline infusions using proton magnetic resonance spectroscopy ((1)H MRS) during the clinical proof-of-concept crossover trial. Levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and the excitatory neurochemicals glutamate+glutamine (Glx) were acquired in the medial prefrontal cortex (MPFC), a region implicated in OCD pathology. Seventeen unmedicated OCD adults received two intravenous infusions at least 1 week apart, one of saline and one of ketamine, while lying supine in a 3.0 T GE MR scanner. The order of each infusion pair was randomized. Levels of GABA and Glx were measured in the MPFC before, during, and after each infusion and normalized to water (W). A mixed effects model found that MPFC GABA/W significantly increased over time in the ketamine compared with the saline infusion. In contrast, there were no significant differences in Glx/W between the ketamine and saline infusions. Together with earlier evidence of low cortical GABA in OCD, our findings suggest that models of OCD pathology should consider the role of GABAergic abnormalities in OCD symptomatology. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  20. Body-Machine Interface Enables People With Cervical Spinal Cord Injury to Control Devices With Available Body Movements: Proof of Concept.

    Science.gov (United States)

    Abdollahi, Farnaz; Farshchiansadegh, Ali; Pierella, Camilla; Seáñez-González, Ismael; Thorp, Elias; Lee, Mei-Hua; Ranganathan, Rajiv; Pedersen, Jessica; Chen, David; Roth, Elliot; Casadio, Maura; Mussa-Ivaldi, Ferdinando

    2017-05-01

    This study tested the use of a customized body-machine interface (BoMI) for enhancing functional capabilities in persons with cervical spinal cord injury (cSCI). The interface allows people with cSCI to operate external devices by reorganizing their residual movements. This was a proof-of-concept phase 0 interventional nonrandomized clinical trial. Eight cSCI participants wore a custom-made garment with motion sensors placed on the shoulders. Signals derived from the sensors controlled a computer cursor. A standard algorithm extracted the combinations of sensor signals that best captured each participant's capacity for controlling a computer cursor. Participants practiced with the BoMI for 24 sessions over 12 weeks performing 3 tasks: reaching, typing, and game playing. Learning and performance were evaluated by the evolution of movement time, errors, smoothness, and performance metrics specific to each task. Through practice, participants were able to reduce the movement time and the distance from the target at the 1-second mark in the reaching task. They also made straighter and smoother movements while reaching to different targets. All participants became faster in the typing task and more skilled in game playing, as the pong hit rate increased significantly with practice. The results provide proof-of-concept for the customized BoMI as a means for people with absent or severely impaired hand movements to control assistive devices that otherwise would be manually operated.

  1. Efficient assessment of efficacy in post-traumatic peripheral neuropathic pain patients: pregabalin in a randomized, placebo-controlled, crossover study

    Directory of Open Access Journals (Sweden)

    Jenkins TM

    2012-07-01

    Full Text Available Tim M Jenkins, Trevor S Smart, Frances Hackman, Carol Cooke, Keith KC TanClinical Research, Pfizer Worldwide Research and Development, Sandwich, Kent, UKBackground: Detecting the efficacy of novel analgesic agents in neuropathic pain is challenging. There is a critical need for study designs with the desirable characteristics of assay sensitivity, low placebo response, reliable pain recordings, low cost, short duration of exposure to test drug and placebo, and relevant and recruitable population.Methods: We designed a proof-of-concept, double-blind, randomized, placebo-controlled, crossover study in patients with post-traumatic peripheral neuropathic pain (PTNP to evaluate whether such a study design had the potential to detect efficacious agents. Pregabalin, known to be efficacious in neuropathic pain, was used as the active analgesic. We also assessed physical activity throughout the study.Results: Twenty-five adults (20–70 years of age with PTNP for ≥3 months entered a screening week and were then randomized to one of the two following treatment sequences: (1 pregabalin followed by placebo or (2 placebo followed by pregabalin. These 2-week treatment periods were separated by a 2-week washout period. Patients on pregabalin treatment received escalating doses to a final dosage of 300 mg/day (days 5–15. In an attempt to minimize placebo response, patients received placebo treatment during the screening week and the 2-week washout period. Average daily pain scores (primary endpoint were significantly reduced for pregabalin versus placebo, with a mean treatment difference of -0.81 (95% confidence interval: -1.45 to -0.17; P = 0.015.Conclusion: The efficacy of pregabalin was similar to that identified in a large, parallel group trial in PTNP. Therefore, this efficient crossover study design has potential utility for future proof-of-concept studies in neuropathic pain.Keywords: pregabalin, post-traumatic peripheral neuropathic pain, randomized

  2. Double-blind, placebo-controlled food challenge with apple

    DEFF Research Database (Denmark)

    Skamstrup Hansen, K; Vestergaard, H; Stahl Skov, P

    2001-01-01

    The aim of the study was to develop and evaluate different methods of double-blind, placebo-controlled food challenge (DBPCFC) with apple. Three different DBPCFC models were evaluated: fresh apple juice, freshly grated apple, and freeze-dried apple powder. All challenges were performed outside...

  3. Testing Public Anxiety Treatments against a Credible Placebo Control

    Science.gov (United States)

    Duff, Desiree C.; Levine, Timothy R.; Beatty, Michael J.; Woolbright, Jessica; Park, Hee Sun

    2007-01-01

    Research investigating public speaking anxiety treatments is subject to demand effects. This study tests the relative effectiveness of systematic desensitization (SD) and multiple treatment method (MT) containing visualization therapy against no-treatment and credible placebo controls. Data (N = 238) were collected at six points in a public…

  4. Dose-Escalated Intensity-Modulated Radiotherapy Is Feasible and May Improve Locoregional Control and Laryngeal Preservation in Laryngo-Hypopharyngeal Cancers

    Energy Technology Data Exchange (ETDEWEB)

    Miah, Aisha B.; Bhide, Shreerang A.; Guerrero-Urbano, M. Teresa [Head and Neck Unit, The Royal Marsden National Health Service (NHS) Foundation Trust, London (United Kingdom); Institute of Cancer Research, London (United Kingdom); Clark, Catharine; Bidmead, A. Margaret [Institute of Cancer Research, London (United Kingdom); Department of Physics, The Royal Marsden NHS Foundation Trust, London (United Kingdom); St Rose, Suzanne; Barbachano, Yolanda; A' Hern, Roger [Department of Statistics, The Royal Marsden NHS Foundation Trust, London (United Kingdom); Tanay, Mary; Hickey, Jennifer; Nicol, Robyn; Newbold, Kate L. [Head and Neck Unit, The Royal Marsden National Health Service (NHS) Foundation Trust, London (United Kingdom); Harrington, Kevin J. [Head and Neck Unit, The Royal Marsden National Health Service (NHS) Foundation Trust, London (United Kingdom); Institute of Cancer Research, London (United Kingdom); Nutting, Christopher M., E-mail: chris.nutting@rmh.nhs.uk [Head and Neck Unit, The Royal Marsden National Health Service (NHS) Foundation Trust, London (United Kingdom); Institute of Cancer Research, London (United Kingdom)

    2012-02-01

    Purpose: To determine the safety and outcomes of induction chemotherapy followed by dose-escalated intensity-modulated radiotherapy (IMRT) with concomitant chemotherapy in locally advanced squamous cell cancer of the larynx and hypopharynx (LA-SCCL/H). Methods and Materials: A sequential cohort Phase I/II trial design was used to evaluate moderate acceleration and dose escalation. Patients with LA-SCCL/H received IMRT at two dose levels (DL): DL1, 63 Gy/28 fractions (Fx) to planning target volume 1 (PTV1) and 51.8 Gy/28 Fx to PTV2; DL2, 67.2 Gy/28 Fx and 56 Gy/28 Fx to PTV1 and PTV2, respectively. Patients received induction cisplatin/5-fluorouracil and concomitant cisplatin. Acute and late toxicities and tumor control rates were recorded. Results: Between September 2002 and January 2008, 60 patients (29 DL1, 31 DL2) with Stage III (41% DL1, 52% DL2) and Stage IV (52% DL1, 48% DL2) disease were recruited. Median (range) follow-up for DL1 was 51.2 (12.1-77.3) months and for DL2 was 36.2 (4.2-63.3) months. Acute Grade 3 (G3) dysphagia was higher in DL2 (87% DL2 vs. 59% DL1), but other toxicities were equivalent. One patient in DL1 required dilatation of a pharyngeal stricture (G3 dysphagia). In DL2, 2 patients developed benign pharyngeal strictures at 1 year. One underwent a laryngo-pharyngectomy and the other a dilatation. No other G3/G4 toxicities were reported. Overall complete response was 79% (DL1) and 84% (DL2). Two-year locoregional progression-free survival rates were 64.2% (95% confidence interval, 43.5-78.9%) in DL1 and 78.4% (58.1-89.7%) in DL2. Two-year laryngeal preservation rates were 88.7% (68.5-96.3%) in DL1 and 96.4% (77.7-99.5%) in DL2. Conclusions: At a mean follow-up of 36 months, dose-escalated chemotherapy-IMRT at DL2 has so far been safe to deliver. In this study, DL2 delivered high rates of locoregional control, progression-free survival, and organ preservation and has been selected as the experimental arm in a Cancer Research UK Phase III

  5. FOLFIRI and regorafenib combination therapy with dose escalation of irinotecan as fourth-line treatment for patients with metastatic colon cancer according to UGT1A1 genotyping

    Directory of Open Access Journals (Sweden)

    Lu CY

    2014-11-01

    Full Text Available Chien-Yu Lu,1,2 Yung-Sung Yeh,3–5 Ching-Wen Huang,5,6, Cheng-Jen Ma,4,5 Fang-Jung Yu,1,2 Jaw-Yuan Wang4–10 1Division of Gastroenterology, Department of Internal Medicine, 2Department of Internal Medicine, Faculty of Medicine, College of Medicine, 3Department of Emergency Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, 4Graduate Institute of Clinical Medicine, College of Medicine, 5Division of Gastroenterology and General Surgery, Department of Surgery, Kaohsiung Medical University Hospital, 6Graduate Institute of Medicine, College of Medicine, 7Cancer Center, Kaohsiung Medical University Hospital, 8Department of Genomic Medicine, 9Department of Surgery, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 10Center for Biomarkers and Biotech Drugs, Kaohsiung Medical University, Kaohsiung, Taiwan Abstract: Here we report a case of metastatic colon cancer treated with 5-fluorouracil, leucovorin, and escalated doses of irinotecan (FOLFIRI combined with regorafenib in the fourth-line setting after uridine diphosphate glucuronosyltransferase (UGT1A1 genotyping analysis. A 66-year-old male was initially diagnosed with Union Internationale Contre le Cancer stage III descending colon cancer and underwent curative surgery. He received postoperative adjuvant chemotherapy; however, liver metastasis developed and a partial hepatectomy was performed thereafter. Unfortunately, pulmonary metastases and recurrent liver tumors were found despite a series of systemic treatments with multiple combinations of cytotoxic and biologic agents. Recently, a novel multikinase inhibitor, regorafenib, was approved for the treatment of metastatic colorectal cancer refractory to other therapeutic modalities. As further treatment, we combined regorafenib with FOLFIRI, which included dose escalations of irinotecan, after UGT1A1 genotyping analysis. The therapeutic results were promising, with the improvement in liver and pulmonary metastases being

  6. Off-label biologic regimens in psoriasis: a systematic review of efficacy and safety of dose escalation, reduction, and interrupted biologic therapy.

    Directory of Open Access Journals (Sweden)

    Elizabeth A Brezinski

    Full Text Available OBJECTIVES: While off-label dosing of biologic treatments may be necessary in selected psoriasis patients, no systematic review exists to date that synthesizes the efficacy and safety of these off-label dosing regimens. The aim of this systematic review is to evaluate efficacy and safety of off-label dosing regimens (dose escalation, dose reduction, and interrupted treatment with etanercept, adalimumab, infliximab, ustekinumab, and alefacept for psoriasis treatment. DATA SOURCES AND STUDY SELECTION: We searched OVID Medline from January 1, 1990 through August 1, 2011 for prospective clinical trials that studied biologic therapy for psoriasis treatment in adults. Individual articles were screened for studies that examined escalated, reduced, or interrupted therapy with etanercept, adalimumab, infliximab, ustekinumab, or alefacept. DATA SYNTHESIS: A total of 23 articles with 12,617 patients matched the inclusion and exclusion criteria for the systematic review. Data were examined for primary and secondary efficacy outcomes and adverse events including infections, malignancies, cardiovascular events, and anti-drug antibodies. The preponderance of data suggests that continuous treatment with anti-TNF agents and anti-IL12/23 agent was necessary for maintenance of disease control. Among non-responders, dose escalation with etanercept, adalimumab, ustekinumab, and alefacept typically resulted in greater efficacy than standard dosing. Dose reduction with etanercept and alefacept resulted in reduced efficacy. Withdrawal of the examined biologics led to an increase in disease activity; efficacy from retreatment did not result in equivalent initial response rates for most biologics. Safety data on off-label dosing regimens are limited. CONCLUSION: Dose escalation in non-responders generally resulted in increased efficacy in the examined biologics used to treat moderate-to-severe psoriasis. Continuous treatment with anti-TNF agents and anti-IL12/23 agent

  7. Theophylline as an add-on to thrombolytic therapy in acute ischaemic stroke (TEA-Stroke): A randomized, double-blinded, placebo-controlled, two-centre phase II study

    DEFF Research Database (Denmark)

    Modrau, Boris; Hjort, Niels; Østergaard, Leif;

    2016-01-01

    the collateral supply in acute ischaemic brain tissue and thus facilitate reperfusion despite proximal vessel occlusion. The primary study objective is to evaluate whether theophylline is safe and efficient in acute ischaemic stroke patients as an add-on to thrombolytic therapy.MethodsThe TEA-Stroke Trial...... is a two-centre, proof of concept phase II clinical study with a randomized, double-blinded, placebo-controlled design. One hundred and twenty patients with acute ischaemic stroke and significant perfusion?diffusion mismatch, as determined by magnetic resonance imaging, are randomized 1:1 to either...... theophylline or placebo as an add-on to standard thrombolytic therapy.Study outcomeThe dual primary outcome measures include penumbra salvage (penumbral tissue not developing into infarcted tissue) and clinical improvement at the 24-h follow-up.DiscussionResults from studies of theophylline in stroke animal...

  8. Hypoxia imaging with [18F]-FMISO-PET for guided dose escalation with intensity-modulated radiotherapy in head-and-neck cancers

    Energy Technology Data Exchange (ETDEWEB)

    Henriques de Figueiredo, B. [Institut Bergonie, Department of Radiotherapy, Bordeaux (France); INCIA UMR-CNRS 5287, Bordeaux (France); Zacharatou, C. [Institut Bergonie, Department of Radiotherapy, Bordeaux (France); Galland-Girodet, S.; Benech, J. [Hospital Haut-Leveque, Department of Radiotherapy, CHRU Bordeaux (France); Clermont-Gallerande, H. de [Hospital Pellegrin, Department of Nuclear Medicine, CHRU Bordeaux (France); Lamare, F. [INCIA UMR-CNRS 5287, Bordeaux (France); Hospital Haut-Leveque, Department of Radiotherapy, CHRU Bordeaux (France); Hatt, M. [LaTIM INSERM U1101, Brest (France); Digue, L. [Hospital Saint-Andre, Department of Clinical Oncology, CHRU Bordeaux (France); Mones del Pujol, E. de [Department of Oto-rhino-laryngology, CHRU Bordeaux (France); Fernandez, P. [INCIA UMR-CNRS 5287, Bordeaux (France); Hospital Pellegrin, Department of Nuclear Medicine, CHRU Bordeaux (France); University Bordeaux 2, Bordeaux (France)

    2014-09-23

    Positron emission tomography (PET) with [{sup 18}F]-fluoromisonidazole ([{sup 18}F]-FMISO) provides a non-invasive assessment of hypoxia. The aim of this study is to assess the feasibility of a dose escalation with volumetric modulated arc therapy (VMAT) guided by [{sup 18}F]-FMISO-PET for head-and-neck cancers (HNC). Ten patients with inoperable stages III-IV HNC underwent [{sup 18}F]-FMISO-PET before radiotherapy. Hypoxic target volumes (HTV) were segmented automatically by using the fuzzy locally adaptive Bayesian method. Retrospectively, two VMAT plans were generated delivering 70 Gy to the gross tumour volume (GTV) defined on computed tomography simulation or 79.8 Gy to the HTV. A dosimetric comparison was performed, based on calculations of tumour control probability (TCP), normal tissue complication probability (NTCP) for the parotid glands and uncomplicated tumour control probability (UTCP). The mean hypoxic fraction, defined as the ratio between the HTV and the GTV, was 0.18. The mean average dose for both parotids was 22.7 Gy and 25.5 Gy without and with dose escalation respectively. FMISO-guided dose escalation led to a mean increase of TCP, NTCP for both parotids and UTCP by 18.1, 4.6 and 8 % respectively. A dose escalation up to 79.8 Gy guided by [{sup 18}F]-FMISO-PET with VMAT seems feasible with improvement of TCP and without excessive increase of NTCP for parotids. (orig.) [German] Die Positronenemissionstomographie (PET) mit [{sup 18}F]-Fluoromisonidazol ([{sup 18}F]-FMISO) ermoeglicht eine nichtinvasive Beurteilung der Hypoxie. Ziel dieser Studie ist es, die Durchfuehrbarkeit einer [{sup 18}F]-FMISO-PET-gefuehrten Dosissteigerung bei volumetrisch modulierter Arc-Therapie (VMAT) von Kopf-Hals-Tumoren (KHT) zu bewerten. Zehn Patienten mit inoperablen KHT der Stadien III-IV erhielten vor der Strahlentherapie eine [{sup 18}F]-FMISO-PET. Hypoxische Zielvolumina (HV) wurden automatisch mit Hilfe des FLAB(Fuzzy Locally Adaptive Bayesian

  9. A phase I dose-escalation study of MSC1992371A, an oral inhibitor of aurora and other kinases, in advanced hematologic malignancies.

    Science.gov (United States)

    Graux, Carlos; Sonet, Anne; Maertens, Johan; Duyster, Justus; Greiner, Jochen; Chalandon, Yves; Martinelli, Giovanni; Hess, Dagmar; Heim, Dominik; Giles, Francis J; Kelly, Kevin R; Gianella-Borradori, Athos; Longerey, Blandine; Asatiani, Ekaterine; Rejeb, Narmyn; Ottmann, Oliver G

    2013-09-01

    A phase I dose-escalation study of MSC1992371A, an oral aurora kinase inhibitor, was carried out in patients with hematologic malignancies. Patients received escalating doses either on days 1-3 and 8-10 (n=36) or on days 1-6 (n=39) of a 21-day cycle. The maximum tolerated doses were 37 and 28 mg/m(2)/day, respectively. Dose-limiting toxicities included severe neutropenia with infection and sepsis, mucositis/stomatitis, and diarrhea. Complete responses occurred in 3 patients. Four disease-specific expansion cohorts then received the dose and schedule dictated by the escalation phase but the study was prematurely discontinued due to hematologic and gastrointestinal toxicity at clinically effective doses. Copyright © 2013 Elsevier Ltd. All rights reserved.

  10. A phase I, dose-escalation study of TB-403, a monoclonal antibody directed against PlGF, in patients with advanced solid tumours

    DEFF Research Database (Denmark)

    Lassen, U; Nielsen, D L; Sørensen, M

    2012-01-01

    , dyspnoea, and nausea. One serious AE, a lung embolus in a patient with non-small cell lung cancer treated with 10 mg kg(-1) weekly, was deemed possibly related to TB-403. No dose-limiting toxicities were observed, and a maximum-tolerated dose was not reached. The PK parameters were dose linear...... and the terminal half-life values ranged from 9 to 14 days. Six patients exhibited stable disease for at least 8 weeks. Two patients, (oesophageal squamous cell carcinoma and pancreatic adenocarcinoma) both treated with 5 mg kg(-1) weekly, remained stable for 12 months. CONCLUSION: TB-403 treatment in this patient......BACKGROUND: TB-403 (RO 5323441), a humanised monoclonal antibody, is a novel antiangiogenesis agent directed against placental growth factor. The safety, pharmacokinetics (PK), and antitumour activity of TB-403 were assessed in a phase I, dose-escalation study in patients with advanced solid...

