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Sample records for primary endpoints included

  1. Considerations in choosing a primary endpoint that measures durability of virological suppression in an antiretroviral trial.

    Science.gov (United States)

    Gilbert, P B; Ribaudo, H J; Greenberg, L; Yu, G; Bosch, R J; Tierney, C; Kuritzkes, D R

    2000-09-08

    At present, many clinical trials of anti-HIV-1 therapies compare treatments by a primary endpoint that measures the durability of suppression of HIV-1 replication. Several durability endpoints are compared. Endpoints are compared by their implicit assumptions regarding surrogacy for clinical outcomes, sample size requirements, and accommodations for inter-patient differences in baseline plasma HIV-1-RNA levels and in initial treatment response. Virological failure is defined by the non-suppression of virus levels at a prespecified follow-up time T(early virological failure), or by relapse. A binary virological failure endpoint is compared with three time-to-virological failure endpoints: time from (i) randomization that assigns early failures a failure time of T weeks; (ii) randomization that extends the early failure time T for slowly responding subjects; and (iii) virological response that assigns non-responders a failure time of 0 weeks. Endpoint differences are illustrated with Agouron's trial 511. In comparing high with low-dose nelfinavir (NFV) regimens in Agouron 511, the difference in Kaplan-Meier estimates of the proportion not failing by 24 weeks is 16.7% (P = 0.048), 6.5% (P = 0.29) and 22.9% (P = 0.0030) for endpoints (i), (ii) and (iii), respectively. The results differ because NFV suppresses virus more quickly at the higher dose, and the endpoints weigh this treatment difference differently. This illustrates that careful consideration needs to be given to choosing a primary endpoint that will detect treatment differences of interest. A time from randomization endpoint is usually recommended because of its advantages in flexibility and sample size, especially at interim analyses, and for its interpretation for patient management.

  2. A covariant open bosonic string field theory including the endpoint and middlepoint interaction

    International Nuclear Information System (INIS)

    Liu, B.G.; Northwest Univ., Xian; Chen, Y.X.

    1988-01-01

    Extending the usual endpoint and midpoint interactions, we introduce numerous kinds of interactions, labelled by a parameter λ and obtain a non-commutative and associative string field algebra by adding up all interactions. With this algebra we develop a covariant open bosonic string field theory, which reduces to Witten's open bosonic string field theory under a special string length choice. (orig.)

  3. Reducing sample size by combining superiority and non-inferiority for two primary endpoints in the Social Fitness study.

    Science.gov (United States)

    Donkers, Hanneke; Graff, Maud; Vernooij-Dassen, Myrra; Nijhuis-van der Sanden, Maria; Teerenstra, Steven

    2017-01-01

    In randomized controlled trials, two endpoints may be necessary to capture the multidimensional concept of the intervention and the objectives of the study adequately. We show how to calculate sample size when defining success of a trial by combinations of superiority and/or non-inferiority aims for the endpoints. The randomized controlled trial design of the Social Fitness study uses two primary endpoints, which can be combined into five different scenarios for defining success of the trial. We show how to calculate power and sample size for each scenario and compare these for different settings of power of each endpoint and correlation between them. Compared to a single primary endpoint, using two primary endpoints often gives more power when success is defined as: improvement in one of the two endpoints and no deterioration in the other. This also gives better power than when success is defined as: improvement in one prespecified endpoint and no deterioration in the remaining endpoint. When two primary endpoints are equally important, but a positive effect in both simultaneously is not per se required, the objective of having one superior and the other (at least) non-inferior could make sense and reduce sample size. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. Note on simultaneous inferences about non-inferiority and superiority for a primary and a secondary endpoint.