  11. Short-term Androgen-Deprivation Therapy Improves Prostate Cancer-Specific Mortality in Intermediate-Risk Prostate Cancer Patients Undergoing Dose-Escalated External Beam Radiation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Zumsteg, Zachary S.; Spratt, Daniel E.; Pei, Xin; Yamada, Yoshiya; Kalikstein, Abraham [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Kuk, Deborah; Zhang, Zhigang [Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Zelefsky, Michael J., E-mail: zelefskm@mskcc.org [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States)

    2013-03-15

    Purpose: We investigated the benefit of short-term androgen-deprivation therapy (ADT) in patients with intermediate-risk prostate cancer (PC) receiving dose-escalated external beam radiation therapy. Methods and Materials: The present retrospective study comprised 710 intermediate-risk PC patients receiving external beam radiation therapy with doses of ≥81 Gy at a single institution from 1992 to 2005, including 357 patients receiving neoadjuvant and concurrent ADT. Prostate-specific antigen recurrence-free survival (PSA-RFS) and distant metastasis (DM) were compared using the Kaplan-Meier method and Cox proportional hazards models. PC-specific mortality (PCSM) was assessed using competing-risks analysis. Results: The median follow-up was 7.9 years. Despite being more likely to have higher PSA levels, Gleason score 4 + 3 = 7, multiple National Comprehensive Cancer Network intermediate-risk factors, and older age (P≤.001 for all comparisons), patients receiving ADT had improved PSA-RFS (hazard ratio [HR], 0.598; 95% confidence interval [CI], 0.435-0.841; P=.003), DM (HR, 0.424; 95% CI, 0.219-0.819; P=.011), and PCSM (HR, 0.380; 95% CI, 0.157-0.921; P=.032) on univariate analysis. Using multivariate analysis, ADT was an even stronger predictor of improved PSA-RFS (adjusted HR [AHR], 0.516; 95% CI, 0.360-0.739; P<.001), DM (AHR, 0.347; 95% CI, 0.176-0.685; P=.002), and PCSM (AHR, 0.297; 95% CI, 0.128-0.685; P=.004). Gleason score 4 + 3 = 7 and ≥50% positive biopsy cores were other independent predictors of PCSM. Conclusions: Short-term ADT improves PSA-RFS, DM, and PCSM in patients with intermediate-risk PC undergoing dose-escalated external beam radiation therapy.

  12. Percentage of Cancer Volume in Biopsy Cores Is Prognostic for Prostate Cancer Death and Overall Survival in Patients Treated With Dose-Escalated External Beam Radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Vance, Sean M.; Stenmark, Matthew H.; Blas, Kevin; Halverson, Schulyer [Department of Radiation Oncology, University of Michigan Medical Center, Ann Arbor, Michigan (United States); Hamstra, Daniel A., E-mail: dhamm@umich.edu [Department of Radiation Oncology, University of Michigan Medical Center, Ann Arbor, Michigan (United States); Feng, Felix Y. [Department of Radiation Oncology, University of Michigan Medical Center, Ann Arbor, Michigan (United States); Department of Radiation Oncology, Veterans Affairs Medical Center, Ann Arbor, Michigan (United States)

    2012-07-01

    Purpose: To investigate the prognostic utility of the percentage of cancer volume (PCV) in needle biopsy specimens for prostate cancer patients treated with dose-escalated external beam radiotherapy. Methods and Materials: The outcomes were analyzed for 599 men treated for localized prostate cancer with external beam radiotherapy to a minimal planning target volume dose of 75 Gy (range, 75-79.2). We assessed the effect of PCV and the pretreatment and treatment-related factors on the freedom from biochemical failure, freedom from metastasis, cause-specific survival, and overall survival. Results: The median number of biopsy cores was 7 (interquartile range, 6-12), median PCV was 10% (interquartile range, 2.5-25%), and median follow-up was 62 months. The PCV correlated with the National Comprehensive Cancer Network risk group and individual risk features, including T stage, prostate-specific antigen level, Gleason score, and percentage of positive biopsy cores. On log-rank analysis, the PCV stratified by quartile was prognostic for all endpoints, including overall survival. In addition, the PCV was a stronger prognostic factor than the percentage of positive biopsy cores when the two metrics were analyzed together. On multivariate analysis, the PCV predicted a worse outcome for all endpoints, including freedom from biochemical failure, (hazard ratio, 1.9; p = .0035), freedom from metastasis (hazard ratio, 1.7, p = .09), cause-specific survival (hazard ratio, 3.9, p = .014), and overall survival (hazard ratio, 1.8, p = .02). Conclusions: For patients treated with dose-escalated external beam radiotherapy, the volume of cancer in the biopsy specimen adds prognostic value for clinically relevant endpoints, particularly in intermediate- and high-risk patients. Although the PCV determination is more arduous than the percentage of positive biopsy cores, it provides superior risk stratification.

  13. Hyperfractionated accelerated radiotherapy with concomitant integrated boost of 70-75 Gy in 5 weeks for advanced head and neck cancer. A phase I dose escalation study

    Energy Technology Data Exchange (ETDEWEB)

    Cvek, J.; Skacelikova, E.; Otahal, B.; Halamka, M.; Feltl, D. [University Hospital Ostrava (Czech Republic). Dept. of Oncology; Kubes, J. [University Hospital Bulovka, Prague (Czech Republic). Dept. of Radiation Oncology; Kominek, P. [University Hospital Ostrava (Czech Republic). Dept. of Otolaryngology

    2012-08-15

    Background and purpose: The present study was performed to evaluate the feasibility of a new, 5-week regimen of 70-75 Gy hyperfractionated accelerated radiotherapy with concomitant integrated boost (HARTCIB) for locally advanced, inoperable head and neck cancer. Methods and materials: A total of 39 patients with very advanced, stage IV nonmetastatic head and neck squamous cell carcinoma (median gross tumor volume 72 ml) were included in this phase I dose escalation study. A total of 50 fractions intensity-modulated radiotherapy (IMRT) were administered twice daily over 5 weeks. Prescribed total dose/dose per fraction for planning target volume (PTV{sub tumor}) were 70 Gy in 1.4 Gy fractions, 72.5 Gy in 1.45 Gy fractions, and 75 Gy in 1.5 Gy fractions for 10, 13, and 16 patients, respectively. Uninvolved lymphatic nodes (PTV{sub uninvolved}) were irradiated with 55 Gy in 1.1 Gy fractions using the concomitant integrated boost. Results: Acute toxicity was evaluated according to the RTOG/EORTC scale; the incidence of grade 3 mucositis was 51% in the oral cavity/pharynx and 0% in skin and the recovery time was {<=} 9 weeks for all patients. Late toxicity was evaluated in patients in complete remission according to the RTOG/EORTC scale. No grade 3/4 late toxicity was observed. The 1-year locoregional progression-free survival was 50% and overall survival was 55%. Conclusion: HARTCIB (75 Gy in 5 weeks) is feasible for patients deemed unsuitable for chemoradiation. Acute toxicity was lower than predicted from radiobiological models; duration of dysphagia and confluent mucositis were particularly short. Better conformity of radiotherapy allows the use of more intensive altered fractionation schedules compared with older studies. These results suggest that further dose escalation might be possible when highly conformal techniques (e.g., stereotactic radiotherapy) are used.

  14. Dosimetric feasibility of ablative dose escalated focal monotherapy with MRI-guided high-dose-rate (HDR) brachytherapy for prostate cancer.

    Science.gov (United States)

    Hosni, Ali; Carlone, Marco; Rink, Alexandra; Ménard, Cynthia; Chung, Peter; Berlin, Alejandro

    2017-01-01

    To determine the dosimetric feasibility of dose-escalated MRI-guided high-dose-rate brachytherapy (HDR-BT) focal monotherapy for prostate cancer (PCa). In all patients, GTV was defined with mpMRI, and deformably registered onto post-catheter insertion planning MRI. PTV included the GTV plus 9mm craniocaudal and 5mm in every other direction. In discovery-cohort, plans were obtained for each PTV independently aiming to deliver ⩾16.5Gy/fraction (two fraction schedule) while respecting predefined organs-at-risk (OAR) constraints or halted when achieved equivalent single-dose plan (24Gy). Dosimetric results of original and focal HDR-BT plans were evaluated to develop a planning protocol for the validation-cohort. In discovery-cohort (20-patients, 32-GTVs): PTV D95% ⩾16.5Gy could not be reached in a single plan (3%) and was accomplished (range 16.5-23.8Gy) in 15 GTVs (47%). Single-dose schedule was feasible in 16 (50%) plans. In the validation-cohort (10-patients, 10-GTVs, two separate implants each): plans met acceptable and ideal criteria in 100% and 43-100% respectively. Migration to single-dose treatment schedule was feasible in 7 implants (35%), without relaxing OAR's constraints or increasing the dose (D100% and D35%) to mpMRI-normal prostate (p>0.05). Focal ablative dose-escalated radiation is feasible with the proposed protocol. Prospective studies are warranted to determine the clinical outcomes. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  15. Dose escalation in large anterior skull-base tumors by means of IMRT. First experience with the Novalis {sup registered} system

    Energy Technology Data Exchange (ETDEWEB)

    Ernst-Stecken, A.; Sauer, R.; Grabenbauer, G. [Dept. of Radiation Therapy and Novalis Shaped Beam Surgery Center, Univ. Hospital of Erlangen-Nuremberg, Erlangen (Germany); Lambrecht, U.; Mueller, R. [Dept. of Radiation Therapy and Novalis Shaped Beam Surgery Center, Univ. Hospital of Erlangen-Nuremberg, Erlangen (Germany); Div. of Medical Physics, Dept. of Radiation Therapy, Univ. Hospital of Erlangen-Nuremberg, Erlangen (Germany); Ganslandt, O. [Dept. of Neurosurgery, Univ. of Erlangen-Nuremberg, Erlangen (Germany)

    2006-03-15

    Purpose: to evaluate the feasibility and tolerance of dose escalation with stereotactic intensity-modulated radiotherapy (sIMRT) for skull-base tumors. Patients and Methods: between 01/2003 and 12/2004, twelve patients were treated. Nine were exclusively treated at the Novalis {sup registered} site with one planning target volume (PTV) field boost, three were administered boost IMRT treatment (two with each one PTV-shrinking field, one with single PTV) after conventional three-dimensional conformal radiotherapy. This resulted in 23 PTVs with a median volume of 93.63 cm{sup 3} (range, 88.58-125.88 cm{sup 3}). Dose calculation was done by the pencil-beam algorithm. Median total doses of 66.6, 77.4, and 63.9 Gy were prescribed for sIMRT alone, sIMRT after 3-D conformal irradiation of the nasopharynx and cervical lymph nodes with 59.4 Gy, and for reirradiation, respectively. Results: 95% isodose PTV coverage was reached in 86.5% (range, 80-93%). Homogeneity (D{sub max}/D{sup ref}) was 1.11, 1.09, and 1.08. Median total doses to 50% of chiasm, right and left optic nerve were 16.21, 16.82 and 10.23 Gy. 11/12 patients are locally controlled with a median follow-up of 11 months (range, 3-23 months), one has died of pulmonary embolism after cerebrospinal dissemination of retinal adenocarcinoma. Conclusion: SIMRT enables dose escalation to tumors located close to critical organs. Inverse planning for micro-multileaf collimator stereotactic irradiation is practicable in the daily routine irradiation program. SIMRT needs special verification and still, the following parameters have to be standardized: IMRT dose specification, dose maxima, length of radiation delivery time. (orig.)

  16. A randomized, double-blind, placebo-controlled trial of citicoline for bipolar and unipolar depression and methamphetamine dependence.

    Science.gov (United States)

    Brown, E Sherwood; Gabrielson, Barry

    2012-12-20

    Methamphetamine use disorders are common and severe problems. Persons with mood disorders, particularly bipolar disorder, have high rates of substance use disorders. We previously reported promising findings on drug use, memory and study retention in patients with a history of mania and cocaine dependence given the nutritional supplement citicoline. In the current proof-of-concept study, we examined citicoline in bipolar or unipolar depression and methamphetamine dependence. Sixty adults with bipolar depression or major depressive disorder and methamphetamine dependence were randomized to citicoline (2000mg/day) or placebo for 12 weeks. Mood was assessed using Inventory of Depressive Symptomatology-Clinician Version (IDS-C), and cognition with the Hopkins Auditory Verbal Learning Test (HVLT). Drug use was assessed by urine drug screens. An ANCOVA of the intent-to-treat sample showed that those receiving citicoline (n=28) had a statistically significantly greater improvement in IDS-C scores than those receiving placebo (n=20). Survival in the study was significantly longer and completion rates significantly greater with citicoline than placebo. No significant differences were observed in memory or methamphetamine use. Citicoline was well tolerated. Sample heterogeneity and small sample size were limitations. To our knowledge this is the first placebo-controlled trial in a dual diagnosis sample with methamphetamine use disorders. Findings suggest that citicoline may have antidepressant properties in this population. Greater treatment retention with citicoline is also noteworthy in a patient population with substance dependence. Larger trials targeting depressive symptoms and treatment retention seem warranted. Copyright © 2012 Elsevier B.V. All rights reserved.

  17. Biomolecular structure manipulation using tailored electromagnetic radiation: a proof of concept on a simplified model of the active site of bacterial DNA topoisomerase.

    Science.gov (United States)

    Jarukanont, Daungruthai; Coimbra, João T S; Bauerhenne, Bernd; Fernandes, Pedro A; Patel, Shekhar; Ramos, Maria J; Garcia, Martin E

    2014-10-21

    We report on the viability of breaking selected bonds in biological systems using tailored electromagnetic radiation. We first demonstrate, by performing large-scale simulations, that pulsed electric fields cannot produce selective bond breaking. Then, we present a theoretical framework for describing selective energy concentration on particular bonds of biomolecules upon application of tailored electromagnetic radiation. The theory is based on the mapping of biomolecules to a set of coupled harmonic oscillators and on optimal control schemes to describe optimization of temporal shape, the phase and polarization of the external radiation. We have applied this theory to demonstrate the possibility of selective bond breaking in the active site of bacterial DNA topoisomerase. For this purpose, we have focused on a model that was built based on a case study. Results are given as a proof of concept.

  18. Development of a new test for the easy characterization of the adhesion at the interface of bilayer tablets: proof-of-concept study by experimental design.

    Science.gov (United States)

    Busignies, Virginie; Mazel, Vincent; Diarra, Harona; Tchoreloff, Pierre

    2014-12-30

    Although, adhesion at the interface of bilayer tablets is critical for their design it is difficult to characterize this adhesion between layers. In view of this, a new test with an easy implementation was proposed for the characterization of the interface of bilayer tablets. This work is presented as a proof-of-concept study to investigate the reliability of this new test with regard to the effects of some critical process parameters (e.g., compaction pressure applied on each layer) and material attributes (e.g., elasticity of the layered materials) on the interfacial adhesion of bilayer tablets. This was investigated using a design of experiment approach and the results obtained were in good accordance with those obtained with other tests and thus, confirms the potential of such a method for the measurement of the interfacial adhesion of bilayer tablets. Copyright © 2014 Elsevier B.V. All rights reserved.

  19. Bifunctional Inhibition of Human Immunodeficiency Virus Type 1 Reverse Transcriptase: Mechanism and Proof-of-Concept as a Novel Therapeutic Design Strategy

    Science.gov (United States)

    Bailey, Christopher M.; Sullivan, Todd J.; Iyidogan, Pinar; Tirado-Rives, Julian; Chung, Raymond; Ruiz-Caro, Juliana; Mohamed, Ebrahim; Jorgensen, William; Hunter, Roger; Anderson, Karen S.

    2013-01-01

    Human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) is a major target for currently approved anti-HIV drugs. These drugs are divided into two classes: nucleoside and non-nucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs). This study illustrates the synthesis and biochemical evaluation of a novel bifunctional RT inhibitor utilizing d4T (NRTI) and a TMC-derivative (a diarylpyrimidine NNRTI) linked via a poly(ethylene glycol) (PEG) linker. HIV-1 RT successfully incorporates the triphosphate of d4T-4PEG-TMC bifunctional inhibitor in a base-specific manner. Moreover, this inhibitor demonstrates low nanomolar potency that has 4.3-fold and 4300-fold enhancement of polymerization inhibition in vitro relative to the parent TMC-derivative and d4T, respectively. This study serves as a proof-of-concept for the development and optimization of bifunctional RT inhibitors as potent inhibitors of HIV-1 viral replication. PMID:23659183

  20. 'P-cadherin functional role is dependent on E-cadherin cellular context: a proof of concept using the breast cancer model'.

    Science.gov (United States)

    2016-05-01

    This article corrects: P-cadherin functional role is dependent on E-cadherin cellular context: a proof of concept using the breast cancer model Volume 229, Issue 5, 705–718, Article first published online: 24 January 2013. By Ana Sofia Ribeiro, Bárbara Sousa, Laura Carreto, Nuno Mendes, Ana Rita Nobre, Sara Ricardo, André Albergaria, Jorge F Cameselle-Teijeiro, Rene Gerhard, Ola Söderberg, Raquel Seruca, Manuel A Santos, Fernando Schmitt and Joana Paredes, J Pathol 2013; 229: 708–718. DOI: 10.1002/path.4143. The above article, published online on 24 January 2013 on Wiley Online Library (wileyonlinelibrary.com). The funding information, “This work was also funded by FEDER funds through the Operational Programme for Competitiveness Factors - COMPETE (FCOMP-01-0124-FEDER-021209).” was omitted from the Acknowledgements section. We apologise for any inconvenience caused.

  1. In vivo proof-of-concept of removal of the huntingtin caspase cleavage motif-encoding exon 12 approach in the YAC128 mouse model of Huntington's disease.

    Science.gov (United States)

    Casaca-Carreira, João; Toonen, Lodewijk J A; Evers, Melvin M; Jahanshahi, Ali; van-Roon-Mom, Willeke M C; Temel, Yasin

    2016-12-01

    Huntington's disease (HD) is a progressive autosomal dominant disease, caused by a CAG repeat expansion in the HTT gene, resulting in an expanded polyglutamine stretch at the N-terminal of the huntingtin protein. An important event in HD pathogenesis appears to be the proteolysis of the mutant protein, which forms N-terminal huntingtin fragments. These fragments form insoluble aggregates and are found in nuclei and cytoplasm of affected neurons where they interfere with normal cell functioning. Important cleavage sites are encoded by exon 12 of HTT. A novel approach is Htt protein modification through exon skipping, which has recently been proven effective both in vitro and in vivo. Here we report proof-of-concept of AON 12.1 in vivo using the YAC128 mouse model of HD. Our results support and encourage future longitudinal studies exploring the therapeutic effects of sustained infusions in the YAC128 mouse model.

  2. Electrochemical degradation of PAH compounds in process water: A kinetic study on model solutions and a proof of concept study on runoff water from harbour sediment purification

    DEFF Research Database (Denmark)

    Muff, Jens; Søgaard, Erik Gydesen

    2010-01-01

    The present study has investigated the possibility to apply electrochemical oxidation in the treatment of polycyclic aromatic hydrocarbon (PAHs) pollutants in water. The reaction kinetics of naphthalene, fluoranthene, and pyrene oxidation have been studied in a batch recirculation experimental....... Decreased current densities from 200 to 15 mA cm-2 in the NaCl electrolyte also decreased the removal rates, but significantly enhanced the current efficiencies of the PAH oxidation, based on a defined current efficiency constant, kq. This observation is believed to be due to the suppression of the water...... oxidation side reaction at lower applied voltages. A proof of concept study in real polluted water demonstrated the applicability of the electrochemical oxidation technique for larger scale use, where especially the indirect chloride mediated oxidation approach was a promising technique. However, the risk...

  3. Technology Assessment for Proof-of-Concept UF6 Cylinder Unique Identification Task 3.1.2 Report – Survey and Assessment of Technologies

    Energy Technology Data Exchange (ETDEWEB)

    Wylie, Joann; Hockert, John

    2014-04-24

    The National Nuclear Security Administration (NNSA) Office of Nonproliferation and International Security’s (NA-24) Next Generation Safeguards Initiative (NGSI) and the nuclear industry have begun to develop approaches to identify and monitor uranium hexafluoride (UF6) cylinders. The NA-24 interest in a global monitoring system for UF6 cylinders relates to its interest in supporting the International Atomic Energy Agency (IAEA) in deterring and detecting diversion of UF6 (e.g., loss of cylinder in transit) and undeclared excess production at conversion and enrichment facilities. The industry interest in a global monitoring system for UF6 cylinders relates to the improvements in operational efficiencies that such a system would provide. This task is part of an effort to survey and assess technologies for a UF6 cylinder to identify candidate technologies for a proof-of-concept demonstration and evaluation for the Cylinder Identification System (CIS).

  4. An Adaptive Treatment to Improve Positive Airway Pressure (PAP) Adherence in Patients With Obstructive Sleep Apnea: A Proof of Concept Trial.

    Science.gov (United States)

    Cvengros, Jamie A; Rodríguez, Vivian M; Snyder, Sarah; Hood, Megan M; Crawford, Megan; Park, Margaret

    2017-01-01

    Despite the benefits of positive airway pressure (PAP) treatment, rates of adherence to treatment are suboptimal. This proof-of-concept study assessed the feasibility, acceptability, and clinical significance of an adaptive treatment strategy to improve adherence to PAP. All participants first completed a brief educational intervention. Those who did not show at least a 25% increase in PAP use were randomized to receive a second, more intensive intervention, either motivational enhancement treatment or self-management treatment. Results suggested adequate feasibility and acceptability. In addition, participants demonstrated significant increases in objective PAP use, improvements in sleep quality, and decreases in daytime sleepiness. This study represents a first step in the development and validation of an adaptive treatment strategy to improve PAP adherence.

  5. Quantification of coffee blends for authentication of Asian palm civet coffee (Kopi Luwak) via metabolomics: A proof of concept.

    Science.gov (United States)

    Jumhawan, Udi; Putri, Sastia Prama; Yusianto; Bamba, Takeshi; Fukusaki, Eiichiro

    2016-07-01

    Asian palm civet coffee (Kopi Luwak), an animal-digested coffee with an exotic feature, carries a notorious reputation of being the rarest and most expensive coffee beverage in the world. Considering that illegal mixture of cheap coffee into civet coffee is a growing concern among consumers, we evaluated the use of metabolomics approach and orthogonal projection to latent structures (OPLS) prediction technique to quantify the degree of coffee adulteration. Two prediction sets, consisting of certified and commercial coffee, were made from a blend of civet and regular coffee with eleven mixing percentages. The prediction model exhibited accurate estimation of coffee blend percentage thus, successfully validating the prediction and quantification of the mixing composition of known-unknown samples. This work highlighted proof of concept of metabolomics application to predict degree of coffee adulteration by determining the civet coffee fraction in blends.

  6. Placebo-controlled trials and the Declaration of Helsinki.

    Science.gov (United States)

    Lewis, John A; Jonsson, Bertil; Kreutz, Gottfried; Sampaio, Cristina; van Zwieten-Boot, Barbara

    2002-04-13

    A revised version of the Declaration of Helsinki, issued in October, 2000, remains a vital expression of medical ethics, and deserves unanimous support. A strict interpretation of the declaration seems to rule out clinical trials that use a placebo control group whenever licensed therapeutic methods already exist, preferring active controls. Although the efficacy of some new medicines can be satisfactorily established without the use of a placebo, for others the judicious use of placebo remains essential to establish their effectiveness.

  7. A Virtual Reality avatar interaction (VRai) platform to assess residual executive dysfunction in active military personnel with previous mild traumatic brain injury: proof of concept.

    Science.gov (United States)

    Robitaille, Nicolas; Jackson, Philip L; Hébert, Luc J; Mercier, Catherine; Bouyer, Laurent J; Fecteau, Shirley; Richards, Carol L; McFadyen, Bradford J

    2017-10-01

    This proof of concept study tested the ability of a dual task walking protocol using a recently developed avatar-based virtual reality (VR) platform to detect differences between military personnel post mild traumatic brain injury (mTBI) and healthy controls. The VR platform coordinated motion capture, an interaction and rendering system, and a projection system to present first (participant-controlled) and third person avatars within the context of a specific military patrol scene. A divided attention task was also added. A healthy control group was compared to a group with previous mTBI (both groups comprised of six military personnel) and a repeated measures ANOVA tested for differences between conditions and groups based on recognition errors, walking speed and fluidity and obstacle clearance. The VR platform was well tolerated by both groups. Walking fluidity was degraded for the control group within the more complex navigational dual tasking involving avatars, and appeared greatest in the dual tasking with the interacting avatar. This navigational behaviour was not seen in the mTBI group. The present findings show proof of concept for using avatars, particularly more interactive avatars, to expose differences in executive functioning when applying context-specific protocols (here for the military). Implications for rehabilitation Virtual reality provides a means to control context-specific factors for assessment and intervention. Adding human interaction and agency through avatars increases the ecologic nature of the virtual environment. Avatars in the present application of the Virtual Reality avatar interaction platform appear to provide a better ability to reveal differences between trained, military personal with and without mTBI.

  8. Investigations of motor-cortex cortical plasticity following facilitatory and inhibitory transcranial theta-burst stimulation in schizophrenia: a proof-of-concept study.

    Science.gov (United States)

    Hasan, Alkomiet; Brinkmann, Caroline; Strube, Wolfgang; Palm, Ulrich; Malchow, Berend; Rothwell, John C; Falkai, Peter; Wobrock, Thomas

    2015-02-01

    Impaired neural plasticity has been proposed as an important pathophysiological feature underlying the neurobiology and symptomatology of schizophrenia. In this proof-of-concept study, we aimed to explore cortical plasticity in schizophrenia patients with two different transcranial theta-burst (TBS) paradigms. TBS induces Ca(2+)-dependent long-term-potentiation (LTP)-like and long-term-depression (LTP)-like plasticity in the human motor cortex. A total of 10 schizophrenia patients and 10 healthy controls were included in this study. Cortical excitability was investigated using transcranial magnetic stimulation in each study participant before and after TBS applied to the left primary motor-cortex on two different days. cTBS600 was used to induce LTD-like and cTBS300 was used to induce LTP-like plasticity in the absence of any prior motor-cortex activation. Repeated measures ANOVAs showed a significant interaction between the timecourse, the study group and the stimulation paradigm (cTBS600 vs. cTBS300) for the left, but not for the right hemisphere. Healthy controls showed an MEP amplitude decrease at a trend level following cTBS600 and a numeric, but not significant, increase in MEP amplitudes following cTBS300. Schizophrenia patients did not show an MEP amplitude decrease following cTBS600, but surprisingly a significant MEP decrease following cTBS300. The proportion of subjects showing the expected changes in motor-cortex excitability following both cTBS paradigms was higher in healthy controls. These preliminary results indicate differences in cortical plasticity following two different cTBS protocols in schizophrenia patients compared to healthy controls. However, the incomplete plasticity response in the healthy controls and the proof-of-concept nature of this study need to be considered as important limitations.

  9. A Phase II Multicentre, Open-Label, Proof-of-Concept Study of Tasquinimod in Hepatocellular, Ovarian, Renal Cell, and Gastric Cancers.

    Science.gov (United States)

    Escudier, Bernard; Faivre, Sandrine; Van Cutsem, Eric; Germann, Nathalie; Pouget, Jean-Christophe; Plummer, Ruth; Vergote, Ignace; Thistlethwaite, Fiona; Bjarnason, Georg A; Jones, Robert; Mackay, Helen; Edeline, Julien; Fartoux, Laetitia; Hirte, Hal; Oza, Amit

    2017-08-10

    Tasquinimod is a small molecule with immunomodulatory, anti-angiogenic, and anti-metastatic properties that targets the tumor microenvironment. This study aimed to obtain a clinical proof of concept that tasquinimod was active and tolerable in patients with advanced solid tumors. This early stopping design, open-label, proof-of-concept clinical trial evaluated the clinical activity of tasquinimod in four independent cohorts of patients with advanced hepatocellular (n = 53), ovarian (n = 55), renal cell (n = 38), and gastric (n = 21) cancers. Tasquinimod was given orally every day (0.5 mg/day for at least 2 weeks, with dose increase to 1 mg/day) until radiological progression according to Response Evaluation Criteria in Solid Tumor (RECIST) 1.1 criteria, intolerable toxicity, or patient withdrawal. The primary efficacy endpoint was progression-free survival (PFS) rate according to RECIST 1.1 by central assessment. Interim futility analyses at 8 weeks (6 weeks for the gastric cancer cohort) found adequate clinical activity of tasquinimod only in the hepatocellular cohort and recruitment to the other three cohorts was stopped. PFS rates were 26.9% at 16 weeks, 7.3% at 24 weeks, 13.2% at 16 weeks, and 9.5% at 12 weeks, respectively, in hepatocellular, ovarian, renal cell, and gastric cancer cohorts. The pre-defined PFS threshold was not reached in the hepatocellular cancer cohort at the second stage of the trial. The most common treatment-related adverse events were fatigue (48.5%), nausea (34.1%), decreased appetite (31.7%), and vomiting (24.6%). This study failed to demonstrate clinical activity of tasquinimod in heavily pre-treated patients with advanced hepatocellular, ovarian, renal cell, and gastric cancer. NCT01743469.

  10. Prefrontal Transcranial Direct Current Stimulation for Treatment of Schizophrenia With Predominant Negative Symptoms: A Double-Blind, Sham-Controlled Proof-of-Concept Study.

    Science.gov (United States)

    Palm, Ulrich; Keeser, Daniel; Hasan, Alkomiet; Kupka, Michael J; Blautzik, Janusch; Sarubin, Nina; Kaymakanova, Filipa; Unger, Ina; Falkai, Peter; Meindl, Thomas; Ertl-Wagner, Birgit; Padberg, Frank

    2016-09-01

    Negative symptoms are highly relevant in the long-term course of schizophrenia and are an important target domain for the development of novel interventions. Recently, transcranial direct current stimulation (tDCS) of the prefrontal cortex has been investigated as a treatment option in schizophrenia. In this proof-of-concept study, 20 schizophrenia patients with predominantly negative symptoms were randomized to either 10 sessions of add-on active (2 mA, 20min) or sham tDCS (anode: left DLPFC/F3; cathode: right supraorbital/F4). Primary outcome measure was the change in the Scale for the Assessment of Negative Symptoms (SANS) sum score; secondary outcomes included reduction in Positive and Negative Syndrome Scale (PANSS) scores and improvement of depressive symptoms, cognitive processing speed, and executive functioning. Sixteen patients underwent 4 functional connectivity magnetic resonance imaging (fcMRI) scans (pre and post 1st and pre and post 10th tDCS) to investigate changes in resting state network connectivity after tDCS. Per-protocol analysis showed a significantly greater decrease in SANS score after active (-36.1%) than after sham tDCS (-0.7%). PANSS sum scores decreased significantly more with active (-23.4%) than with sham stimulation (-2.2%). Explorative analysis of fcMRI data indicated changes in subgenual cortex and dorsolateral prefrontal cortex (DLPFC) connectivity within frontal-thalamic-temporo-parietal networks. The results of this first proof-of-concept study indicate that prefrontal tDCS may be a promising intervention for treatment of schizophrenia with predominant negative symptoms. Large-scale randomized controlled studies are needed to further establish prefrontal tDCS as novel treatment for negative symptoms in schizophrenia. © The Author 2016. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  11. A multi-channel bioluminescent bacterial biosensor for the on-line detection of metals and toxicity. Part II: technical development and proof of concept of the biosensor

    Energy Technology Data Exchange (ETDEWEB)

    Charrier, Thomas; Thouand, Gerald [UMR CNRS 6144 GEPEA, CBAC, Nantes University, PRES UNAM, Campus de la Courtaisiere-IUT, La Roche-sur-Yon cedex (France); Chapeau, Cyrille [Biolumine, Biokar Diagnostic, Rue des Quarante Mines ZAC de Ther-Allonne, Beauvais Cedex (France); Bendria, Loubna; Daniel, Philippe [UMR CNRS 6087 LPEC, Universite du Maine, Av Olivier Messiaen, Le Mans cedex 9 (France); Picart, Pascal [UMR CNRS 6613 IAM-LAUM, Ecole Nationale des Ingenieurs du Mans, Universite du Maine, Le Mans Cedex 9 (France)

    2011-05-15

    This research study deals with the on-line detection of heavy metals and toxicity within the context of environmental pollution monitoring. It describes the construction and the proof of concept of a multi-channel bioluminescent bacterial biosensor in immobilized phase: Lumisens3. This new versatile device, designed for the non-stop analysis of water pollution, enables the insertion of any bioluminescent strains (inducible or constitutive), immobilized in a multi-well removable card. The technical design of Lumisens3 has benefited from both a classical and a robust approach and includes four main parts: (1) a dedicated removable card contains 64 wells, 3 mm in depth, arranged in eight grooves within which bacteria are immobilized, (2) this card is incubated on a Pelletier block with a CCD cooled camera on top for bioluminescence monitoring, (3) a fluidic network feeds the card with the sample to be analyzed and finally (4) a dedicated computer interface, BIOLUX 1.0, controls all the elements of the biosensor, allowing it to operate autonomously. The proof of concept of this biosensor was performed using a set of four bioluminescent bacteria (Escherichia coli DH1 pBzntlux, pBarslux, pBcoplux, and E. coli XL1 pBfiluxCDABE) in the on-line detection of CdCl{sub 2} 0.5 {mu}M and As{sub 2}O{sub 3} 5 {mu}M from an influent. When considering metals individually, the ''fingerprints'' from the biosensor were as expected. However, when metals were mixed together, cross reaction and synergistic effects were detected. This biosensor allowed us to demonstrate the simultaneous on-line cross detection of one or several heavy metals as well as the measurement of the overall toxicity of the sample. (orig.)

  12. Early peripheral laser photocoagulation of nonperfused retina improves vision in patients with central retinal vein occlusion (Results of a proof of concept study).

    Science.gov (United States)

    Rehak, Matus; Tilgner, Eric; Franke, Annegret; Rauscher, Franziska G; Brosteanu, Oana; Wiedemann, Peter

    2014-05-01

    To evaluate the effect of combination of ranibizumab and laser photocoagulation to peripheral retinal areas of nonperfusion in patients with non-ischemic central retinal vein occlusion (CRVO) without neovascularizations. This prospective, proof of concept study randomized 22 CRVO patients into two arms. The RL group (ranibizumab + laser; n = 10) received ranibizumab with additive laser photocoagulation; the control R group (n = 12) was treated with ranibizumab only. All patients received three initial monthly ranibizumab injections followed by PRN regimen. Changes in best corrected visual acuity (BCVA) and in central retinal thickness (CRT) were documented over 6 months. Median of BCVA improved in the RL group from 65 ETDRS letters (interquartile range IQR = 10 letters) at baseline to 70 (IQR = 23.2) letters at month 6. In the control group BCVA remained stable [baseline: 61 (IQR = 19.5) and month 6: 61 (IQR = 22) letters]. CRT decreased between baseline and final visit in the RL group from 547 (IQR = 513) μm to 246.5 (IQR = 346.3) μm, and in the control group from 637.5 (IQR = 344) μm to 423 (IQR = 737) μm. More pronounced improvements in BCVA were seen in the RL group (medians = 14 vs. 6.5 letters) although the observed group differences were not statistically significant due to small samples. The selective laser photocoagulation of peripheral areas of nonperfusion seems to lead to additional visual improvement in patients with CRVO. A larger replication trial is necessary to confirm the results of this proof of concept study.

  13. Feasibility of PET-CT based hypofractionated accelerated dose escalation in oropharyngeal cancers: Final dosimetric results of the VORTIGERN study. (Secondary endpoint of UK NCRI portfolio: MREC No: 08/H0907/127, UKCRN ID 7341

    Directory of Open Access Journals (Sweden)

    Sanjoy Chatterjee

    2015-01-01

    Conclusion: Hypofractionated, slightly accelerated dose escalation in oropharyngeal cancers is likely to be safe and the chance of trismus is not any higher than when standard dose radiotherapy is used. Active measures to reduce dose to the MA achieves acceptable dose volume parameters even at escalated doses.

  14. Clinical-grade manufacturing of autologous mature mRNA-electroporated dendritic cells and safety testing in acute myeloid leukemia patients in a phase I dose-escalation clinical trial.

    NARCIS (Netherlands)

    Driessche, A. Van; Velde, A.L. Van de; Nijs, G.; Braeckman, T.; Stein, B.; Vries, I.J.M. de; Berneman, Z.N.; Tendeloo, V.F. Van

    2009-01-01

    BACKGROUND AIMS: RNA-electroporated dendritic cell (DC)-based vaccines are rapidly gaining interest as therapeutic cancer vaccines. We report on a phase I dose-escalation trial using clinical-grade manufactured mature RNA-electroporated DC in acute myeloid leukemia (AML) patients. METHODS: CD14(+)

  15. [18F]fluoroethylcholine-PET/CT imaging for radiation treatment planning of recurrent and primary prostate cancer with dose escalation to PET/CT-positive lymph nodes

    Directory of Open Access Journals (Sweden)

    Wahl Andreas

    2011-05-01

    Full Text Available Abstract Background At present there is no consensus on irradiation treatment volumes for intermediate to high-risk primary cancers or recurrent disease. Conventional imaging modalities, such as CT, MRI and transrectal ultrasound, are considered suboptimal for treatment decisions. Choline-PET/CT might be considered as the imaging modality in radiooncology to select and delineate clinical target volumes extending the prostate gland or prostate fossa. In conjunction with intensity modulated radiotherapy (IMRT and imaged guided radiotherapy (IGRT, it might offer the opportunity of dose escalation to selected sites while avoiding unnecessary irradiation of healthy tissues. Methods Twenty-six patients with primary (n = 7 or recurrent (n = 19 prostate cancer received Choline-PET/CT planned 3D conformal or intensity modulated radiotherapy. The median age of the patients was 65 yrs (range 45 to 78 yrs. PET/CT-scans with F18-fluoroethylcholine (FEC were performed on a combined PET/CT-scanner equipped for radiation therapy planning. The majority of patients had intermediate to high risk prostate cancer. All patients received 3D conformal or intensity modulated and imaged guided radiotherapy with megavoltage cone beam CT. The median dose to primary tumours was 75.6 Gy and to FEC-positive recurrent lymph nodal sites 66,6 Gy. The median follow-up time was 28.8 months. Results The mean SUVmax in primary cancer was 5,97 in the prostate gland and 3,2 in pelvic lymph nodes. Patients with recurrent cancer had a mean SUVmax of 4,38. Two patients had negative PET/CT scans. At 28 months the overall survival rate is 94%. Biochemical relapse free survival is 83% for primary cancer and 49% for recurrent tumours. Distant disease free survival is 100% and 75% for primary and recurrent cancer, respectively. Acute normal tissue toxicity was mild in 85% and moderate (grade 2 in 15%. No or mild late side effects were observed in the majority of patients (84%. One patient had

  16. Risk of Late Toxicity in Men Receiving Dose-Escalated Hypofractionated Intensity Modulated Prostate Radiation Therapy: Results From a Randomized Trial

    Energy Technology Data Exchange (ETDEWEB)

    Hoffman, Karen E., E-mail: khoffman1@mdanderson.org; Voong, K. Ranh; Pugh, Thomas J.; Skinner, Heath; Levy, Lawrence B.; Takiar, Vinita; Choi, Seungtaek; Du, Weiliang; Frank, Steven J.; Johnson, Jennifer; Kanke, James; Kudchadker, Rajat J.; Lee, Andrew K.; Mahmood, Usama; McGuire, Sean E.; Kuban, Deborah A.