    Science.gov (United States)

    Guilbaud, Olivier

    2011-11-01

    In their review of challenges to multiple testing in clinical trials, Hung and Wang (2010) considered the situation where a treatment is to be compared with an active comparator and the aim is to show non-inferiority and (if possible) superiority with respect to a primary and a secondary endpoint. This note extends their discussion of this particular situation, taking the sequentially rejective procedure they used for illustration as a starting point. Some alternative multiple testing procedures (MTPs) are considered, and corresponding simultaneous confidence regions are discussed that provide additional information "for free". The choice may then be based on the properties of these MTPs and corresponding confidence regions. 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. Primary endpoint results of the OMEGA Study: One-year clinical outcomes after implantation of a novel platinum chromium bare metal stent

    Energy Technology Data Exchange (ETDEWEB)

    Wang, John C., E-mail: john.wang@medstar.net [MedStar Union Memorial Hospital, Baltimore MD (United States); Carrié, Didier, E-mail: carrie.didier@chu-toulouse.fr [Centre Hôpital Universitaire Rangueil, Toulouse (France); Masotti, Monica, E-mail: MASOTTI@clinic.ub.es [Hospital Clinic, University of Barcelona (Spain); Erglis, Andrejs, E-mail: a.a.erglis@stradini.lv [Pauls Stradins Clinical University Hospital, University of Latvia, Riga (Latvia); Mego, David, E-mail: David.Mego@arheart.com [Arkansas Heart Hospital, Little Rock, AR (United States); Watkins, Matthew W., E-mail: Matthew.Watkins@vtmednet.org [University of Vermont Medical Center, Burlington VT (United States); Underwood, Paul, E-mail: Paul.underwood@bsci.com [Boston Scientific, Marlborough MA USA (United States); Allocco, Dominic J., E-mail: Dominic.allocco@bsci.com [Boston Scientific, Marlborough MA USA (United States); Hamm, Christian W., E-mail: C.Hamm@kerckhoff-klinik.de [Kerckhoff Heart and Thoraxcenter, Bad Nauheim (Germany)

    2015-03-15

    Background/purpose: Bare metal stents (BMS) have similar rates of death and myocardial infarction (MI) compared to drug-eluting stents (DES). DES lower repeat revascularization rates compared to BMS, but may have higher rates of late stent thrombosis (ST) potentially due to impaired endothelialization requiring longer dual anti-platelet therapy (DAPT). OMEGA evaluated a novel BMS designed to have improved deliverability and radiopacity, in comparison to currently available platforms. Methods/materials: OMEGA was a prospective, multicenter, single-arm study enrolling 328 patients at 37 sites (US and Europe). Patients received the OMEGA stent (bare platinum chromium element stent) for the treatment of de novo native coronary artery lesions (≤ 28 mm long; diameter ≥ 2.25 mm to ≤ 4.50 mm). The primary endpoint was 9-month target lesion failure (TLF: cardiac death, target vessel-related MI, target lesion revascularization [TLR]) compared to a prespecified performance goal (PG) based on prior generation BMS. All major cardiac events were independently adjudicated. DAPT was required for a minimum of 1 month post procedure. Results: In the OMEGA study, the mean age was 65; 17% had diabetes mellitus. The primary endpoint was met; 9 month TLF rate was 11.5%, and the upper 1-sided 95% confidence bound of 14.79% was less than the prespecified PG of 21.2% (p < 0.0001). One-year event rates were low including a TLF rate of 12.8% and an ST rate of 0.6% at 12 months. Conclusions: One-year outcomes of OMEGA show low rates of TLF, revascularization and ST. This supports safety and efficacy of the OMEGA BMS for the treatment of coronary artery disease. - Highlights: • The OMEGA study evaluated a novel platinum chromium bare metal stent. • OMEGA enrolled 328 patients at 37 sites (US and Europe). • The primary endpoint of 9 month target lesion failure was 11.5%. • One-year event rates were low including an ST rate of 0.6% at 12 months.

  6. Primary endpoint results of the OMEGA Study: One-year clinical outcomes after implantation of a novel platinum chromium bare metal stent

    International Nuclear Information System (INIS)

    Wang, John C.; Carrié, Didier; Masotti, Monica; Erglis, Andrejs; Mego, David; Watkins, Matthew W.; Underwood, Paul; Allocco, Dominic J.; Hamm, Christian W.