    2014-04-01

    Objective: To report late toxicity outcomes from a randomized trial comparing conventional and hypofractionated prostate radiation therapy and to identify dosimetric and clinical parameters associated with late toxicity after hypofractionated treatment. Methods and Materials: Men with localized prostate cancer were enrolled in a trial that randomized men to either conventionally fractionated intensity modulated radiation therapy (CIMRT, 75.6 Gy in 1.8-Gy fractions) or to dose-escalated hypofractionated IMRT (HIMRT, 72 Gy in 2.4-Gy fractions). Late (≥90 days after completion of radiation therapy) genitourinary (GU) and gastrointestinal (GI) toxicity were prospectively evaluated and scored according to modified Radiation Therapy Oncology Group criteria. Results: 101 men received CIMRT and 102 men received HIMRT. The median age was 68, and the median follow-up time was 6.0 years. Twenty-eight percent had low-risk, 71% had intermediate-risk, and 1% had high-risk disease. There was no difference in late GU toxicity in men treated with CIMRT and HIMRT. The actuarial 5-year grade ≥2 GU toxicity was 16.5% after CIMRT and 15.8% after HIMRT (P=.97). There was a nonsignificant numeric increase in late GI toxicity in men treated with HIMRT compared with men treated with CIMRT. The actuarial 5-year grade ≥2 GI toxicity was 5.1% after CIMRT and 10.0% after HIMRT (P=.11). In men receiving HIMRT, the proportion of rectum receiving 36.9 Gy, 46.2 Gy, 64.6 Gy, and 73.9 Gy was associated with the development of late GI toxicity (P<.05). The 5-year actuarial grade ≥2 GI toxicity was 27.3% in men with R64.6Gy ≥ 20% but only 6.0% in men with R64.6Gy < 20% (P=.016). Conclusions: Dose-escalated IMRT using a moderate hypofractionation regimen (72 Gy in 2.4-Gy fractions) can be delivered safely with limited grade 2 or 3 late toxicity. Minimizing the proportion of rectum that receives moderate and high dose decreases the risk of late rectal toxicity after this

  17. SU-E-T-69: A Radiobiological Investigation of Dose Escalation in Lower Oesophageal Tumours with a Focus On Gastric Toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Carrington, R [Cardiff University, Cardiff, Wales (United Kingdom); Staffurth, J; Spezi, E; Crosby, T [Velindre Cancer Centre, Cardiff, Wales (United Kingdom); Warren, S; Partridge, M; Hawkins, M [CRUK/MRC Oxford Institute for Radiation Oncology, Oxford (United Kingdom); Gwynne, S [Singleton Hospital, Swansea, Wales (United Kingdom)

    2015-06-15

    The incidence of lower third oesophageal tumours is increasing in most Western populations. With the role of radiotherapy dose escalation being identified as a research priority in improving outcomes, it is important to quantify the increased toxicity that this may pose to sites such as the lower oesophagus. This study therefore aims to investigate the feasibility of lower oesophageal dose escalation with a focus on stomach tissue toxicity.The original 3D-conformal plans (50Gy3D) from 10 patients in the SCOPE1 trial were reviewed and compared to two RapidArc plans created retrospectively to represent the treatment arms of the forthcoming SCOPE2 trial: 50GyRA and 60GyRA (50Gy to PTV1 with a simultaneously integrated boost of 60Gy to PTV2). The stomach was contoured as stomach wall and dose constraints set according to QUANTEC. Normal tissue complication probability (NTCP) was estimated for the stomach wall for an endpoint of gastric bleeding. There was a mean increase of 5.93% in NTCP from 50Gy3D to 60GyRA and a mean increase of 8.15% in NTCP from the 50GyRA to 60GyRA. With NTCP modelling restricted to volumes outside PTV2, there was a mean decrease of 0.92% in NTCP from the 50Gy3D to 60GyRA, and a mean increase of 2.25% from 50GyRA to 60GyRA. There was a strong correlation between the NTCP and Stomach Wall/PTV1 overlap volume for all plans (R=0.80, 0.77 and 0.77 for 60GyRA, 50GyRA and 50Gy3D respectively). There was also a strong correlation between NTCP and the Stomach Wall/PTV2 overlap volume for 60GyRA (R= 0.82).Radiobiological modelling suggests that increasing the prescribed dose to 60Gy may be associated with a significantly increased risk of toxicity to the stomach within the boost volume. It is recommended that stomach toxicity be closely monitored prospectively when treating patients with lower oesophageal tumours in the forthcoming SCOPE 2 trial. Rhys Carrington received a PhD studentship grant from Cancer Research Wales. Grant number: 2445; Dr Warren and

  18. Somatostatin-based radiotherapy with [90Y-DOTA]-TOC in neuroendocrine tumors: long-term outcome of a phase I dose escalation study

    Directory of Open Access Journals (Sweden)

    Marincek Nicolas

    2013-01-01

    Full Text Available Abstract Background We describe the long-term outcome after clinical introduction and dose escalation of somatostatin receptor targeted therapy with [90Y-DOTA]-TOC in patients with metastasized neuroendocrine tumors. Methods In a clinical phase I dose escalation study we treated patients with increasing [90Y-DOTA]-TOC activities. Multivariable Cox regression and competing risk regression were used to compare efficacy and toxicities of the different dosage protocols. Results Overall, 359 patients were recruited; 60 patients were enrolled for low dose (median: 2.4 GBq/cycle, range 0.9-7.8 GBq/cycle, 77 patients were enrolled for intermediate dose (median: 3.3 GBq/cycle, range: 2.0-7.4 GBq/cycle and 222 patients were enrolled for high dose (median: 6.7 GBq/cycle, range: 3.7-8.1 GBq/cycle [90Y-DOTA]-TOC treatment. The incidences of hematotoxicities grade 1–4 were 65.0%, 64.9% and 74.8%; the incidences of grade 4/5 kidney toxicities were 8.4%, 6.5% and 14.0%, and the median survival was 39 (range: 1–158 months, 34 (range: 1–118 months and 29 (range: 1–113 months. The high dose protocol was associated with an increased risk of kidney toxicity (Hazard Ratio: 3.12 (1.13-8.59 vs. intermediate dose, p = 0.03 and a shorter overall survival (Hazard Ratio: 2.50 (1.08-5.79 vs. low dose, p = 0.03. Conclusions Increasing [90Y-DOTA]-TOC activities may be associated with increasing hematological toxicities. The dose related hematotoxicity profile of [90Y-DOTA]-TOC could facilitate tailoring [90Y-DOTA]-TOC in patients with preexisting hematotoxicities. The results of the long-term outcome suggest that fractionated [90Y-DOTA]-TOC treatment might allow to reduce renal toxicity and to improve overall survival. (ClinicalTrials.gov number NCT00978211.

  19. Acute anxiolytic effects of quetiapine during virtual reality exposure--a double-blind placebo-controlled trial in patients with specific phobia.

    Science.gov (United States)

    Diemer, Julia; Domschke, Katharina; Mühlberger, Andreas; Winter, Bernward; Zavorotnyy, Maxim; Notzon, Swantje; Silling, Karen; Arolt, Volker; Zwanzger, Peter

    2013-11-01

    Anxiety disorders are among the most frequent psychiatric disorders. With regard to pharmacological treatment, antidepressants, the calcium modulator pregabalin and benzodiazepines are recommended according to current treatment guidelines. With regard to acute states of anxiety, so far practically only benzodiazepines provide an immediate anxiolytic effect. However, the risk of tolerance and dependency limits the use of this class of medication. Therefore, there is still a need for alternative pharmacologic strategies. Increasing evidence points towards anxiety-reducing properties of atypical antipsychotics, particularly quetiapine. Therefore, we aimed to evaluate the putative acute anxiolytic effects of this compound, choosing the induction of acute anxiety in patients with specific phobia as a model for the evaluation of ad-hoc anxiolytic properties in a proof-of-concept approach. In a randomized, double-blind, placebo-controlled study, 58 patients with arachnophobia were treated with a single dose of quetiapine XR or placebo prior to a virtual reality spider challenge procedure. Treatment effects were monitored using rating scales for acute anxiety as well as measurements of heart rate and skin conductance. Overall, quetiapine showed significant anxiolytic effects compared to placebo. However, effects were not seen on the primary outcome measure (VAS Anxiety), but were limited to somatic anxiety symptoms. Additionally, a significant reduction of skin conductance was observed. Further exploratory analyses hint towards a mediating role of the (COMT) val158met genotype on treatment response. The present results thus suggest a possible suitability of quetiapine in the acute treatment of anxiety, particularly with regard to somatic symptoms.

  20. Safety and Proof-of-Concept Study of Oral QLT091001 in Retinitis Pigmentosa Due to Inherited Deficiencies of Retinal Pigment Epithelial 65 Protein (RPE65) or Lecithin:Retinol Acyltransferase (LRAT): e0143846

    National Research Council Canada - National Science Library

    Hendrik P N Scholl; Anthony T Moore; Robert K Koenekoop; Yuquan Wen; Gerald A Fishman; Ingeborgh van den Born; Ava Bittner; Kristen Bowles; Emily C Fletcher; Frederick T Collison; Gislin Dagnelie; Simona Degli Eposti; Michel Michaelides; David A Saperstein; Ronald A Schuchard; Claire Barnes; Wadih Zein; Ditta Zobor; David G Birch; Janine D Mendola; Eberhart Zrenner

    2015-01-01

    ...). Safety and visual outcomes of a once-daily oral dose of 40 mg/m2/day QLT091001 for 7 consecutive days was investigated in an international, multi-center, open-label, proof-of-concept study in 18...

  1. Safety and Proof-of-Concept Study of Oral QLT091001 in Retinitis Pigmentosa Due to Inherited Deficiencies of Retinal Pigment Epithelial 65 Protein (RPE65) or Lecithin:Retinol Acyltransferase (LRAT)

    National Research Council Canada - National Science Library

    Scholl, Hendrik P N; Moore, Anthony T; Koenekoop, Robert K; Wen, Yuquan; Fishman, Gerald A; van den Born, L Ingeborgh; Bittner, Ava; Bowles, Kristen; Fletcher, Emily C; Collison, Frederick T; Dagnelie, Gislin; Degli Eposti, Simona; Michaelides, Michel; Saperstein, David A; Schuchard, Ronald A; Barnes, Claire; Zein, Wadih; Zobor, Ditta; Birch, David G; Mendola, Janine D; Zrenner, Eberhart

    2015-01-01

    ...). Safety and visual outcomes of a once-daily oral dose of 40 mg/m2/day QLT091001 for 7 consecutive days was investigated in an international, multi-center, open-label, proof-of-concept study in 18...

  2. Why people download the freeware AIDA v4.3a diabetes software program: a proof-of-concept semi-automated analysis.

    Science.gov (United States)

    Lehmann, Eldon D

    2003-01-01

    AIDA is a diabetes-computing program freely available at www.2aida.org on the Web. The software is intended to serve as an educational support tool and can be used by anyone who has an interest in diabetes, whether they be patients, relatives, health-care professionals, or students. In previous "Diabetes Information Technology & WebWatch" columns various indicators of usage of the AIDA program have been reviewed, and various comments from users of the software have been documented. The purpose of this column is to overview a proof-of-concept semi-automated analysis about why people are downloading the latest version of the AIDA educational diabetes program. AIDA permits the interactive simulation of plasma insulin and blood glucose profiles for teaching, demonstration, self-learning, and research purposes. It has been made freely available, without charge, on the Internet as a noncommercial contribution to continuing diabetes education. Since its launch in 1996 over 300,000 visits have been logged at the main AIDA Website-www.2aida.org-and over 60,000 copies of the AIDA program have been downloaded free-of-charge. This column documents the results of a semi-automated analysis of comments left by Website visitors while they were downloading the AIDA software, before they had a chance to use the program. The Internet-based survey methodology and semi-automated analysis were both found to be robust and reliable. Over a 5-month period (from October 3, 2001 to February 28, 2002) 400 responses were received. During the corresponding period 1,770 actual visits were made to the Website survey page-giving a response rate to this proof-of-concept study of 22.6%. Responses were received from participants in over 54 countries-with nearly half of these (n = 194; 48.5%) originating from the United States, United Kingdom, and Canada; 208 responses (52.0%) were received from patients with diabetes, 50 (12.5%) from doctors, 49 (12.3%) from relatives of patients, with fewer

  3. Use of the Blom Tracheotomy Tube with Suction Inner Cannula to Decontaminate Microorganisms from the Subglottic Space. A Proof of Concept.

    Science.gov (United States)

    Rabach, Lesley; Siegel, Mark D; Puchalski, Jonathan T; Towle, Dana; Follert, Michelle; Johnson, Kelsey M; Rademaker, Alfred W; Leder, Steven B

    2015-06-01

    Preventing pulmonary complications during mechanical ventilation via tracheotomy is a high priority. To investigate if the Blom tracheotomy tube with suction-above-the-cuff inner cannula reduced the quantity of normal flora and pathogens in supra- versus subglottic spaces. We enrolled 20 consecutive medical ICU adults requiring tracheostomy for mechanical ventilation in this proof-of-concept, prospective, single-center study. All participants received a Blom tracheotomy tube with suction-above-the-cuff inner cannula to decontaminate microorganisms from the supra- and subglottic spaces. Supra- and subglottic sputum samples were obtained for microbiologic analysis while an endotracheal tube was in place before tracheotomy and once per week for up to 4 weeks of mechanical ventilation after tracheotomy. Demographics, duration of endotracheal tube intubation, and duration of mechanical ventilation post-tracheotomy were recorded. There was a significant reduction for supraglottic (2.86 ± 1.11 [mean ± SD]) versus subglottic suction samples (2.48 ± 1.07) (paired t test, P = 0.048; Wilcoxon test, P = 0.045) when all data pairs for normal flora and pathogens were combined across times. There was a significant reduction of normal flora pooled across times in 19 data pairs for supraglottic (3.00 ± 1.05) versus subglottic suction samples (2.00 ± 0.94) (paired t test, P = 0.0004; Wilcoxon test, P = 0.0007). There was no significant reduction of pathogens pooled across times in 25 data pairs for supraglottic (2.76 ± 1.16) versus subglottic suction samples (2.84 ± 1.03) (paired t test, P = 0.75; Wilcoxon test, P = 0.83). Proof-of-concept was confirmed. The Blom tracheotomy tube with disposable suction-above-the-cuff inner cannula decontaminated microorganisms from the subglottic space when normal flora and pathogens were combined. Future research should investigate if decreased quantity of normal flora and pathogens in the subglottic space reduces the incidence of

  4. Topical, Non-Medicated LOYON(®) in Facilitating the Removal of Scaling in Infants and Children with Cradle Cap: a Proof-of-Concept Pilot Study.

    Science.gov (United States)

    Hengge, Ulrich R

    2014-12-01

    Cradle cap is a very common condition in infants that presents as greasy, scaly patches on the scalp within the first weeks of life. Although usually disappearing by itself, the condition worries parents because of its appearance. When removing the scales, it is crucial to prevent spot bleedings to avoid infections. The investigational medical device LOYON(®) (Cetiol(®) CC, dimethicone) solution (G. Pohl-Boskamp GmbH & Co. KG, Hohenlockstedt, Germany) has the potential to meet these needs since it removes scales gently. It was, therefore, the aim of this proof-of-concept study to assess the efficacy and safety of topically applied, non-medicated LOYON(®) in facilitating the removal of scaling in infants and children with cradle cap without inducing spot bleedings. This single-center, open, proof-of-concept, pilot study was conducted in 20 male or female infants/children aged 3-36 months with clinically diagnosed cradle cap. The 8-day study period included one to three applications of LOYON(®). Clinical assessment of scaling and secondary parameters was performed at baseline and after treatment. Adverse events were recorded. A questionnaire on subjective efficacy and usability was handed out to the parents. With a maximum of three applications of LOYON(®) applied to 20 subjects, a reduction in scaling intensity from moderate or severe to very mild or mild was achieved in 80% of the subjects. Treatment success, defined as the reduction of the scaling baseline score by at least two points, was achieved in 50% of subjects. Results of this study do not indicate any safety concern. No spot bleedings were observed. LOYON(®) was generally well tolerated and overall treatment was rated as "good" by the parents/legal guardians. This study suggests that LOYON(®) is well tolerated, safe and effective in facilitating the removal of scaling in infants and children with cradle cap. With its gentle approach and rapid effect, LOYON(®) thus represents a good alternative to

  5. Monitoring pharmacologically induced immunosuppression by immune repertoire sequencing to detect acute allograft rejection in heart transplant patients: a proof-of-concept diagnostic accuracy study.

    Directory of Open Access Journals (Sweden)

    Christopher Vollmers

    2015-10-01

    Full Text Available It remains difficult to predict and to measure the efficacy of pharmacological immunosuppression. We hypothesized that measuring the B-cell repertoire would enable assessment of the overall level of immunosuppression after heart transplantation.In this proof-of-concept study, we implemented a molecular-barcode-based immune repertoire sequencing assay that sensitively and accurately measures the isotype and clonal composition of the circulating B cell repertoire. We used this assay to measure the temporal response of the B cell repertoire to immunosuppression after heart transplantation. We selected a subset of 12 participants from a larger prospective cohort study (ClinicalTrials.gov NCT01985412 that is ongoing at Stanford Medical Center and for which enrollment started in March 2010. This subset of 12 participants was selected to represent post-heart-transplant events, with and without acute rejection (six participants with moderate-to-severe rejection and six without. We analyzed 130 samples from these patients, with an average follow-up period of 15 mo. Immune repertoire sequencing enables the measurement of a patient's net state of immunosuppression (correlation with tacrolimus level, r = -0.867, 95% CI -0.968 to -0.523, p = 0.0014, as well as the diagnosis of acute allograft rejection, which is preceded by increased immune activity with a sensitivity of 71.4% (95% CI 30.3% to 94.9% and a specificity of 82.0% (95% CI 72.1% to 89.1% (cell-free donor-derived DNA as noninvasive gold standard. To illustrate the potential of immune repertoire sequencing to monitor atypical post-transplant trajectories, we analyzed two more patients, one with chronic infections and one with amyloidosis. A larger, prospective study will be needed to validate the power of immune repertoire sequencing to predict rejection events, as this proof-of-concept study is limited to a small number of patients who were selected based on several criteria including the

  6. Monitoring Pharmacologically Induced Immunosuppression by Immune Repertoire Sequencing to Detect Acute Allograft Rejection in Heart Transplant Patients: A Proof-of-Concept Diagnostic Accuracy Study

    Science.gov (United States)

    Valantine, Hannah A.; Penland, Lolita; Luikart, Helen; Strehl, Calvin; Cohen, Garrett; Khush, Kiran K.; Quake, Stephen R.

    2015-01-01

    Background It remains difficult to predict and to measure the efficacy of pharmacological immunosuppression. We hypothesized that measuring the B-cell repertoire would enable assessment of the overall level of immunosuppression after heart transplantation. Methods and Findings In this proof-of-concept study, we implemented a molecular-barcode-based immune repertoire sequencing assay that sensitively and accurately measures the isotype and clonal composition of the circulating B cell repertoire. We used this assay to measure the temporal response of the B cell repertoire to immunosuppression after heart transplantation. We selected a subset of 12 participants from a larger prospective cohort study (ClinicalTrials.gov NCT01985412) that is ongoing at Stanford Medical Center and for which enrollment started in March 2010. This subset of 12 participants was selected to represent post-heart-transplant events, with and without acute rejection (six participants with moderate-to-severe rejection and six without). We analyzed 130 samples from these patients, with an average follow-up period of 15 mo. Immune repertoire sequencing enables the measurement of a patient’s net state of immunosuppression (correlation with tacrolimus level, r = −0.867, 95% CI −0.968 to −0.523, p = 0.0014), as well as the diagnosis of acute allograft rejection, which is preceded by increased immune activity with a sensitivity of 71.4% (95% CI 30.3% to 94.9%) and a specificity of 82.0% (95% CI 72.1% to 89.1%) (cell-free donor-derived DNA as noninvasive gold standard). To illustrate the potential of immune repertoire sequencing to monitor atypical post-transplant trajectories, we analyzed two more patients, one with chronic infections and one with amyloidosis. A larger, prospective study will be needed to validate the power of immune repertoire sequencing to predict rejection events, as this proof-of-concept study is limited to a small number of patients who were selected based on several

  7. Enhancing global vaccine pharmacovigilance: Proof-of-concept study on aseptic meningitis and immune thrombocytopenic purpura following measles-mumps containing vaccination.

    Science.gov (United States)

    Perez-Vilar, Silvia; Weibel, Daniel; Sturkenboom, Miriam; Black, Steven; Maure, Christine; Castro, Jose Luis; Bravo-Alcántara, Pamela; Dodd, Caitlin N; Romio, Silvana A; de Ridder, Maria; Nakato, Swabra; Molina-León, Helvert Felipe; Elango, Varalakshmi; Zuber, Patrick L F

    2017-05-27

    New vaccines designed to prevent diseases endemic in low and middle-income countries (LMICs) are now being introduced without prior record of utilization in countries with robust pharmacovigilance systems. To address this deficit, our objective was to demonstrate feasibility of an international hospital-based network for the assessment of potential epidemiological associations between serious and rare adverse events and vaccines in any setting. This was done through a proof-of-concept evaluation of the risk of immune thrombocytopenic purpura (ITP) and aseptic meningitis (AM) following administration of the first dose of measles-mumps-containing vaccines using the self-controlled risk interval method in the primary analysis. The World Health Organization (WHO) selected 26 sentinel sites (49 hospitals) distributed in 16 countries of the six WHO regions. Incidence rate ratios (IRR) of 5.0 (95% CI: 2.5-9.7) for ITP following first dose of measles-containing vaccinations, and of 10.9 (95% CI: 4.2-27.8) for AM following mumps-containing vaccinations were found. The strain-specific analyses showed significantly elevated ITP risk for measles vaccines containing Schwarz (IRR: 20.7; 95% CI: 2.7-157.6), Edmonston-Zagreb (IRR: 11.1; 95% CI: 1.4-90.3), and Enders'Edmonston (IRR: 8.5; 95% CI: 1.9-38.1) strains. A significantly elevated AM risk for vaccines containing the Leningrad-Zagreb mumps strain (IRR: 10.8; 95% CI: 1.3-87.4) was also found. This proof-of-concept study has shown, for the first time, that an international hospital-based network for the investigation of rare vaccine adverse events, using common standardized procedures and with high participation of LMICs, is feasible, can produce reliable results, and has the potential to characterize differences in risk between vaccine strains. The completion of this network by adding large reference hospitals, particularly from tropical countries, and the systematic WHO-led implementation of this approach, should permit the

  8. The influence of amniotic membrane extracts on cell growth depends on the part of membrane and childbirth mode selected: a proof-of-concept study.

    Science.gov (United States)

    Litwiniuk, M; Radowicka, M; Krejner, A; Grzela, T

    2017-08-02

    The amniotic membrane (AM) is a rich source of biologically active factors, important for wound healing and is widely used in various clinical applications, including tissue engineering, reconstructive surgery and wound management. The aim of the present proof-of-concept study was to assess the influence of amniotic membrane extracts on in vitro proliferation of main cells involved in tissue regeneration. The assessment was done in regards to the content of selected biologically active factors in amniotic membrane extracts. The quantitative analysis of EGF, TGF-β and TIMP-1 in tested samples was assayed by enzyme-linked immunosorbent assay (ELISA) tests. The influence of amniotic membrane extracts on proliferation of keratinocytes (HaCaT), fibroblasts (Wi-38) and endothelial cell lines (HECa-10) was assessed using a colorimetric tetrazolium salt reduction assay. In all of the amnion samples high amounts of EGF, TGF-β and TIMP-1 were detected. However, the content of these factors varied between placental and cervical portions of the same membrane. Moreover, various concentrations of biologically active factors between physiological at-term delivery and caesarean section-derived membranes were also observed. All of the assessed amnion extracts stimulated proliferation of HaCaT and Wi-38 cells, although samples prepared from caesarean section-derived cervical portion of amniotic membrane stimulated more proliferation of keratinocytes than of fibroblasts. In contrast to HaCaT and Wi-38 cells, proliferation of HECa-10 cell line was inhibited by all tested extracts. The results of our proof-of-concept study confirm that biological dressings prepared from amniotic membrane, especially its placental portion, since they stimulated both fibroblasts and keratinocytes, may provide relevant support for wound healing. On the other hand, dressings prepared from caesarean section-derived cervical portion of amniotic membrane, since they stimulate mainly epidermal cells, may be

  9. Promotion of the mind through exercise (PROMoTE: a proof-of-concept randomized controlled trial of aerobic exercise training in older adults with vascular cognitive impairment

    Directory of Open Access Journals (Sweden)

    Davis Jennifer C

    2010-02-01

    Full Text Available Abstract Background Sub-cortical vascular ischaemia is the second most common etiology contributing to cognitive impairment in older adults, and is frequently under-diagnosed and under-treated. Although evidence is mounting that exercise has benefits for cognitive function among seniors, very few randomized controlled trials of exercise have been conducted in populations at high-risk for progression to dementia. Aerobic-based exercise training may be of specific benefit in delaying the progression of cognitive decline among seniors with vascular cognitive impairment by reducing key vascular risk factors associated with metabolic syndrome. Thus, we aim to carry out a proof-of-concept single-blinded randomized controlled trial primarily designed to provide preliminary evidence of efficacy aerobic-based exercise training program on cognitive and everyday function among older adults with mild sub-cortical ischaemic vascular cognitive impairment. Methods/Design A proof-of-concept single-blinded randomized trial comparing a six-month, thrice-weekly, aerobic-based exercise training group with usual care on cognitive and everyday function. Seventy older adults who meet the diagnostic criteria for sub-cortical ischaemic vascular cognitive impairment as outlined by Erkinjuntti and colleagues will be recruited from a memory clinic of a metropolitan hospital. The aerobic-based exercise training will last for 6 months. Participants will be followed for an additional six months after the cessation of exercise training. Discussion This research will be an important first step in quantifying the effect of an exercise intervention on cognitive and daily function among seniors with sub-cortical ischaemic vascular cognitive impairment, a recognized risk state for progression to dementia. Exercise has the potential to be an effective, inexpensive, and accessible intervention strategy with minimal adverse effects. Reducing the rate of cognitive decline among seniors

  10. A Phase I Dose Escalation Study Demonstrates Quercetin Safety and Explores Potential for Bioflavonoid Antivirals in Patients with Chronic Hepatitis C.

    Science.gov (United States)

    Lu, Nu T; Crespi, Catherine M; Liu, Natalie M; Vu, James Q; Ahmadieh, Yasaman; Wu, Sheng; Lin, Sherry; McClune, Amy; Durazo, Francisco; Saab, Sammy; Han, Steven; Neiman, David C; Beaven, Simon; French, Samuel W

    2016-01-01

    The hepatitis C virus (HCV) infects more than 180 million people worldwide, with long-term consequences including liver failure and hepatocellular carcinoma. Quercetin bioflavonoids can decrease HCV production in tissue culture, in part through inhibition of heat shock proteins. If quercetin demonstrates safety and antiviral activity in patients, then it could be developed into an inexpensive HCV treatment for third world countries or other affected populations that lack financial means to cover the cost of mainstream antivirals. A phase 1 dose escalation study was performed to evaluate the safety of quercetin in 30 untreated patients with chronic HCV infection and to preliminarily characterize quercetin's potential in suppressing viral load and/or liver injury. Quercetin displayed safety in all trial participants. Additionally, 8 patients showed a "clinically meaningful" 0.41-log viral load decrease. There was a positive correlation (r = 0.41, p = 0.03) indicating a tendency for HCV decrease in patients with a lower ratio of plasma quercetin relative to dose. No significant changes in aspartate transaminase and alanine transaminase were detected. In conclusion, quercetin exhibited safety (up to 5 g daily) and there was a potential for antiviral activity in some hepatitis C patients.

  11. Predictors of Rectal Tolerance Observed in a Dose-Escalated Phase 1-2 Trial of Stereotactic Body Radiation Therapy for Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Kim, D.W. Nathan [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Cho, L. Chinsoo [Department of Radiation Oncology, University of Minnesota, Minneapolis, Minnesota (United States); Straka, Christopher [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Christie, Alana [Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Lotan, Yair [Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Pistenmaa, David [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Kavanagh, Brian D. [Department of Radiation Oncology, University of Colorado, Denver, Colorado (United States); Nanda, Akash [Department of Radiation Oncology, University of Florida Health Cancer Center at Orlando Health, Orlando, Florida (United States); Kueplian, Patrick [Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, California (United States); Brindle, Jeffrey [Prairie Lakes Hospital, Watertown, South Dakota (United States); Cooley, Susan; Perkins, Alida [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Raben, David [Department of Radiation Oncology, University of Colorado, Denver, Colorado (United States); Xie, Xian-Jin [Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Timmerman, Robert D., E-mail: robert.timmerman@utsouthwestern.edu [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States)

    2014-07-01

    Purpose: To convey the occurrence of isolated cases of severe rectal toxicity at the highest dose level tested in 5-fraction stereotactic body radiation therapy (SBRT) for localized prostate cancer; and to rationally test potential causal mechanisms to guide future studies and experiments to aid in mitigating or altogether avoiding such severe bowel injury. Methods and Materials: Clinical and treatment planning data were analyzed from 91 patients enrolled from 2006 to 2011 on a dose-escalation (45, 47.5, and 50 Gy in 5 fractions) phase 1/2 clinical study of SBRT for localized prostate cancer. Results: At the highest dose level, 6.6% of patients treated (6 of 91) developed high-grade rectal toxicity, 5 of whom required colostomy. Grade 3+ delayed rectal toxicity was strongly correlated with volume of rectal wall receiving 50 Gy >3 cm{sup 3} (P<.0001), and treatment of >35% circumference of rectal wall to 39 Gy (P=.003). Grade 2+ acute rectal toxicity was significantly correlated with treatment of >50% circumference of rectal wall to 24 Gy (P=.010). Conclusion: Caution is advised when considering high-dose SBRT for treatment of tumors near bowel structures, including prostate cancer. Threshold dose constraints developed from physiologic principles are defined, and if respected can minimize risk of severe rectal toxicity.

  12. Ultra-high-resolution 3D imaging of atherosclerosis in mice with synchrotron differential phase contrast: a proof of concept study

    Science.gov (United States)

    Bonanno, Gabriele; Coppo, Simone; Modregger, Peter; Pellegrin, Maxime; Stuber, Annina; Stampanoni, Marco; Mazzolai, Lucia; Stuber, Matthias; van Heeswijk, Ruud B.

    2015-07-01

    The goal of this study was to investigate the performance of 3D synchrotron differential phase contrast (DPC) imaging for the visualization of both macroscopic and microscopic aspects of atherosclerosis in the mouse vasculature ex vivo. The hearts and aortas of 2 atherosclerotic and 2 wild-type control mice were scanned with DPC imaging with an isotropic resolution of 15 μm. The coronary artery vessel walls were segmented in the DPC datasets to assess their thickness, and histological staining was performed at the level of atherosclerotic plaques. The DPC imaging allowed for the visualization of complex structures such as the coronary arteries and their branches, the thin fibrous cap of atherosclerotic plaques as well as the chordae tendineae. The coronary vessel wall thickness ranged from 37.4 ± 5.6 μm in proximal coronary arteries to 13.6 ± 3.3 μm in distal branches. No consistent differences in coronary vessel wall thickness were detected between the wild-type and atherosclerotic hearts in this proof-of-concept study, although the standard deviation in the atherosclerotic mice was higher in most segments, consistent with the observation of occasional focal vessel wall thickening. Overall, DPC imaging of the cardiovascular system of the mice allowed for a simultaneous detailed 3D morphological assessment of both large structures and microscopic details.

  13. Auditory-motor mapping training as an intervention to facilitate speech output in non-verbal children with autism: a proof of concept study.

    Directory of Open Access Journals (Sweden)

    Catherine Y Wan

    Full Text Available Although up to 25% of children with autism are non-verbal, there are very few interventions that can reliably produce significant improvements in speech output. Recently, a novel intervention called Auditory-Motor Mapping Training (AMMT has been developed, which aims to promote speech production directly by training the association between sounds and articulatory actions using intonation and bimanual motor activities. AMMT capitalizes on the inherent musical strengths of children with autism, and offers activities that they intrinsically enjoy. It also engages and potentially stimulates a network of brain regions that may be dysfunctional in autism. Here, we report an initial efficacy study to provide 'proof of concept' for AMMT. Six non-verbal children with autism participated. Prior to treatment, the children had no intelligible words. They each received 40 individual sessions of AMMT 5 times per week, over an 8-week period. Probe assessments were conducted periodically during baseline, therapy, and follow-up sessions. After therapy, all children showed significant improvements in their ability to articulate words and phrases, with generalization to items that were not practiced during therapy sessions. Because these children had no or minimal vocal output prior to treatment, the acquisition of speech sounds and word approximations through AMMT represents a critical step in expressive language development in children with autism.

  14. Proof-of-Concept Testing of the Passive Cooling System (T-CLIP™) for Solar Thermal Applications at an Elevated Temperature

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Seung Jun [Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Applied Engineering and Technology; Quintana, Donald L. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Applied Engineering and Technology; Vigil, Gabrielle M. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Applied Engineering and Technology; Perraglio, Martin Juan [Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Applied Engineering and Technology; Farley, Cory Wayne [Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Applied Engineering and Technology; Tafoya, Jose I. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Applied Engineering and Technology; Martinez, Adam L. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Applied Engineering and Technology

    2015-11-30

    The Applied Engineering and Technology-1 group (AET-1) at Los Alamos National Laboratory (LANL) conducted the proof-of-concept tests of SolarSPOT LLC’s solar thermal Temperature- Clipper, or T-CLIP™ under controlled thermal conditions using a thermal conditioning unit (TCU) and a custom made environmental chamber. The passive T-CLIP™ is a plumbing apparatus that attaches to a solar thermal collector to limit working fluid temperature and to prevent overheating, since overheating may lead to various accident scenarios. The goal of the current research was to evaluate the ability of the T-CLIP™ to control the working fluid temperature by using its passive cooling mechanism (i.e. thermosiphon, or natural circulation) in a small-scale solar thermal system. The assembled environmental chamber that is thermally controlled with the TCU allows one to simulate the various possible weather conditions, which the solar system will encounter. The performance of the T-CLIP™ was tested at two different target temperatures: 1) room temperature (70 °F) and 2) an elevated temperature (130 °F). The current test campaign demonstrated that the T-CLIP™ was able to prevent overheating by thermosiphon induced cooling in a small-scale solar thermal system. This is an important safety feature in situations where the pump is turned off due to malfunction or power outages.

  15. Proof of concept of a method that assesses the spread of microbial infections with spatially explicit and non-spatially explicit data

    Directory of Open Access Journals (Sweden)

    Smith Stephen D

    2008-11-01

    Full Text Available Abstract Background A method that assesses bacterial spatial dissemination was explored. It measures microbial genotypes (defined by electrophoretic patterns or EP, host, location (farm, interfarm Euclidean distance, and time. Its proof of concept (construct and internal validity was evaluated using a dataset that included 113 Staphylococcus aureus EPs from 1126 bovine milk isolates collected on 23 farms between 1988 and 2005. Results Construct validity was assessed by comparing results based on the interfarm Euclidean distance (a spatially explicit measure and those produced by the (non-spatial interfarm number of isolates reporting the same EP. The distance associated with EP spread correlated with the interfarm number of isolates/EP (r = .59, P r = .72, P r = .87, P Conclusion Findings supported both construct and internal validity. Because 3 EPs explained 12 times more isolates than expected and at least twice as many isolates as other EPs did, false negative results associated with the remaining EPs (those erroneously identified as lacking spatial dispersal when, in fact, they disseminated spatially, if they occurred, seemed to have negligible effects. Spatial analysis of laboratory data may support disease surveillance systems by generating hypotheses on microbial dispersal ability.

  16. Persistent Luminescence Nanophosphor Involved Near-Infrared Optical Bioimaging for Investigation of Foodborne Probiotics Biodistribution in Vivo: A Proof-of-Concept Study.

    Science.gov (United States)

    Liu, Yaoyao; Liu, Jing-Min; Zhang, Dongdong; Ge, Kun; Wang, Peihua; Liu, Huilin; Fang, Guozhen; Wang, Shuo

    2017-09-20

    Probiotics has attracted great attention in food nutrition and safety research field, but thus far there are limited analytical techniques for visualized and real-time monitoring of the probiotics when they are ingested in vivo. Herein, the optical bioimaging technique has been introduced for investigation of foodborne probiotics biodistribution in vivo, employing the near-infrared (NIR) emitting persistent luminescence nanophosphors (PLNPs) of Cr(3+)-doped zinc gallogermanate (ZGGO) as the contrast nanoprobes. The ultrabrightness, super long afterglow, polydispersed size, low toxicity, and excellent photostability and biocompatibility of PLNPs were demonstrated to be qualified as a tracer for labeling probiotics via antibody (anti-Gram positive bacteria LTA antibody) recognition as well as contrast agent for long-term bioimaging the probiotics. In vivo optical bioimaging assay showed that the LTA antibody functionalized ZGGO nanoprobes that could be efficiently tagged to the probiobics were successfully applied for real-time monitoring and nondamaged probing of the biodistribution of probiotics inside the living body after oral administration. This work presents a proof-of-concept that exploited the bioimaging methodology for real-time and nondamaged researching the foodborne probiotics behaviors in vivo, which would open up a novel way of food safety detection and nutrition investigation.

  17. A New Proof of Concept in Bacterial Reduction: Antimicrobial Action of Violet-Blue Light (405 nm in Ex Vivo Stored Plasma

    Directory of Open Access Journals (Sweden)

    Michelle Maclean

    2016-01-01

    Full Text Available Bacterial contamination of injectable stored biological fluids such as blood plasma and platelet concentrates preserved in plasma at room temperature is a major health risk. Current pathogen reduction technologies (PRT rely on the use of chemicals and/or ultraviolet light, which affects product quality and can be associated with adverse events in recipients. 405 nm violet-blue light is antibacterial without the use of photosensitizers and can be applied at levels safe for human exposure, making it of potential interest for decontamination of biological fluids such as plasma. As a pilot study to test whether 405 nm light is capable of inactivating bacteria in biological fluids, rabbit plasma and human plasma were seeded with bacteria and treated with a 405 nm light emitting diode (LED exposure system (patent pending. Inactivation was achieved in all tested samples, ranging from low volumes to prebagged plasma. 99.9% reduction of low density bacterial populations (≤103 CFU mL−1, selected to represent typical “natural” contamination levels, was achieved using doses of 144 Jcm−2. The penetrability of 405 nm light, permitting decontamination of prebagged plasma, and the nonrequirement for photosensitizing agents provide a new proof of concept in bacterial reduction in biological fluids, especially injectable fluids relevant to transfusion medicine.

  18. An open and flexible interface proposal and proof of concept implementation to support service orientated architectures and interoperability in the tactical environment

    Science.gov (United States)

    Peach, Nicholas

    2012-06-01

    The development of SOAs in the tactical domain has been hindered by a lack of interface standards suitable for the environment of unpredictable and low bandwidth communications, low powered computers and dynamic ad-hoc grouping of tactical participants. Existing commercial SOA standards have assumed reliable access to central servers and services and having relatively static participants. The proposal describes an open and published message-oriented interface created to support the aims of the upcoming MOD Generic Base Architecture1 (GBA) Defence Standard and the associated Land Open Systems Architecture2. The aims are; a) to support multiple open transport protocols, such as HTTP, SMTP, DDS and MQTT; b) to be suitable for integrating together low-level utility functions with their controlling systems (such as water, waste and power) and integrating together high-level mission-support functions (such as ISTAR and C2); c) reduce operator burden by using automated discovery and configuration where possible; d) dynamically integrate with MOD Generic Vehicle Architecture3 platforms to link base and vehicle mission and logistics systems over tactical radio links; e) extensible to support features such as security classification; f) to be lightweight in implementation and bandwidth and not dependent on central servers for operation. The paper will present the proposed interface and describe the features required for a military tactical rather than a commercial environment, and will report the outcome of a MOD-funded proof of concept that uses the proposed interface to interoperate several military systems.

  19. Enhancing the evaluation of pathogen transmission risk in a hospital by merging hand-hygiene compliance and contact data: a proof-of-concept study

    CERN Document Server

    Mastrandrea, Rossana; Brouqui, Philippe; Barrat, Alain

    2016-01-01

    Hand-hygiene compliance and contacts of health-care workers largely determine the potential paths of pathogen transmission in hospital wards. We explored how the combination of data collected by two automated infrastructures based on wearable sensors and recording (i) use of hydro-alcoholic solution and (ii) contacts of health-care workers provide an enhanced view of the risk of transmission events in the ward. We perform a proof-of-concept observational study. Detailed data on contact patterns and hand-hygiene compliance of health-care workers were collected by wearable sensors over 12 days in an infectious disease unit of a hospital in Marseilles, France. 10837 contact events among 10 doctors, 4 nurses, 4 nurses' aids and 4 housekeeping staff were recorded during the study. Most contacts took place among medical doctors. Aggregate contact durations were highly heterogeneous and the resulting contact network was highly structured. 510 visits of health-care workers to patients' rooms were recorded, with a low...

  20. First Human Use of a Radiopharmaceutical Prepared by Continuous-Flow Microfluidic Radiofluorination: Proof of Concept with the Tau Imaging Agent [18F]T807

    Directory of Open Access Journals (Sweden)

    Steven H. Liang

    2014-10-01

    Full Text Available Despite extensive preclinical imaging with radiotracers developed by continuous-flow microfluidics, a positron emission tomographic (PET radiopharmaceutical has not been reported for human imaging studies by this technology. The goal of this study was to validate the synthesis of the tau radiopharmaceutical 7-(6-fluoropyridin-3-yl-5H-pyrido[4,3-b]indole ([18F]T807 and perform first-in-human PET scanning enabled by microfluidic flow chemistry. [18F]T807 was synthesized by our modified one-step method and adapted to suit a commercial microfluidic flow chemistry module. For this proof of concept, the flow system was integrated to a GE Tracerlab FXFN unit for high-performance liquid chromatography purification and formulation. Three consecutive productions of [18F]T807 were conducted to validate this radiopharmaceutical. Uncorrected radiochemical yields of 17 ± 1% of crude [18F]T807 (≈ 500 mCi, radiochemical purity 95% were obtained from the microfluidic device. The crude material was then purified, and > 100 mCi of the final product was obtained in an overall uncorrected radiochemical yield of 5 ± 1% (n = 3, relative to starting [18F]fluoride (end of bombardment, with high radiochemical purity (≥ 99% and high specific activities (6 Ci/μmol in 100 minutes. A clinical research study was carried out with [18F]T807, representing the first reported human imaging study with a radiopharmaceutical prepared by this technology.

  1. Proof of concept for AAV2/5-mediated gene therapy in iPSC-derived retinal pigment epithelium of a choroideremia patient.

    Science.gov (United States)

    Cereso, Nicolas; Pequignot, Marie O; Robert, Lorenne; Becker, Fabienne; De Luca, Valerie; Nabholz, Nicolas; Rigau, Valerie; De Vos, John; Hamel, Christian P; Kalatzis, Vasiliki

    2014-01-01

    Inherited retinal dystrophies (IRDs) comprise a large group of genetically and clinically heterogeneous diseases that lead to progressive vision loss, for which a paucity of disease-mimicking animal models renders preclinical studies difficult. We sought to develop pertinent human cellular IRD models, beginning with choroideremia, caused by mutations in the CHM gene encoding Rab escort protein 1 (REP1). We reprogrammed REP1-deficient fibroblasts from a CHM (-/y) patient into induced pluripotent stem cells (iPSCs), which we differentiated into retinal pigment epithelium (RPE). This iPSC-derived RPE is a polarized monolayer with a classic morphology, expresses characteristic markers, is functional for fluid transport and phagocytosis, and mimics the biochemical phenotype of patients. We assayed a panel of adeno-associated virus (AAV) vector serotypes and showed that AAV2/5 is the most efficient at transducing the iPSC-derived RPE and that CHM gene transfer normalizes the biochemical phenotype. The high, and unmatched, in vitro transduction efficiency is likely aided by phagocytosis and mimics the scenario that an AAV vector encounters in vivo in the subretinal space. We demonstrate the superiority of AAV2/5 in the human RPE and address the potential of patient iPSC-derived RPE to provide a proof-of-concept model for gene replacement in the absence of an appropriate animal model.