    2015-01-01

    Background/purpose: Bare metal stents (BMS) have similar rates of death and myocardial infarction (MI) compared to drug-eluting stents (DES). DES lower repeat revascularization rates compared to BMS, but may have higher rates of late stent thrombosis (ST) potentially due to impaired endothelialization requiring longer dual anti-platelet therapy (DAPT). OMEGA evaluated a novel BMS designed to have improved deliverability and radiopacity, in comparison to currently available platforms. Methods/materials: OMEGA was a prospective, multicenter, single-arm study enrolling 328 patients at 37 sites (US and Europe). Patients received the OMEGA stent (bare platinum chromium element stent) for the treatment of de novo native coronary artery lesions (≤ 28 mm long; diameter ≥ 2.25 mm to ≤ 4.50 mm). The primary endpoint was 9-month target lesion failure (TLF: cardiac death, target vessel-related MI, target lesion revascularization [TLR]) compared to a prespecified performance goal (PG) based on prior generation BMS. All major cardiac events were independently adjudicated. DAPT was required for a minimum of 1 month post procedure. Results: In the OMEGA study, the mean age was 65; 17% had diabetes mellitus. The primary endpoint was met; 9 month TLF rate was 11.5%, and the upper 1-sided 95% confidence bound of 14.79% was less than the prespecified PG of 21.2% (p < 0.0001). One-year event rates were low including a TLF rate of 12.8% and an ST rate of 0.6% at 12 months. Conclusions: One-year outcomes of OMEGA show low rates of TLF, revascularization and ST. This supports safety and efficacy of the OMEGA BMS for the treatment of coronary artery disease. - Highlights: • The OMEGA study evaluated a novel platinum chromium bare metal stent. • OMEGA enrolled 328 patients at 37 sites (US and Europe). • The primary endpoint of 9 month target lesion failure was 11.5%. • One-year event rates were low including an ST rate of 0.6% at 12 months

  7. Biomarkers of Host Response Predict Primary End-Point Radiological Pneumonia in Tanzanian Children with Clinical Pneumonia: A Prospective Cohort Study.

    Directory of Open Access Journals (Sweden)

    Laura K Erdman

    Full Text Available Diagnosing pediatric pneumonia is challenging in low-resource settings. The World Health Organization (WHO has defined primary end-point radiological pneumonia for use in epidemiological and vaccine studies. However, radiography requires expertise and is often inaccessible. We hypothesized that plasma biomarkers of inflammation and endothelial activation may be useful surrogates for end-point pneumonia, and may provide insight into its biological significance.We studied children with WHO-defined clinical pneumonia (n = 155 within a prospective cohort of 1,005 consecutive febrile children presenting to Tanzanian outpatient clinics. Based on x-ray findings, participants were categorized as primary end-point pneumonia (n = 30, other infiltrates (n = 31, or normal chest x-ray (n = 94. Plasma levels of 7 host response biomarkers at presentation were measured by ELISA. Associations between biomarker levels and radiological findings were assessed by Kruskal-Wallis test and multivariable logistic regression. Biomarker ability to predict radiological findings was evaluated using receiver operating characteristic curve analysis and Classification and Regression Tree analysis.Compared to children with normal x-ray, children with end-point pneumonia had significantly higher C-reactive protein, procalcitonin and Chitinase 3-like-1, while those with other infiltrates had elevated procalcitonin and von Willebrand Factor and decreased soluble Tie-2 and endoglin. Clinical variables were not predictive of radiological findings. Classification and Regression Tree analysis generated multi-marker models with improved performance over single markers for discriminating between groups. A model based on C-reactive protein and Chitinase 3-like-1 discriminated between end-point pneumonia and non-end-point pneumonia with 93.3% sensitivity (95% confidence interval 76.5-98.8, 80.8% specificity (72.6-87.1, positive likelihood ratio 4.9 (3.4-7.1, negative likelihood ratio 0

  8. Biomarkers of Host Response Predict Primary End-Point Radiological Pneumonia in Tanzanian Children with Clinical Pneumonia: A Prospective Cohort Study

    Science.gov (United States)

    Erdman, Laura K.; D’Acremont, Valérie; Hayford, Kyla; Kilowoko, Mary; Kyungu, Esther; Hongoa, Philipina; Alamo, Leonor; Streiner, David L.; Genton, Blaise; Kain, Kevin C.