  2. The Use of Screen-Printed Electrodes in a Proof of Concept Electrochemical Estimation of Homocysteine and Glutathione in the Presence of Cysteine Using Catechol

    Directory of Open Access Journals (Sweden)

    Patricia T. Lee

    2014-06-01

    Full Text Available Screen printed electrodes were employed in a proof of concept determination of homocysteine and glutathione using electrochemically oxidized catechol via a 1,4-Michael addition reaction in the absence and presence of cysteine, and each other. Using cyclic voltammetry, the Michael reaction introduces a new adduct peak which is analytically useful in detecting thiols. The proposed procedure relies on the different rates of reaction of glutathione and homocysteine with oxidized catechol so that at fast voltage scan rates only homocysteine is detected in cyclic voltammetry. At slower scan rates, both glutathione and homocysteine are detected. The combination of the two sets of data provides quantification for homocysteine and glutathione. The presence of cysteine is shown not to interfere provided sufficient high concentrations of catechol are used. Calibration curves were determined for each homocysteine and glutathione detection; where the sensitivities are 0.019 µA·µM−1 and 0.0019 µA·µM−1 and limit of detections are ca. 1.2 µM and 0.11 µM for homocysteine and glutathione, respectively, within the linear range. This work presents results with potential and beneficial use in re-useable and/or disposable point-of-use sensors for biological and medical applications.

  3. Use of CBCT Imaging, Open-Source Modeling Software, and Desktop Stereolithography 3D Printing to Duplicate a Removable Dental Prosthesis-A Proof of Concept.

    Science.gov (United States)

    Lin, Wei-Shao; Harris, Bryan T; Morton, Dean

    2017-09-01

    This article describes an alternative computer-aided design/computer-aided manufacturing (CAD/CAM) technique that uses cone-beam computed tomography (CBCT) imaging, open-source 3-dimensional (3D) modeling software, and a desktop stereolithography (SLA) 3D printer to duplicate an existing complete removable dental prosthesis (CRDP). Intended to offer a proof of concept, this proposed technique provides dental clinicians who have access to a CBCT imaging unit and a desktop SLA 3D printer an option to manufacture a duplicated prosthesis in-office. The 3D model of the CRDP can be preserved indefinitely, and the CAD/CAM process makes it possible to manufacture the CRDP multiple times with ease, when necessary. Different materials can be selected for the SLA 3D printer, and the duplicated prosthesis could be used for a variety of clinical and laboratory indications, such as a custom tray, a trial prosthesis, a reference record for a definitive prosthesis in laboratory procedures, or a radiographic template. Clinicians should select and use 3D software, printers, and materials with proper biocompatibility and classification and clearance from respective medical device regulatory bodies (such as US Food & Drug Administration) in different intended applications.

  4. A New Proof of Concept in Bacterial Reduction: Antimicrobial Action of Violet-Blue Light (405 nm) in Ex Vivo Stored Plasma

    Science.gov (United States)

    Maclean, Michelle; Anderson, John G.; MacGregor, Scott J.; White, Tracy

    2016-01-01

    Bacterial contamination of injectable stored biological fluids such as blood plasma and platelet concentrates preserved in plasma at room temperature is a major health risk. Current pathogen reduction technologies (PRT) rely on the use of chemicals and/or ultraviolet light, which affects product quality and can be associated with adverse events in recipients. 405 nm violet-blue light is antibacterial without the use of photosensitizers and can be applied at levels safe for human exposure, making it of potential interest for decontamination of biological fluids such as plasma. As a pilot study to test whether 405 nm light is capable of inactivating bacteria in biological fluids, rabbit plasma and human plasma were seeded with bacteria and treated with a 405 nm light emitting diode (LED) exposure system (patent pending). Inactivation was achieved in all tested samples, ranging from low volumes to prebagged plasma. 99.9% reduction of low density bacterial populations (≤103 CFU mL−1), selected to represent typical “natural” contamination levels, was achieved using doses of 144 Jcm−2. The penetrability of 405 nm light, permitting decontamination of prebagged plasma, and the nonrequirement for photosensitizing agents provide a new proof of concept in bacterial reduction in biological fluids, especially injectable fluids relevant to transfusion medicine. PMID:27774337

  5. Targeted adsorption of molecules in the colon with the novel adsorbent-based medicinal product, DAV132: A proof of concept study in healthy subjects.

    Science.gov (United States)

    de Gunzburg, Jean; Ducher, Annie; Modess, Christiane; Wegner, Danilo; Oswald, Stefan; Dressman, Jennifer; Augustin, Violaine; Feger, Céline; Andremont, Antoine; Weitschies, Werner; Siegmund, Werner

    2015-01-01

    During antibiotic treatments, active residuals reaching the colon profoundly affect the bacterial flora resulting in the emergence of resistance. To prevent these effects, we developed an enteric-coated formulated activated-charcoal based product, DAV132, meant to deliver its adsorbent to the ileum and neutralize antibiotic residues in the proximal colon. In a randomized, control, crossover study, the plasma pharmacokinetics of the probe drugs amoxicillin (500 mg) absorbed in the proximal intestine, and sulfapyridine (25 mg) metabolized from sulfasalazine in the cecum and rapidly absorbed, were compared after a single administration in 18 healthy subjects who had received DAV132, uncoated formulated activated charcoal (FAC) or water 16 and 8 hours before, concomitantly with the probe drugs, and 8 hours thereafter. The AUC0-96 h of amoxicillin was reduced by more than 70% when it was taken with FAC, but bioequivalent when it was taken with water or DAV132. By contrast, the AUC0-96 h of sulfapyridine was reduced by more than 90% when administered with either FAC or DAV132 in comparison with water. The results show that DAV132 can selectively adsorb drug compounds in the proximal colon, without interfering with drug absorption in the proximal small intestine, thereby constituting a proof of concept that DAV132 actually functions in humans.

  6. The Use of Screen-Printed Electrodes in a Proof of Concept Electrochemical Estimation of Homocysteine and Glutathione in the Presence of Cysteine Using Catechol

    Science.gov (United States)

    Lee, Patricia T.; Lowinsohn, Denise; Compton, Richard G.

    2014-01-01

    Screen printed electrodes were employed in a proof of concept determination of homocysteine and glutathione using electrochemically oxidized catechol via a 1,4-Michael addition reaction in the absence and presence of cysteine, and each other. Using cyclic voltammetry, the Michael reaction introduces a new adduct peak which is analytically useful in detecting thiols. The proposed procedure relies on the different rates of reaction of glutathione and homocysteine with oxidized catechol so that at fast voltage scan rates only homocysteine is detected in cyclic voltammetry. At slower scan rates, both glutathione and homocysteine are detected. The combination of the two sets of data provides quantification for homocysteine and glutathione. The presence of cysteine is shown not to interfere provided sufficient high concentrations of catechol are used. Calibration curves were determined for each homocysteine and glutathione detection; where the sensitivities are 0.019 μA·μM−1 and 0.0019 μA·μM−1 and limit of detections are ca. 1.2 μM and 0.11 μM for homocysteine and glutathione, respectively, within the linear range. This work presents results with potential and beneficial use in re-useable and/or disposable point-of-use sensors for biological and medical applications. PMID:24926695

  7. Activity Monitoring and Heart Rate Variability as Indicators of Fall Risk: Proof-of-Concept for Application of Wearable Sensors in the Acute Care Setting.

    Science.gov (United States)

    Razjouyan, Javad; Grewal, Gurtej Singh; Rishel, Cindy; Parthasarathy, Sairam; Mohler, Jane; Najafi, Bijan

    2017-03-02

    Growing concern for falls in acute care settings could be addressed with objective evaluation of fall risk. The current proof-of-concept study evaluated the feasibility of using a chest-worn sensor during hospitalization to determine fall risk. Physical activity and heart rate variability (HRV) of 31 volunteers admitted to a 29-bed adult inpatient unit were recorded using a single chest-worn sensor. Sensor data during the first 24-hour recording were analyzed. Participants were stratified using the Hendrich II fall risk assessment into high and low fall risk groups. Univariate analysis revealed age, daytime activity, nighttime side lying posture, and HRV were significantly different between groups. Results suggest feasibility of wearable technology to consciously monitor physical activity, sleep postures, and HRV as potential markers of fall risk in the acute care setting. Further study is warranted to confirm the results and examine the efficacy of the proposed wearable technology to manage falls in hospitals. [Journal of Gerontological Nursing, xx(x), xx-xx.].

  8. A quantitative framework to group nanoscale and microscale particles by hazard potency to derive occupational exposure limits: Proof of concept evaluation.

    Science.gov (United States)

    Drew, Nathan M; Kuempel, Eileen D; Pei, Ying; Yang, Feng

    2017-08-05

    The large and rapidly growing number of engineered nanomaterials (ENMs) presents a challenge to assessing the potential occupational health risks. An initial database of 25 rodent studies including 1929 animals across various experimental designs and material types was constructed to identify materials that are similar with respect to their potency in eliciting neutrophilic pulmonary inflammation, a response relevant to workers. Doses were normalized across rodent species, strain, and sex as the estimated deposited particle mass dose per gram of lung. Doses associated with specific measures of pulmonary inflammation were estimated by modeling the continuous dose-response relationships using benchmark dose modeling. Hierarchical clustering was used to identify similar materials. The 18 nanoscale and microscale particles were classified into four potency groups, which varied by factors of approximately two to 100. Benchmark particles microscale TiO2 and crystalline silica were in the lowest and highest potency groups, respectively. Random forest methods were used to identify the important physicochemical predictors of pulmonary toxicity, and group assignments were correctly predicted for five of six new ENMs. Proof-of-concept was demonstrated for this framework. More comprehensive data are needed for further development and validation for use in deriving categorical occupational exposure limits. Published by Elsevier Inc.

  9. Medication eluting devices for the field of OBGYN (MEDOBGYN): 3D printed biodegradable hormone eluting constructs, a proof of concept study.

    Science.gov (United States)

    Tappa, Karthik; Jammalamadaka, Udayabhanu; Ballard, David H; Bruno, Todd; Israel, Marissa R; Vemula, Harika; Meacham, J Mark; Mills, David K; Woodard, Pamela K; Weisman, Jeffery A

    2017-01-01

    3D printing has the potential to deliver personalized implants and devices for obstetric and gynecologic applications. The aim of this study is to engineer customizable and biodegradable 3D printed implant materials that can elute estrogen and/or progesterone. All 3D constructs were printed using polycaprolactone (PCL) biodegradable polymer laden with estrogen or progesterone and were subjected to hormone-release profile studies using ELISA kits. Material thermal properties were tested using thermogravimetric analysis and differential scanning calorimetry. The 3D printed constructs showed extended hormonal release over a one week period. Cytocompatibility and bioactivity were assessed using a luciferase assay. The hormone-laden 3D printed constructs demonstrated an increase in luciferase activity and without any deleterious effects. Thermal properties of the PCL and hormones showed degradation temperatures above that of the temperature used in the additive manufacturing process-suggesting that 3D printing can be achieved below the degradation temperatures of the hormones. Sample constructs in the shape of surgical meshes, subdermal rods, intrauterine devices and pessaries were designed and printed. 3D printing of estrogen and progesterone-eluting constructs was feasible in this proof of concept study. These custom designs have the potential to act as a form of personalized medicine for drug delivery and optimized fit based on patient-specific anatomy.

  10. Using Video Conferencing to Deliver a Brief Motivational Intervention for Alcohol and Sex Risk to Emergency Department Patients: A Proof-of-Concept Pilot Study.

    Science.gov (United States)

    Celio, Mark A; Mastroleo, Nadine R; DiGuiseppi, Graham; Barnett, Nancy P; Colby, Suzanne M; Kahler, Christopher W; Operario, Don; Suffoletto, Brian; Monti, Peter M

    2017-01-01

    Brief motivational intervention (MI) is an efficacious approach to reduce heavy drinking and associated sexual risk behavior among Emergency Department (ED) patients, but the intensity of demands placed on ED staff makes the implementation of in-person MIs logistically challenging. This proof-of-concept pilot study examined the acceptability and logistic feasibility of using video-conferencing technology to deliver an MI targeting heavy drinking and risky sexual behavior to patients in an ED setting. Rigorous screening procedures were employed to ensure that the pilot sample represents the target portion of ED patients who would benefit from this multi-target MI. Mixed qualitative and quantitative data from a sample of seven ED patients (57% Female; Mage = 35 years) who received MI by video conference consistently demonstrated high levels of satisfaction, engagement, and acceptability. The observed completion rate supports logistic feasibility, and patient feedback identified methods to improve the experience by using high-definition hardware, ensuring stronger network connectivity, and effectively communicating information regarding protection of privacy. Post-intervention patient ratings and independent ratings of the audio-recorded sessions (using the Motivational Interviewing Skills Coding system) were very high, suggesting that intervention fidelity and MI adherence was not compromised by delivery modality. Collectively, these data suggest video conferencing is a viable technology that can be employed to implement brief evidence-based MIs in ED settings.

  11. A Proof of Concept to Bridge the Gap between Mass Spectrometry Imaging, Protein Identification and Relative Quantitation: MSI~LC-MS/MS-LF

    Science.gov (United States)

    Théron, Laëtitia; Centeno, Delphine; Coudy-Gandilhon, Cécile; Pujos-Guillot, Estelle; Astruc, Thierry; Rémond, Didier; Barthelemy, Jean-Claude; Roche, Frédéric; Feasson, Léonard; Hébraud, Michel; Béchet, Daniel; Chambon, Christophe

    2016-01-01

    Mass spectrometry imaging (MSI) is a powerful tool to visualize the spatial distribution of molecules on a tissue section. The main limitation of MALDI-MSI of proteins is the lack of direct identification. Therefore, this study focuses on a MSI~LC-MS/MS-LF workflow to link the results from MALDI-MSI with potential peak identification and label-free quantitation, using only one tissue section. At first, we studied the impact of matrix deposition and laser ablation on protein extraction from the tissue section. Then, we did a back-correlation of the m/z of the proteins detected by MALDI-MSI to those identified by label-free quantitation. This allowed us to compare the label-free quantitation of proteins obtained in LC-MS/MS with the peak intensities observed in MALDI-MSI. We managed to link identification to nine peaks observed by MALDI-MSI. The results showed that the MSI~LC-MS/MS-LF workflow (i) allowed us to study a representative muscle proteome compared to a classical bottom-up workflow; and (ii) was sparsely impacted by matrix deposition and laser ablation. This workflow, performed as a proof-of-concept, suggests that a single tissue section can be used to perform MALDI-MSI and protein extraction, identification, and relative quantitation. PMID:28248242

  12. A Proof of Concept to Bridge the Gap between Mass Spectrometry Imaging, Protein Identification and Relative Quantitation: MSI~LC-MS/MS-LF.

    Science.gov (United States)

    Théron, Laëtitia; Centeno, Delphine; Coudy-Gandilhon, Cécile; Pujos-Guillot, Estelle; Astruc, Thierry; Rémond, Didier; Barthelemy, Jean-Claude; Roche, Frédéric; Feasson, Léonard; Hébraud, Michel; Béchet, Daniel; Chambon, Christophe

    2016-10-26

    Mass spectrometry imaging (MSI) is a powerful tool to visualize the spatial distribution of molecules on a tissue section. The main limitation of MALDI-MSI of proteins is the lack of direct identification. Therefore, this study focuses on a MSI~LC-MS/MS-LF workflow to link the results from MALDI-MSI with potential peak identification and label-free quantitation, using only one tissue section. At first, we studied the impact of matrix deposition and laser ablation on protein extraction from the tissue section. Then, we did a back-correlation of the m/z of the proteins detected by MALDI-MSI to those identified by label-free quantitation. This allowed us to compare the label-free quantitation of proteins obtained in LC-MS/MS with the peak intensities observed in MALDI-MSI. We managed to link identification to nine peaks observed by MALDI-MSI. The results showed that the MSI~LC-MS/MS-LF workflow (i) allowed us to study a representative muscle proteome compared to a classical bottom-up workflow; and (ii) was sparsely impacted by matrix deposition and laser ablation. This workflow, performed as a proof-of-concept, suggests that a single tissue section can be used to perform MALDI-MSI and protein extraction, identification, and relative quantitation.

  13. Engineering of benzylglucosinolate in tobacco provides proof-of-concept for dead-end trap crops genetically modified to attract Plutella xylostella (diamondback moth).

    Science.gov (United States)

    Møldrup, Morten E; Geu-Flores, Fernando; de Vos, Martin; Olsen, Carl E; Sun, Joel; Jander, Georg; Halkier, Barbara A

    2012-05-01

    Glucosinolates are biologically active natural products characteristic of crucifers, including oilseed rape, cabbage vegetables and the model plant Arabidopsis thaliana. Crucifer-specialist insect herbivores, like the economically important pest Plutella xylostella (diamondback moth), frequently use glucosinolates as oviposition stimuli. This suggests that the transfer of a glucosinolate biosynthetic pathway to a non-crucifer would stimulate oviposition on an otherwise non-attractive plant. Here, we demonstrate that stable genetic transfer of the six-step benzylglucosinolate pathway from A. thaliana to Nicotiana tabacum (tobacco) results in the production of benzylglucosinolate without causing morphological alterations. Benzylglucosinolate-producing tobacco plants were more attractive for oviposition by female P. xylostella moths than wild-type tobacco plants. As newly hatched P. xylostella larvae were unable to survive on tobacco, these results represent a proof-of-concept strategy for rendering non-host plants attractive for oviposition by specialist herbivores with the long-term goal of generating efficient dead-end trap crops for agriculturally important pests.

  14. Reverse genetics vaccine seeds for influenza: Proof of concept in the source of PB1 as a determinant factor in virus growth and antigen yield.

    Science.gov (United States)

    Gíria, Marta; Santos, Luís; Louro, João; Rebelo de Andrade, Helena

    2016-09-01

    Growth deficits of reverse genetics vaccine seeds have compromised effective immunization. The impairment has been attributed to sub-optimal protein interactions. Some level of dependence may exist between PB1 and antigenic glycoproteins, however, further research is necessary to clarify the extent to which it can be used in favor of seed production. Our objective was to establish proof of concept on the phenotypic outcome of PB1 source in the PR8: A(H1N1)pdm09 reassortants. Reassortants were generated with the gene constellation of the classical 6:2 PR8: HA, NApdm09 seed prototype and the 5:3 reassortant PR8: HA, NA, PB1pdm09. Viral growth and antigen yield were evaluated 12-60h post-infection. The 5:3 reassortant presented statistically significant growth and antigen yield improvements when compared to the 6:2. We believe these findings to be of promising value to vaccine research towards an improvement of reverse genetic seeds, an overall more cost-effective vaccine manufacture and timely delivery. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. The Application of Informatics in Delineating the Proof of Concept for Creating Knowledge of the Value Added by Interprofessional Practice and Education.

    Science.gov (United States)

    Cerra, Frank; Pacala, James; Brandt, Barbara F; Lutfiyya, May Nawal

    2015-11-12

    The resurgence of interest in the promise of interprofessional education and collaborative practice (IPECP) to positively impact health outcomes, requires the collection of appropriate data that can be analyzed and from which information and knowledge linking IPECP interventions to improved health outcomes might be produced and reported to stakeholders such as health systems, policy makers and regulators, payers, and accreditation agencies. To generate such knowledge the National Center for Interprofessional Practice and Education at the University of Minnesota has developed three strategies, the first two of which are: (1) creating an IPECP research agenda, and (2) a national Nexus Innovation Network (NIN) of intervention projects that are generating data that are being input and housed in a National Center Data Repository (NCDR). In this paper, the informatics platform supporting the work of these first two strategies is presented as the third interconnected strategy for knowledge generation. The proof of concept for the informatics strategy is developed in this paper by describing: data input from the NIN into the NCDR, the linking and merging of those data to produce analyzable data files that incorporate institutional and individual level data, and the production of meaningful analyses to create and provide relevant information and knowledge. This paper is organized around the concepts of data, information and knowledge-the three conceptual foundations of informatics.

  16. A Proof of Concept to Bridge the Gap between Mass Spectrometry Imaging, Protein Identification and Relative Quantitation: MSI~LC-MS/MS-LF

    Directory of Open Access Journals (Sweden)

    Laëtitia Théron

    2016-10-01

    Full Text Available Mass spectrometry imaging (MSI is a powerful tool to visualize the spatial distribution of molecules on a tissue section. The main limitation of MALDI-MSI of proteins is the lack of direct identification. Therefore, this study focuses on a MSI~LC-MS/MS-LF workflow to link the results from MALDI-MSI with potential peak identification and label-free quantitation, using only one tissue section. At first, we studied the impact of matrix deposition and laser ablation on protein extraction from the tissue section. Then, we did a back-correlation of the m/z of the proteins detected by MALDI-MSI to those identified by label-free quantitation. This allowed us to compare the label-free quantitation of proteins obtained in LC-MS/MS with the peak intensities observed in MALDI-MSI. We managed to link identification to nine peaks observed by MALDI-MSI. The results showed that the MSI~LC-MS/MS-LF workflow (i allowed us to study a representative muscle proteome compared to a classical bottom-up workflow; and (ii was sparsely impacted by matrix deposition and laser ablation. This workflow, performed as a proof-of-concept, suggests that a single tissue section can be used to perform MALDI-MSI and protein extraction, identification, and relative quantitation.

  17. Understanding Social Situations (USS): A proof-of-concept social-cognitive intervention targeting theory of mind and attributional bias in individuals with psychosis.

    Science.gov (United States)

    Fiszdon, Joanna M; Roberts, David L; Penn, David L; Choi, Kee-Hong; Tek, Cenk; Choi, Jimmy; Bell, Morris D

    2017-03-01

    In this proof-of-concept trial, we examined the feasibility and preliminary efficacy of Understanding Social Situations (USS), a new social-cognitive intervention that targets higher level social-cognitive skills using methods common to neurocognitive remediation, including drill and practice and hierarchically structured training, which may compensate for the negative effects of cognitive impairment on learning. Thirty-eight individuals with schizophrenia spectrum disorders completed the same baseline assessment of cognitive and social-cognitive functioning twice over a 1-month period to minimize later practice effects, then received 7-10 sessions of USS training, and then completed the same assessment again at posttreatment. USS training was well tolerated and received high treatment satisfaction ratings. Large improvements on the USS Skills Test, which contained items similar to but not identical to training stimuli, suggest that we were effective in teaching specific training content. Content gains generalized to improvements on some of the social-cognitive tasks, including select measures of attributional bias and theory of mind. Importantly, baseline neurocognition did not impact the amount of learning during USS (as indexed by the USS Skills Test) or the amount of improvement on social-cognitive measures. USS shows promise as a treatment for higher level social-cognitive skills. Given the lack of relationship between baseline cognition and treatment effects, it may be particularly appropriate for individuals with lower range cognitive function. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  18. Digital TAcy: proof of concept

    Science.gov (United States)

    Bubel, Annie; Sylvain, Jean-François; Martin, François

    2009-06-01

    Anthocyanins are water soluble pigments in plants that are recognized for their antioxidant property. These pigments are found in high concentration in cranberries, which give their characteristic dark red color. The Total Anthocyanin concentration (TAcy) measurement process requires precious time, consumes chemical products and needs to be continuously repeated during the harvesting period. The idea of the digital TAcy system is to explore the possibility of estimating the TAcy based on analysing the color of the fruits. A calibrated color image capture set-up was developed and characterized, allowing calibrated color data capture from hundreds of samples over two harvesting years (fall of 2007 and 2008). The acquisition system was designed in such a way to avoid specular reflections and provide good resolution images with an extended range of color values representative of the different stages of fruit ripeness. The chemical TAcy value being known for every sample, a mathematical model was developed to predict the TAcy based on color information. This model, which also takes into account bruised and rotten fruits, shows a RMS error of less than 6% over the TAcy interest range [0-50].

  19. Connected Me - Proof of Concept

    OpenAIRE

    Vajravelu, Dilip Kumar

    2013-01-01

    Connected Me is a Human Body Communication (HBC) system, which is used fortransferring data through human body. The working principle is based on theorycalled Body Coupled Communication (BCC), which uses electrostatic couplingfor transferring data between device and human body. Capacitance between bodyand electrode acts as an electrical interface between devices. BCC has become aprominent research area in the field of Personal Area Network (PAN), introducedby Zimmerman in 1995. Until now ther...

  20. Long-term outcomes from dose-escalated image-guided intensity-modulated radiotherapy with androgen deprivation: encouraging results for intermediate- and high-risk prostate cancer

    Directory of Open Access Journals (Sweden)

    Wilcox SW

    2014-08-01

    Full Text Available Shea W Wilcox,1,4 Noel J Aherne,2,4 Linus C Benjamin,1 Bosco Wu,1 Thomaz de Campos Silva,3 Craig S McLachlan,4 Michael J McKay,3,5 Andrew J Last,1 Thomas P Shakespeare1–4 1North Coast Cancer Institute, Port Macquarie, NSW, Australia; 2North Coast Cancer Institute, Coffs Harbour, NSW, Australia; 3North Coast Cancer Institute, Lismore, NSW, Australia; 4The University of New South Wales, Rural Clinical School, Sydney, NSW, Australia; 5The University of Sydney, Sydney, NSW, Australia Purpose: Dose-escalated (DE radiotherapy in the setting of localized prostate cancer has been shown to improve biochemical disease-free survival (bDFS in several studies. In the same group of patients, androgen deprivation therapy (ADT has been shown to confer a survival benefit when combined with radiotherapy doses of up to 70 Gy; however, there is currently little long-term data on patients who have received high-dose intensity-modulated radiotherapy (IMRT with ADT. We report the long-term outcomes in a large cohort of patients treated with the combination of DE image-guided IMRT (IG-IMRT and ADT. Methods and materials: Patients with localized prostate cancer were identified from a centralized database across an integrated cancer center. All patients received DE IG-IMRT, combined with ADT, and had a minimum follow up of 12 months post-radiotherapy. All relapse and toxicity data were collected prospectively. Actuarial bDFS, metastasis-free survival, prostate cancer-specific survival, and multivariate analyses were calculated using the SPSS v20.0 statistical package. Results: Seven hundred and eighty-two eligible patients were identified with a median follow up of 46 months. Overall, 4.3% of patients relapsed, 2.0% developed distant metastases, and 0.6% died from metastatic prostate cancer. At 5-years, bDFS was 88%, metastasis-free survival was 95%, and prostate cancer-specific survival was 98%. Five-year grade 2 genitourinary and gastrointestinal toxicity was 2

  1. A phase I dose-escalation study of the safety and pharmacokinetics of a tablet formulation of voxtalisib, a phosphoinositide 3-kinase inhibitor, in patients with solid tumors.

    Science.gov (United States)

    Mehnert, Janice M; Edelman, Gerald; Stein, Mark; Camisa, Heather; Lager, Joanne; Dedieu, Jean-François; Ghuysen, Anne-Frédérique; Sharma, Jyoti; Liu, Li; LoRusso, Patricia M

    2017-04-17

    Background Voxtalisib, a PI3K/mTOR inhibitor, has shown antitumor activity in capsule formulation in patients with solid tumors. This Phase I study assessed safety and pharmacokinetics of voxtalisib administered as immediate-release tablets in patients with solid tumors (NCT01596270). Methods A "3 + 3" dose escalation design was used. Adverse events (AEs), pharmacokinetics (PK), food effect and tumor response were evaluated. Results Thirty-two patients received voxtalisib doses ranging from 50 mg to 70 mg once daily (QD) and 17 patients received voxtalisib doses ranging from 30 mg to 50 mg twice daily (BID), for two 28-day cycles. Dose-limiting toxicities (DLTs) were Grade 3 fatigue (two patients at 70 mg QD, one patient at 40 mg BID) and Grade 3 rash (two patients at 50 mg BID). The maximum tolerated dose (MTD) was 60 mg for QD and 40 mg for BID regimens. Common treatment-emergent AEs were diarrhea (41%), nausea (37%) and fatigue (33%). Voxtalisib appeared to follow linear PK, with a general increase in plasma exposure with dose and no significant accumulation. Administration with food caused a slight decrease in exposure; however, given the high variability observed in the exposure parameters, this should be interpreted with caution. Best response was stable disease in 29% and 50% of patients (QD and BID regimens, respectively). Conclusions The safety profile of voxtalisib tablets at the MTD in patients with solid tumors was consistent with that observed with voxtalisib capsules. Given the limited activity observed across multiple clinical trials, no further trials of voxtalisib are planned.

  2. Combination of Trabectedin and Gemcitabine for Advanced Soft Tissue Sarcomas: Results of a Phase I Dose Escalating Trial of the German Interdisciplinary Sarcoma Group (GISG

    Directory of Open Access Journals (Sweden)

    Bernd Kasper

    2015-01-01

    Full Text Available Background: Evaluation of the potential efficacy and safety of combination therapies for advanced soft tissue sarcomas (STS has increased substantially after approval of trabectedin and pazopanib. Trabectedin's introduction in Europe in 2007 depended mainly on its activity in so-called L-sarcomas (liposarcoma and leiomyosarcoma; combination of trabectedin with other chemotherapies used in STS seems of particular interest. Methods: We initiated within the German Interdisciplinary Sarcoma Group (GISG a phase I dose escalating trial evaluating the combination of trabectedin and gemcitabine in patients with advanced and/or metastatic L-sarcomas (GISG-02; ClinicalTrials.gov NCT01426633. Patients were treated with increasing doses of trabectedin and gemcitabine. The primary endpoint was to determine the maximum tolerated dose. Results: Five patients were included in the study. Two patients were treated on dose level 1 comprising trabectedin 0.9 mg/m2 on day 1 and gemcitabine 700 mg/m2 on days 1 + 8, every 3 weeks. Due to dose-limiting toxicity (DLT in both patients (elevated transaminases and thrombocytopenia, an additional three patients were treated on dose level −1 with trabectedin 0.7 mg/m2 plus gemcitabine 700 mg/m2. Of these three patients, two demonstrated another DLT; therefore, the trial was stopped and none of the dose levels could be recommended for phase II testing. Conclusion: The GISG-02 phase I study was stopped with the conclusion that the combination of gemcitabine and trabectedin is generally not recommended for the treatment of patients with advanced and/or metastatic leiomyosarcoma or liposarcoma. Also, this phase I study strongly supports the necessity for careful evaluation of combination therapies.

  3. A phase 1 dose-escalation study of the oral histone deacetylase inhibitor abexinostat in combination with standard hypofractionated radiotherapy in advanced solid tumors

    Science.gov (United States)

    Deutsch, Eric; Moyal, Elizabeth Cohen-Jonathan; Gregorc, Vanesa; Zucali, Paolo Andrea; Menard, Jean; Soria, Jean-Charles; Kloos, Ioana; Hsu, Jeff; Luan, Ying; Liu, Emily; Vezan, Remus; Graef, Thorsten; Rivera, Sofia

    2017-01-01

    Current treatments for advanced solid tumors tend to be only palliative. Although radiotherapy is administered with a curative intent, radioresistance and dose-limiting toxicities pose limitations to treatment. Abexinostat, an oral pan-histone deacetylase inhibitor, demonstrated enhanced sensitivity to radiation in various solid tumor cell lines. We conducted an exploratory, phase 1, dose-escalation study of abexinostat in combination with standard hypofractionated radiotherapy in patients with advanced solid tumors treated in a palliative setting. Among 58 treated patients, the median age was 61.5 years (range, 20-82); 47% of the patients had M1 stage disease, and 95% had received previous chemotherapy alone or chemotherapy in combination with surgery and/or radiotherapy. The recommended phase 2 dose was determined to be 90 mg/m2 (140 mg). Of the 51 patients evaluable for response, best overall response was 8% (1 complete response [CR], 3 partial responses [PRs]), and best loco-regional response was 12% (1 CR and 5 PRs) at a median follow-up of 16 weeks. Of note, patients with target or non-target brain lesions showed encouraging responses, with 1 patient achieving a best loco-regional response of CR. Treatment-emergent grade ≥3 adverse events (AEs) were few, with most common being thrombocytopenia (17%), lymphopenia (12%), and hypokalemia (7%). Six patients (10%) discontinued treatment due to AEs. No grade ≥3 prolongation of the QTc interval was observed, with no treatment discontinuations due to this AE. Oral abexinostat combined with radiotherapy was well tolerated in patients with advanced solid tumors. The combination may have potential for treatment of patients with brain lesions. PMID:28915584

  4. A phase 1 dose-escalation study of the oral histone deacetylase inhibitor abexinostat in combination with standard hypofractionated radiotherapy in advanced solid tumors.

    Science.gov (United States)

    Deutsch, Eric; Cohen-Jonathan Moyal, Elizabeth; Gregorc, Vanesa; Zucali, Paolo Andrea; Menard, Jean; Soria, Jean-Charles; Kloos, Ioana; Hsu, Jeff; Luan, Ying; Liu, Emily; Vezan, Remus; Graef, Thorsten; Rivera, Sofia

    2016-12-24

    Current treatments for advanced solid tumors tend to be only palliative. Although radiotherapy is administered with a curative intent, radioresistance and dose-limiting toxicities pose limitations to treatment. Abexinostat, an oral pan-histone deacetylase inhibitor, demonstrated enhanced sensitivity to radiation in various solid tumor cell lines. We conducted an exploratory, phase 1, dose-escalation study of abexinostat in combination with standard hypofractionated radiotherapy in patients with advanced solid tumors treated in a palliative setting. Among 58 treated patients, the median age was 61.5 years (range, 20-82); 47% of the patients had M1 stage disease, and 95% had received previous chemotherapy alone or chemotherapy in combination with surgery and/or radiotherapy. The recommended phase 2 dose was determined to be 90 mg/m2 (140 mg). Of the 51 patients evaluable for response, best overall response was 8% (1 complete response [CR], 3 partial responses [PRs]), and best loco-regional response was 12% (1 CR and 5 PRs) at a median follow-up of 16 weeks. Of note, patients with target or non-target brain lesions showed encouraging responses, with 1 patient achieving a best loco-regional response of CR. Treatment-emergent grade ≥3 adverse events (AEs) were few, with most common being thrombocytopenia (17%), lymphopenia (12%), and hypokalemia (7%). Six patients (10%) discontinued treatment due to AEs. No grade ≥3 prolongation of the QTc interval was observed, with no treatment discontinuations due to this AE. Oral abexinostat combined with radiotherapy was well tolerated in patients with advanced solid tumors. The combination may have potential for treatment of patients with brain lesions.

  5. Superiority of helical tomotherapy on liver sparing and dose escalation in hepatocellular carcinoma: a comparison study of three-dimensional conformal radiotherapy and intensity-modulated radiotherapy

    Science.gov (United States)

    Zhao, Qianqian; Wang, Renben; Zhu, Jian; Jin, Linzhi; Zhu, Kunli; Xu, Xiaoqing; Feng, Rui; Jiang, Shumei; Qi, Zhonghua; Yin, Yong

    2016-01-01

    Background and purpose To compare the difference of liver sparing and dose escalation between three-dimensional conformal radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT), and helical tomotherapy (HT) for hepatocellular carcinoma. Patients and methods Sixteen unresectable HCC patients were enrolled in this study. First, some evaluation factors of 3DCRT, IMRT, and HT plans were calculated with prescription dose at 50 Gy/25 fractions. Then, the doses were increased using HT or IMRT independently until either the plans reached 70 Gy or any normal tissue reached the dose limit according to quantitative analysis of normal tissue effects in the clinic criteria. Results The conformal index of 3DCRT was lower than that of IMRT (PV50% (fraction of normal liver treated to at least 50% of the isocenter dose) of the normal liver, there was a significant difference: 3DCRT > IMRT > HT (P<0.001). HT had a lower Dmean (mean dose) and V20 (Vn, the percentage of organ volume receiving ≥n Gy) of liver compared with 3DCRT (P=0.005 and P=0.005, respectively) or IMRT (P=0.508 and P=0.007, respectively). Dmean of nontarget normal liver and V30 of liver were higher for 3DCRT than IMRT (P=0.005 and P=0.005, respectively) or HT (P=0.005 and P=0.005, respectively). Seven patients in IMRT (43.75%) and nine patients in HT (56.25%) reached the isodose 70 Gy, meeting the dose limit of the organs at risk. Conclusion HT may provide significantly better liver sparing and allow more patients to achieve higher prescription dose in HCC radiotherapy. PMID:27445485

  6. Increase in tumor control and normal tissue complication probabilities in advanced head-and-neck cancer for dose-escalated intensity-modulated photon and proton therapy

    Directory of Open Access Journals (Sweden)

    Annika eJakobi

    2015-11-01

    Full Text Available Introduction:Presently used radio-chemotherapy regimens result in moderate local control rates for patients with advanced head and neck squamous cell carcinoma (HNSCC. Dose escalation (DE may be an option to improve patient outcome, but may also increase the risk of toxicities in healthy tissue. The presented treatment planning study evaluated the feasibility of two DE levels for advanced HNSCC patients, planned with either intensity-modulated photon therapy (IMXT or proton therapy (IMPT.Materials and Methods:For 45 HNSCC patients, IMXT and IMPT treatment plans were created including DE via a simultaneous integrated boost (SIB in the high-risk volume, while maintaining standard fractionation with 2 Gy per fraction in the remaining target volume. Two DE levels for the SIB were compared: 2.3 Gy and 2.6 Gy. Treatment plan evaluation included assessment of tumor control probabilities (TCP and normal tissue complication probabilities (NTCP.Results:An increase of approximately 10% in TCP was estimated between the DE levels. A pronounced high-dose rim surrounding the SIB volume was identified in IMXT treatment. Compared to IMPT, this extra dose slightly increased the TCP values and to a larger extent the NTCP values. For both modalities, the higher DE level led only to a small increase in NTCP values (mean differences < 2% in all models, except for the risk of aspiration, which increased on average by 8% and 6% with IMXT and IMPT, respectively, but showed a considerable patient dependence. Conclusions:Both DE levels appear applicable to patients with IMXT and IMPT since all calculated NTCP values, except for one, increased only little for the higher DE level. The estimated TCP increase is of relevant magnitude. The higher DE schedule needs to be investigated carefully in the setting of a prospective clinical trial, especially regarding toxicities caused by high local doses that lack a sound dose response description, e.g., ulcers.

  7. Dose-escalation study for the targeting of CD44v(+) cancer stem cells by sulfasalazine in patients with advanced gastric cancer (EPOC1205).

    Science.gov (United States)

    Shitara, Kohei; Doi, Toshihiko; Nagano, Osamu; Imamura, Chiyo K; Ozeki, Takeshi; Ishii, Yuya; Tsuchihashi, Kenji; Takahashi, Shunji; Nakajima, Takako E; Hironaka, Shuichi; Fukutani, Miki; Hasegawa, Hiromi; Nomura, Shogo; Sato, Akihiro; Einaga, Yasuaki; Kuwata, Takeshi; Saya, Hideyuki; Ohtsu, Atsushi

    2017-03-01

    Cancer stem cells (CSCs) have enhanced mechanisms of protection from oxidative stress. A variant form of CD44 (CD44v), a major CSC marker, was shown to interact with xCT, a subunit of cystine-glutamate transporter, which maintains high levels of intracellular reduced glutathione (GSH) which defend the cell against oxidative stress. Sulfasalazine (SSZ) is an inhibitor of xCT and was shown to suppress the survival of CD44v-positive stem-like cancer cells both in vitro and in vivo. To find the dose of SSZ which can safely reduce the population of CD44v-positive cells in tumors, a dose-escalation study in patients with advanced gastric cancer was conducted. SSZ was given four times daily by oral administration with 2 weeks as one cycle. Tumor biopsies were obtained before and after 14 days of administration of SSZ to evaluate expression of CD44v and the intratumoral level of GSH. Eleven patients were enrolled and received a dosage from 8 to 12 g/day. Safety was confirmed up to a dosage of 12 g/day, which was considered the maximum tolerated dose. Among the eight patients with CD44v-positive cells in their pretreatment biopsy samples, the CD44v-positive cancer cell population appeared to be reduced in the posttreatment biopsy tissues of four patients. Intratumoral GSH levels were also decreased in two patients, suggesting biological effectiveness of SSZ at 8 g/day or greater. This is the first study of SSZ as an xCT inhibitor for targeting CSCs. Reduction of the levels of CD44v-positive cells and GSH was observed in some patients, consistent with the mode of action of SSZ in CSCs.