    2015-01-01

    Background Diagnosing pediatric pneumonia is challenging in low-resource settings. The World Health Organization (WHO) has defined primary end-point radiological pneumonia for use in epidemiological and vaccine studies. However, radiography requires expertise and is often inaccessible. We hypothesized that plasma biomarkers of inflammation and endothelial activation may be useful surrogates for end-point pneumonia, and may provide insight into its biological significance. Methods We studied children with WHO-defined clinical pneumonia (n = 155) within a prospective cohort of 1,005 consecutive febrile children presenting to Tanzanian outpatient clinics. Based on x-ray findings, participants were categorized as primary end-point pneumonia (n = 30), other infiltrates (n = 31), or normal chest x-ray (n = 94). Plasma levels of 7 host response biomarkers at presentation were measured by ELISA. Associations between biomarker levels and radiological findings were assessed by Kruskal-Wallis test and multivariable logistic regression. Biomarker ability to predict radiological findings was evaluated using receiver operating characteristic curve analysis and Classification and Regression Tree analysis. Results Compared to children with normal x-ray, children with end-point pneumonia had significantly higher C-reactive protein, procalcitonin and Chitinase 3-like-1, while those with other infiltrates had elevated procalcitonin and von Willebrand Factor and decreased soluble Tie-2 and endoglin. Clinical variables were not predictive of radiological findings. Classification and Regression Tree analysis generated multi-marker models with improved performance over single markers for discriminating between groups. A model based on C-reactive protein and Chitinase 3-like-1 discriminated between end-point pneumonia and non-end-point pneumonia with 93.3% sensitivity (95% confidence interval 76.5–98.8), 80.8% specificity (72.6–87.1), positive likelihood ratio 4.9 (3.4–7

  9. Establishing a group of endpoints to support collective operations without specifying unique identifiers for any endpoints

    Science.gov (United States)

    Archer, Charles J.; Blocksom, Michael A.; Ratterman, Joseph D.; Smith, Brian E.; Xue, Hanghon

    2016-02-02

    A parallel computer executes a number of tasks, each task includes a number of endpoints and the endpoints are configured to support collective operations. In such a parallel computer, establishing a group of endpoints receiving a user specification of a set of endpoints included in a global collection of endpoints, where the user specification defines the set in accordance with a predefined virtual representation of the endpoints, the predefined virtual representation is a data structure setting forth an organization of tasks and endpoints included in the global collection of endpoints and the user specification defines the set of endpoints without a user specification of a particular endpoint; and defining a group of endpoints in dependence upon the predefined virtual representation of the endpoints and the user specification.

  10. Endpoints in pediatric pain studies

    NARCIS (Netherlands)

    M. van Dijk (Monique); I. Ceelie (Ilse); D. Tibboel (Dick)

    2011-01-01

    textabstractAssessing pain intensity in (preverbal) children is more difficult than in adults. Tools to measure pain are being used as primary endpoints [e.g., pain intensity, time to first (rescue) analgesia, total analgesic consumption, adverse effects, and long-term effects] in studies on the

  11. Establishing a group of endpoints in a parallel computer

    Science.gov (United States)

    Archer, Charles J.; Blocksome, Michael A.; Ratterman, Joseph D.; Smith, Brian E.; Xue, Hanhong

    2016-02-02

    A parallel computer executes a number of tasks, each task includes a number of endpoints and the endpoints are configured to support collective operations. In such a parallel computer, establishing a group of endpoints receiving a user specification of a set of endpoints included in a global collection of endpoints, where the user specification defines the set in accordance with a predefined virtual representation of the endpoints, the predefined virtual representation is a data structure setting forth an organization of tasks and endpoints included in the global collection of endpoints and the user specification defines the set of endpoints without a user specification of a particular endpoint; and defining a group of endpoints in dependence upon the predefined virtual representation of the endpoints and the user specification.

  12. Inconsistent approaches of the G-BA regarding acceptance of primary study endpoints as being relevant to patients - an analysis of three disease areas: oncological, metabolic, and infectious diseases

    Directory of Open Access Journals (Sweden)