  8. Feasibility of safe ultra-high (EQD{sub 2}>100 Gy) dose escalation on dominant intra-prostatic lesions (DILs) by Helical Tomotheraphy

    Energy Technology Data Exchange (ETDEWEB)

    Maggio, Angelo; Fiorino, Claudio; Mangili, Paola; Cattaneo, Giovanni Mauro; Del Maschio, Alessandro; Calandrino, Riccardo (Medical Physics, San Raffaele Scientific Inst., Milano (Italy)), e-mail: fiorino.claudio@hsr.it; Muzio, Nadia Di; Cozzarini, Cesare (Radiotherapy, San Raffaele Scientific Inst., Milano (Italy)); Cobelli, Francesco de (Radiology, San Raffaele Scientific Inst., Milano (Italy)); Rancati, Tiziana (Programma Prostata, National Inst. of Cancer, Milano (Italy))

    2011-01-15

    Purpose. To verify the possibility of using Helical Tomotherapy to safely escalate dose to single or multiple highly radioresistant dominant intra-prostatic lesions (DILs) as assessed by functional magnetic resonance imaging (MRI). Material. In seven intermediate/high risk patients, T2WI, T1WI and DWI MRI imaging showed evidence of one DIL in four patients and two DILs in three patients in the peripheral zone of the prostate. The planning strategy was to deliver median doses of 80, 90, 100 and 120 Gy to PTVDIL while delivering 71.4 Gy/28 fractions (EQD{sub 2}=75 Gy) to the remaining portion of PTV. A higher priority was assigned to rectal constraints relative to DIL coverage. Rectal NTCP calculations were performed using the most recently available model data. Results. The median dose to DIL could safely be escalated to at least 100 Gy (EQD{sub 2,{alpha}/{beta}=10}=113 Gy) without violating safe constraints for the organs at risk. Typical rectal NTCP values were around or below 1-3% for G3 toxicity and 5-7% for G2-G3 toxicity. For the 100 Gy DIL dose boost strategy, mean D95% of DIL and PTVDIL were 98.8 Gy and 86.7 Gy, respectively. The constraints for bladder, urethra and femoral heads were always respected. Conclusions. IGRT by Helical Tomotherapy may permit the safe escalation of EQD{sub 2,{alpha}/{eta}=10} to at least 113 Gy to DILs without significantly increasing rectal NTCP compared to plans without dose escalation. A Phase I-II clinical study is warranted

  9. Retrospective Evaluation Reveals That Long-term Androgen Deprivation Therapy Improves Cause-Specific and Overall Survival in the Setting of Dose-Escalated Radiation for High-Risk Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Feng, Felix Y., E-mail: ffeng@med.umich.edu [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Department of Radiation Oncology, Veterans Affairs Medical Center, Ann Arbor, Michigan (United States); Blas, Kevin; Olson, Karin; Stenmark, Matthew [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Sandler, Howard [Cedars Sinai Medical Center, Los Angeles, California (United States); Hamstra, Daniel A. [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States)

    2013-05-01

    Purpose: To evaluate the role of androgen deprivation therapy (ADT) and duration for high-risk prostate cancer patients treated with dose-escalated radiation therapy (RT). Methods and Materials: A retrospective analysis of high-risk prostate cancer patients treated with dose-escalated RT (minimum 75 Gy) with or without ADT was performed. The relationship between ADT use and duration with biochemical failure (BF), metastatic failure (MF), prostate cancer-specific mortality (PCSM), non-prostate cancer death (NPCD), and overall survival (OS) was assessed as a function of pretreatment characteristics, comorbid medical illness, and treatment using Fine and Gray's cumulative incidence methodology. Results: The median follow-up time was 64 months. In men with National Comprehensive Cancer Network defined high-risk prostate cancer treated with dose-escalated RT, on univariate analysis, both metastasis (P<.0001; hazard ratio 0.34; 95% confidence interval 0.18-0.67; cumulative incidence at 60 months 13% vs 35%) and PCSM (P=.015; hazard ratio 0.41; 95% confidence interval 0.2-1.0; cumulative incidence at 60 months 6% vs 11%) were improved with the use of ADT. On multivariate analysis for all high-risk patients, Gleason score was the strongest negative prognostic factor, and long-term ADT (LTAD) improved MF (P=.002), PCSM (P=.034), and OS (P=.001). In men with prostate cancer and Gleason scores 8 to 10, on multivariate analysis after adjustment for other risk features, there was a duration-dependent improvement in BF, metastasis, PCSM, and OS, all favoring LTAD in comparison with STAD or RT alone. Conclusion: For men with high-risk prostate cancer treated with dose-escalated EBRT, this retrospective study suggests that the combination of LTAD and RT provided a significant improvement in clinical outcome, which was especially true for those with Gleason scores of 8 to 10.

  10. Proof-of-Concept Randomized Controlled Study of Cognition Effects of the Proprietary Extract Sceletium tortuosum (Zembrin) Targeting Phosphodiesterase-4 in Cognitively Healthy Subjects: Implications for Alzheimer's Dementia.

    Science.gov (United States)

    Chiu, Simon; Gericke, Nigel; Farina-Woodbury, Michel; Badmaev, Vladimir; Raheb, Hana; Terpstra, Kristen; Antongiorgi, Joalex; Bureau, Yves; Cernovsky, Zack; Hou, Jirui; Sanchez, Veronica; Williams, Marissa; Copen, John; Husni, Mariwan; Goble, Liz

    2014-01-01

    Introduction. Converging evidence suggests that PDE-4 (phosphodiesterase subtype 4) plays a crucial role in regulating cognition via the PDE-4-cAMP cascade signaling involving phosphorylated cAMP response element binding protein (CREB). Objective. The primary endpoint was to examine the neurocognitive effects of extract Sceletium tortuosum (Zembrin) and to assess the safety and tolerability of Zembrin in cognitively healthy control subjects. Method. We chose the randomized double-blind placebo-controlled cross-over design in our study. We randomized normal healthy subjects (total n = 21) to receive either 25 mg capsule Zembrin or placebo capsule once daily for 3 weeks, in a randomized placebo-controlled 3-week cross-over design. We administered battery of neuropsychological tests: CNS Vital Signs and Hamilton depression rating scale (HAM-D) at baseline and regular intervals and monitored side effects with treatment emergent adverse events scale. Results. 21 subjects (mean age: 54.6 years ± 6.0 yrs; male/female ratio: 9/12) entered the study. Zembrin at 25 mg daily dosage significantly improved cognitive set flexibility (P Zembrin was well tolerated. Conclusion. The promising cognitive enhancing effects of Zembrin likely implicate the PDE-4-cAMP-CREB cascade, a novel drug target in the potential treatment of early Alzheimer's dementia. This trial is registered with ClinicalTrials.gov NCT01805518.

  11. A non-axial superconducting magnet design for optimized patient access and minimal SAD for use in a Linac-MR hybrid: proof of concept

    Science.gov (United States)

    Yaghoobpour Tari, Shima; Wachowicz, Keith; Fallone, B. Gino

    2017-04-01

    A prototype rotating hybrid magnetic resonance imaging system and linac has been developed to allow for simultaneous imaging and radiation delivery parallel to B 0. However, the design of a compact magnet capable of rotation in a small vault with sufficient patient access and a typical clinical source-to-axis distance (SAD) is challenging. This work presents a novel superconducting magnet design as a proof of concept that allows for a reduced SAD and ample patient access by moving the superconducting coils to the side of the yoke. The yoke and pole-plate structures are shaped to direct the magnetic flux appropriately. The outer surface of the pole plate is optimized subject to the minimization of a cost function, which evaluates the uniformity of the magnetic field over an ellipsoid. The magnetic field calculations required in this work are performed with the 3D finite element method software package Opera-3D. Each tentative design strategy is virtually modeled in this software package, which is externally controlled by MATLAB, with its key geometries defined as variables. The optimization variables are the thickness of the pole plate at control points distributed over the pole plate surface. A novel design concept as a superconducting non-axial magnet is introduced, which could create a large uniform B 0 magnetic field with fewer geometric restriction. This non-axial 0.5 T superconducting magnet has a moderately reduced SAD of 123 cm and a vertical patient opening of 68 cm. This work is presented as a proof of principle to investigate the feasibility of a non-axial magnet with the coils located around the yoke, and the results encourage future design optimizations to maximize the benefits of this non-axial design.

  12. The problem of 2,4,6-trichloroanisole in cork planks studied by attenuated total reflection infrared spectroscopy: proof of concept.

    Science.gov (United States)

    Garcia, Ana R; Lopes, Luís F; Brito de Barros, Ricardo; Ilharco, Laura M

    2015-01-14

    Attenuated total reflection infrared spectroscopy (ATR-IR) proved to be a promising detection technique for 2,4,6-trichloroanisole (TCA), which confers organoleptic defects to bottled alcoholic beverages, allowing the proposal of a criterion for cork plank acceptance when meant for stopper production. By analysis of a significant number of samples, it was proved that the presence of TCA, even in very low concentrations, imparts subtle changes to the cork spectra, namely, the growth of two new bands at ∼1417 (νC═C of TCA ring) and 1314 cm–1 (a shifted νCC of TCA) and an increase in the relative intensities of the bands at ∼1039 cm–1 (δCO of polysaccharides) and ∼813 cm–1 (τCH of suberin), the latter by overlapping with intense bands of TCA. These relative intensities were evaluated in comparison to a fingerprint of suberin (νasC–O–C), at 1161 cm–1. On the basis of those spectral variables, a multivariate statistics linear analysis (LDA) was performed to obtain a discriminant function that allows classifying the samples according to whether they contain or not TCA. The methodology proposed consists of a demanding acceptance criterion for cork planks destined for stopper production (with the guarantee of nonexistence of TCA) that results from combining the quantitative results with the absence of the two TCA correlated bands. ATR infrared spectroscopy is a nondestructive and easy to apply technique, both on cork planks and on stoppers, and has proven more restrictive than other techniques used in the cork industry that analyze the cleaning solutions. At the level of proof of concept, the method here proposed is appealing for high-value stopper applications.

  13. Skin conductance biofeedback training in adults with drug-resistant temporal lobe epilepsy and stress-triggered seizures: a proof-of-concept study.

    Science.gov (United States)

    Micoulaud-Franchi, Jean-Arthur; Kotwas, Iliana; Lanteaume, Laura; Berthet, Christelle; Bastien, Mireille; Vion-Dury, Jean; McGonigal, Aileen; Bartolomei, Fabrice

    2014-12-01

    The present proof-of-concept study investigated the feasibility of skin conductance biofeedback training in reducing seizures in adults with drug-resistant temporal lobe epilepsy (TLE), whose seizures are triggered by stress. Skin conductance biofeedback aims to increase levels of peripheral sympathetic arousal in order to reduce cortical excitability. This might seem somewhat counterintuitive, since such autonomic arousal may also be associated with increased stress and anxiety. Thus, this sought to verify that patients with TLE and stress-triggered seizures are not worsened in terms of stress, anxiety, and negative emotional response to this nonpharmacological treatment. Eleven patients with drug-resistant TLE with seizures triggered by stress were treated with 12 sessions of biofeedback. Patients did not worsen on cognitive evaluation of attentional biases towards negative emotional stimuli (P>.05) or on psychometric evaluation with state anxiety inventory (P = .059); in addition, a significant improvement was found in the Negative Affect Schedule (P = .014) and in the Beck Depression Inventory (P = .009). Biofeedback training significantly reduced seizure frequency with a mean reduction of -48.61% (SD = 27.79) (P = .005). There was a correlation between the mean change in skin conductance activity over the biofeedback treatment and the reduction of seizure frequency (r(11) = .62, P = .042). Thus, the skin conductance biofeedback used in the present study, which teaches patients to achieve an increased level of peripheral sympathetic arousal, was a well-tolerated nonpharmacological treatment. Further, well-controlled studies are needed to confirm the therapeutic value of this nonpharmacological treatment in reducing seizures in adults with drug-resistant TLE with seizures triggered by stress.

  14. Climate change-related temperature impacts on warm season heat mortality: a proof-of-concept methodology using BenMAP.

    Science.gov (United States)

    Voorhees, A Scott; Fann, Neal; Fulcher, Charles; Dolwick, Patrick; Hubbell, Bryan; Bierwagen, Britta; Morefield, Philip

    2011-02-15

    Climate change is anticipated to raise overall temperatures and is likely to increase heat-related human health morbidity and mortality risks. The objective of this work was to develop a proof-of-concept approach for estimating excess heat-related premature deaths in the continental United States resulting from potential changes in future temperature using the BenMAP model. In this approach we adapt the methods and tools that the US Environmental Protection Agency uses to assess air pollution health impacts by incorporating temperature modeling and heat mortality health impact functions. This new method demonstrates the ability to apply the existing temperature-health literature to quantify prospective changes in climate-sensitive heat-related mortality. We compared estimates of future temperature with and without climate change and applied heat-mortality health functions to estimate relative changes in heat-related premature mortality. Using the A1B emissions scenario, we applied the GISS-II global circulation model downscaled to 36-km using MM5 and formatted using the Meteorology-Chemistry Interface Processor. For averaged temperatures derived from the 5 years 2048-2052 relative to 1999-2003 we estimated for the warm season May-September a national U.S. estimate of annual incidence of heat-related mortality to be 3700-3800 from all causes, 3500 from cardiovascular disease, and 21 000-27 000 from nonaccidental death, applying various health impact functions. Our estimates of mortality, produced to validate the application of a new methodology, suggest the importance of quantifying heat impacts in economic assessments of climate change.

  15. Effects of the North Atlantic Oscillation and wind waves on salt marsh dynamics in the Danish Wadden Sea: a quantitative model as proof of concept

    Science.gov (United States)

    Kim, Daehyun; Grant, William E.; Cairns, David M.; Bartholdy, Jesper

    2013-08-01

    Long-term eustatic sea-level variation has been recognized as a primary factor affecting the hydrological and geomorphic dynamics of salt marshes. However, recent studies suggest that wind waves influenced by atmospheric oscillations also may play an important role in many coastal areas. Although this notion has been conceptually introduced for the Wadden Sea, no modeling attempts have been made yet. As a proof of concept, this study developed a simulation model using the commercially available STELLA® software, based on long-term data on water level and sedimentation collected at a back-barrier marsh on the Skallingen peninsula in Denmark. In the model, the frequency (number year-1) of wind-driven extreme high water level (HWL) events (>130 cm Danish Ordnance Zero) was simulated in terms of the North Atlantic Oscillation (NAO) index. Then, surface accretion (cm year-1) and submergence duration (h year-1) were simulated for the period 1933-2007. The model showed good performances: simulated rates of surface accretion and simulated durations of submergence decreased from 1950 to 1980, the point at which the NAO shifted from its negative to its positive phase, and increased thereafter. Despite continuous increases in surface elevation, increases in simulated submergence duration were apparently due to wind-driven HWL events, which generally increased in frequency after 1980. These findings for the Danish Wadden Sea add to the growing body of evidence that the role of atmospheric oscillations—e.g., the NAO—as drivers of wind-generated water level variations merits more attention in assessing the impact of climate change on coastal marshes.

  16. Proof-of-concept demonstration of free-form optics enhanced confocal Raman spectroscopy in combination with optofluidic lab-on-chip

    Science.gov (United States)

    Liu, Qing; De Coster, Diane; Loterie, Damien; Van Erps, Jürgen; Vervaeke, Michael; Missinne, Jeroen; Thienpont, Hugo; Ottevaere, Heidi

    2016-07-01

    Raman spectroscopy is a powerful optical and non-destructive technique and a well-known method for analysis purposes, especially to determine the molecular fingerprint of substances. Traditionally, such analyses are done in a specialized lab, with considerable requirements in terms of equipment, time and manual sampling of substances of interest. In this paper we take a step from bulky Raman spectroscopy laboratory analyses towards lab-on-chip (LOC) analyses. We present an optofluidic lab-on-chip for confocal Raman spectroscopy, which can be used for the analysis of liquids. The confocal detection suppresses the unwanted background from the polymer material out of which the chip is fabricated. We design the free-form optical reflector using non-sequential ray-tracing combined with a mathematical code to simulate the Raman scattering behavior of the substance under test. We prototype the device in Polymethyl methacrylate (PMMA) by means of ultraprecision diamond tooling. In a proof-of-concept demonstration, we first show the confocal behavior of our Raman lab-on-chip system by measuring the Raman spectrum of ethanol. In a next step, we compare the Raman spectra measured in our lab-on-chip with spectra measured with a commercial Raman spectrometer. Finally, to calibrate the system we perform Raman measurements on urea solutions with different concentrations. We achieve a detection limit that corresponds to a noise equivalent concentration of 20mM. Apart from strongly reducing the background perturbations, our confocal Raman spectroscopy system has other advantages as well. The reflector design is robust from a mechanical point of view and has the potential for mass-manufacturing using hot embossing or injection molding.

  17. Phase II proof-of-concept study of pazopanib monotherapy in treatment-naive patients with stage I/II resectable non-small-cell lung cancer.

    Science.gov (United States)

    Altorki, Nasser; Lane, Maureen E; Bauer, Thomas; Lee, Paul C; Guarino, Michael J; Pass, Harvey; Felip, Enriqueta; Peylan-Ramu, Nili; Gurpide, Alfonso; Grannis, Frederic W; Mitchell, John D; Tachdjian, Sabrina; Swann, R Suzanne; Huff, Anne; Roychowdhury, Debasish F; Reeves, Anthony; Ottesen, Lone H; Yankelevitz, David F

    2010-07-01

    Patients with early-stage, resectable, non-small-cell lung cancer (NSCLC) are at risk for recurrent disease, and 5-year survival rates do not exceed 75%. Angiogenesis inhibitors have shown clinical activity in patients with late-stage NSCLC, raising the possibility that targeting the vascular endothelial growth factor pathway in earlier-stage disease may be beneficial. This proof-of-concept study examined safety and efficacy of short-term, preoperative pazopanib monotherapy in patients with operable stage I/II NSCLC. Patients scheduled for resection received oral pazopanib 800 mg/d for 2 to 6 weeks preoperatively. Tumor response was measured by high-resolution computed tomography, permitting estimation of change in tumor volume and diameter. Gene-expression profiling was performed on 77 pre- and post-treatment lung samples from 34 patients. Of 35 patients enrolled, 33 (94%) had clinical stage I NSCLC and two (6%) had clinical stage II NSCLC. Median treatment duration was 16 days (range, 3 to 29 days). Thirty patients (86%) achieved tumor-volume reduction after pazopanib treatment. Two patients achieved tumor-volume reduction > or = 50%, and three patients had partial response according to Response Evaluation Criteria in Solid Tumors. Pazopanib was generally well tolerated. The most common adverse events included grade 2 hypertension, diarrhea, and fatigue. One patient developed pulmonary embolism 11 days after surgery. Several pazopanib target genes and other angiogenic factors were dysregulated post-treatment. Short-duration pazopanib was generally well tolerated and demonstrated single-agent activity in patients with early-stage NSCLC. Several target genes were dysregulated after pazopanib treatment, validating target-specific response and indicating a persistent pazopanib effect on lung cancer tissue. Further clinical evaluation of pazopanib in NSCLC is planned.

  18. Inflammation as a predictive biomarker for response to omega-3 fatty acids in major depressive disorder: a proof-of-concept study.

    Science.gov (United States)

    Rapaport, M H; Nierenberg, A A; Schettler, P J; Kinkead, B; Cardoos, A; Walker, R; Mischoulon, D

    2016-01-01

    This study explores whether inflammatory biomarkers act as moderators of clinical response to omega-3 (n-3) fatty acids in subjects with major depressive disorder (MDD). One hundred fifty-five subjects with Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) MDD, a baseline 17-item Hamilton Depression Rating Scale (HAM-D-17) score ⩾ 15 and baseline biomarker data (interleukin (IL)-1ra, IL-6, high-sensitivity C-reactive protein (hs-CRP), leptin and adiponectin) were randomized between 18 May 2006 and 30 June 2011 to 8 weeks of double-blind treatment with eicosapentaenoic acid (EPA)-enriched n-3 1060 mg day(-1), docosahexaenoic acid (DHA)-enriched n-3 900 mg day(-1) or placebo. Outcomes were determined using mixed model repeated measures analysis for 'high' and 'low' inflammation groups based on individual and combined biomarkers. Results are presented in terms of standardized treatment effect size (ES) for change in HAM-D-17 from baseline to treatment week 8. Although overall treatment group differences were negligible (ES=-0.13 to +0.04), subjects with any 'high' inflammation improved more on EPA than placebo (ES=-0.39) or DHA (ES=-0.60) and less on DHA than placebo (ES=+0.21); furthermore, EPA-placebo separation increased with increasing numbers of markers of high inflammation. Subjects randomized to EPA with 'high' IL-1ra or hs-CRP or low adiponectin ('high' inflammation) had medium ES decreases in HAM-D-17 scores vs subjects 'low' on these biomarkers. Subjects with 'high' hs-CRP, IL-6 or leptin were less placebo-responsive than subjects with low levels of these biomarkers (medium to large ES differences). Employing multiple markers of inflammation facilitated identification of a more homogeneous cohort of subjects with MDD responding to EPA vs placebo in our cohort. Studies are needed to replicate and extend this proof-of-concept work.

  19. Evaluation of banked urine samples for the detection of circulating anodic and cathodic antigens in Schistosoma mekongi and S. japonicum infections: a proof-of-concept study.

    Science.gov (United States)

    van Dam, Govert J; Odermatt, Peter; Acosta, Luz; Bergquist, Robert; de Dood, Claudia J; Kornelis, Dieuwke; Muth, Sinuon; Utzinger, Jürg; Corstjens, Paul L A M

    2015-01-01

    In Asia, Schistosoma japonicum is the predominant schistosome species, while Schistosoma mekongi is confined to limited foci in Cambodia and Lao People's Democratic Republic. While the People's Republic of China has been successful in controlling schistosomiasis, the disease remains a major public health issue in other areas. In order to prioritise intervention areas, not only accurate diagnosis is important but also other factors, such as practicality, time-efficiency and cost-effectiveness, since they strongly influence the success of control programmes. To evaluate the highly specific urine-based assays for the schistosome circulating cathodic antigen (CCA) and the circulating anodic antigen (CAA), banked u