    Thomas Staab

    2016-11-01

    Full Text Available Abstract Background Previous evaluations of oncological medicines in the German early benefit assessment (EBA procedure have demonstrated inconsistent acceptance of endpoints by regulatory authorities and the Federal Joint Committee (G-BA. Accepted standard endpoints for regulatory purposes are frequently not considered as patient-relevant in the German EBA system. In this study the acceptance of clinically acknowledged primary endpoints (PEPs from regulatory trials in EBAs conducted by the G-BA was evaluated across three therapeutic areas. Methods Medicines for oncological, metabolic and infectious diseases with EBAs finalised before 25 January 2016 were evaluated. Respective manufacturer’s dossiers, regulatory assessments, G-BA appraisals and oral hearing minutes were reviewed, and PEPs were examined to determine whether they were considered relevant to patients by the G-BA. Furthermore, the acceptance of symptomatic vs asymptomatic PEPs was also analysed. Results A total of 65 EBAs were evaluated. Mortality PEPs were widely accepted as patient-relevant but were only used in a minority of EBAs and exclusively in oncological diseases. Morbidity PEPs constituted around 72 % of assessed PEPs, but were excluded from the EBA in over half of the corresponding assessments as they were not considered patient-relevant. Symptomatic endpoints were largely deemed patient-relevant, whereas acceptance of asymptomatic endpoints varied between therapeutic areas. Conclusions This evaluation identified inconsistencies in patient relevance of morbidity-related PEPs as well as in acceptance of asymptomatic endpoints by the G-BA in all three disease areas examined. Better harmonisation between the regulatory authorities and the G-BA is still required after 5 years of AMNOG health technology assessment in Germany.

  13. Efficacy and safety of once-weekly GLP-1 receptor agonist albiglutide (HARMONY 2): 52 week primary endpoint results from a randomised, placebo-controlled trial in patients with type 2 diabetes mellitus inadequately controlled with diet and exercise.

    Science.gov (United States)

    Nauck, Michael A; Stewart, Murray W; Perkins, Christopher; Jones-Leone, Angela; Yang, Fred; Perry, Caroline; Reinhardt, Rickey R; Rendell, Marc

    2016-02-01

    Additional safe and effective therapies for type 2 diabetes are needed, especially ones that do not cause weight gain and have a low risk of hypoglycaemia. The present study evaluated albiglutide as monotherapy. In this placebo-controlled study, 309 patients (aged ≥ 18 years) with type 2 diabetes inadequately controlled by diet and exercise and who were not using a glucose-lowering agent (HbA1c 7.0-10.0% [53.00-85.79 mmol/mol], body mass index 20-45 kg/m(2), and fasting C-peptide ≥ 0.26 nmol/l) were randomised (1:1:1 on a fixed randomisation schedule using an interactive voice response system) to receive once-weekly albiglutide 30 mg (n = 102) or 50 mg (n = 102) or matching placebo (n = 105). The study treatments were blinded to both patients and study personnel. All study data were collected at individual patient clinic visits. The primary efficacy endpoint was change in HbA1c from baseline to week 52. The primary analysis was applied to the intent-to-treat population. Additional efficacy and safety endpoints were assessed. At week 52, both albiglutide 30 mg and 50 mg were superior to placebo in reducing HbA1c. The least-squares means treatment difference from placebo was -0.84% (95% CI -1.11%, -0.58%; p < 0.0001) with albiglutide 30 mg and -1.04% (-1.31%, -0.77%; p < 0.0001) with albiglutide 50 mg. Injection-site reactions were reported more frequently with albiglutide (30 mg: 17.8%; 50 mg: 22.2%) than with placebo (9.9%). Other commonly reported adverse events included nausea, diarrhoea, vomiting and hypoglycaemia; the incidences of these were generally similar across treatment groups. Albiglutide is safe and effective as monotherapy and significantly lowered HbA1c levels over 52 weeks, did not cause weight gain, and had good gastrointestinal tolerability and a low rate of hypoglycaemia compared with placebo. Trial registration ClinicalTrials.gov NCT00849017 Funding This study was sponsored by GlaxoSmithKline.

  14. TBI Endpoints Development

    Science.gov (United States)

    2015-10-01

    therapy , and early mild physical activity, which result in fewer symptoms, lower mean severity of symptoms, less social disability, and fewer days off work...developing more precise TBI diagnostic tools, clinical endpoints, and effective therapies . We designed and executed an interactive program that combined...surgery, neuropsychology, neuroradiology, psychiatry, neurology, sports medicine, pediatrics, geriatrics , health economics, biostatistics, and informatics

  15. Gene expression as a sensitive endpoint to evaluate cell differentiation and maturation of the developing central nervous system in primary cultures of rat cerebellar granule cells (CGCs) exposed to pesticides

    International Nuclear Information System (INIS)

    Hogberg, Helena T.; Kinsner-Ovaskainen, Agnieszka; Hartung, Thomas; Coecke, Sandra; Bal-Price, Anna K.

    2009-01-01

    The major advantage of primary neuronal cultures for developmental neurotoxicity (DNT) testing is their ability to replicate the crucial stages of neurodevelopment. In our studies using primary culture of cerebellar granule cells (CGCs) we have evaluated whether the gene expression relevant to the most critical developmental processes such as neuronal differentiation (NF-68 and NF-200) and functional maturation (NMDA and GABA A receptors), proliferation and differentiation of astrocytes (GFAP and S100β) as well as the presence of neural precursor cells (nestin and Sox10) could be used as an endpoint for in vitro DNT. The expression of these genes was assessed after exposure to various pesticides (paraquat parathion, dichlorvos, pentachlorophenol and cycloheximide) that could induce developmental neurotoxicity through different mechanisms. All studied pesticides significantly modified the expression of selected genes, related to the different stages of neuronal and/or glial cell development and maturation. The most significant changes were observed after exposure to paraquat and parathion (i.e. down-regulation of mRNA expression of NF-68 and NF-200, NMDA and GABA A receptors). Similarly, dichlorvos affected mainly neurons (decreased mRNA expression of NF-68 and GABA A receptors) whereas cycloheximide had an effect on neurons and astrocytes, as significant decreases in the mRNA expression of both neurofilaments (NF-68 and NF-200) and the astrocyte marker (S100β) were observed. Our results suggest that toxicity induced by pesticides that target multiple pathways of neurodevelopment can be identified by studying expression of genes that are involved in different stages of cell development and maturation, and that gene expression could be used as a sensitive endpoint for initial screening to identify the compounds with the potential to cause developmental neurotoxicity

  16. Evaluation of early efficacy endpoints for proof-of-concept trials.

    Science.gov (United States)

    Chen, Cong; Sun, Linda; Li, Chih-Lin

    2013-03-11

    A Phase II proof-of-concept (POC) trial usually uses an early efficacy endpoint other than a clinical endpoint as the primary endpoint. Because of the advancement in bioscience and technology, which has yielded a number of new surrogate biomarkers, drug developers often have more candidate endpoints to choose from than they can handle. As a result, selection of endpoint and its effect size as well as choice of type I/II error rates are often at the center of heated debates in design of POC trials. While optimization of the trade-off between benefit and cost is the implicit objective in such a decision-making process, it is seldom explicitly accounted for in practice. In this research note, motivated by real examples from the oncology field, we provide practical measures for evaluation of early efficacy endpoints (E4) for POC trials. We further provide optimal design strategies for POC trials that include optimal Go-No Go decision criteria for initiation of Phase III and optimal resource allocation strategies for conducting multiple POC trials in a portfolio under fixed resources. Although oncology is used for illustration purpose, the same idea developed in this research note also applies to similar situations in other therapeutic areas or in early-stage drug development in that a Go-No Go decision has to rely on limited data from an early efficacy endpoint and cost-effectiveness is the main concern.

  17. Impact of initial platelet count on baseline angiographic finding and end-points in ST-elevation myocardial infarction referred for primary percutaneous coronary intervention.

    Science.gov (United States)

    Kaplan, Sahin; Kaplan, Safiye Tuba; Kiris, Abdulkadir; Gedikli, Omer

    2014-01-01

    The baseline platelet count (BPC) in patients with acute ST elevation myocardial infarction (STEMI) may reflect the baseline anjiografic finding and may also predic long-term outcomes after primary percutaneous coronary intervention (PPCI). Available data for the value of BPC in patients with STEMI treated with PPCI are still questionable. Therefore, we sought to determine the prognostic value of BPC for baseline angiographic finding and the impact of BPC on clinical outcomes of patients treating with PPCI. Blood sample for BPC was obtained on admission in 140 consecutive patients undergoing PPCI. Patients were divided 2 groups that group-1 (104 patients): TIMI flow-grade 0 and group-2 (36 patients): TIMI flow-grade 1-3. Follow-up was performed at 1-9 months. Baseline demographics were comparable, but, BPC was significantly higher in group-1 comparing 2 (293.7±59.8x10(9)/L vs. 237.7±50.9x10(9)/L, pmeasuring of a BPC on admission may also provide further practical and therapeutic profits.

  18. Radiological endpoints relevant to ecological risk assessment

    International Nuclear Information System (INIS)

    Harrison, F.

    1997-01-01

    Because of the potential risk from radiation due to the releases of radionuclides from anthropogenic activities, considerable research was performed to determine for humans the levels of dose received, their responses to the doses and mechanisms of action of radioactivity on living matter. More recently, there is an increased interest in the effects of radioactivity on non-human species. There are differences in approach between risk assessment for humans and ecosystems. For protection of humans, the focus is the individual and the endpoint of primary concern is cancer induction. For protection of ecosystems, the focus is on population stability and the endpoint of concern is reproductive success for organisms important ecologically and economically. For these organisms, information is needed on their responses to irradiation and the potential impact of the doses absorbed on their reproductive success. Considerable information is available on the effects of radiation on organisms from different phyla and types of ecosystems. Databases useful for assessing risk from exposures of populations to radioactivity are the effects of irradiation on mortality, fertility and sterility, the latter two of which are important components of reproductive success. Data on radiation effects on mortality are available both from acute and chronic irradiation. In relation to radiation effects, reproductive success for a given population is related to a number of characteristics of the species, including inherent radiosensitivity of reproductive tissues and early life stages, processes occurring during gametogenesis, reproductive strategy and exposure history. The available data on acute and chronic radiation doses is reviewed for invertebrates, fishes and mammals. The information reviewed indicates that wide ranges in responses with species can be expected. Parameters that most likely contribute to inherent radiosensitivity are discussed. (author)

  19. Bayesian model selection techniques as decision support for shaping a statistical analysis plan of a clinical trial: An example from a vertigo phase III study with longitudinal count data as primary endpoint

    Directory of Open Access Journals (Sweden)

    Adrion Christine

    2012-09-01

    Full Text Available Abstract Background A statistical analysis plan (SAP is a critical link between how a clinical trial is conducted and the clinical study report. To secure objective study results, regulatory bodies expect that the SAP will meet requirements in pre-specifying inferential analyses and other important statistical techniques. To write a good SAP for model-based sensitivity and ancillary analyses involves non-trivial decisions on and justification of many aspects of the chosen setting. In particular, trials with longitudinal count data as primary endpoints pose challenges for model choice and model validation. In the random effects setting, frequentist strategies for model assessment and model diagnosis are complex and not easily implemented and have several limitations. Therefore, it is of interest to explore Bayesian alternatives which provide the needed decision support to finalize a SAP. Methods We focus on generalized linear mixed models (GLMMs for the analysis of longitudinal count data. A series of distributions with over- and under-dispersion is considered. Additionally, the structure of the variance components is modified. We perform a simulation study to investigate the discriminatory power of Bayesian tools for model criticism in different scenarios derived from the model setting. We apply the findings to the data from an open clinical trial on vertigo attacks. These data are seen as pilot data for an ongoing phase III trial. To fit GLMMs we use a novel Bayesian computational approach based on integrated nested Laplace approximations (INLAs. The INLA methodology enables the direct computation of leave-one-out predictive distributions. These distributions are crucial for Bayesian model assessment. We evaluate competing GLMMs for longitudinal count data according to the deviance information criterion (DIC or probability integral transform (PIT, and by using proper scoring rules (e.g. the logarithmic score. Results The instruments under study

  20. Bayesian model selection techniques as decision support for shaping a statistical analysis plan of a clinical trial: an example from a vertigo phase III study with longitudinal count data as primary endpoint.

    Science.gov (United States)

    Adrion, Christine; Mansmann, Ulrich

    2012-09-10

    A statistical analysis plan (SAP) is a critical link between how a clinical trial is conducted and the clinical study report. To secure objective study results, regulatory bodies expect that the SAP will meet requirements in pre-specifying inferential analyses and other important statistical techniques. To write a good SAP for model-based sensitivity and ancillary analyses involves non-trivial decisions on and justification of many aspects of the chosen setting. In particular, trials with longitudinal count data as primary endpoints pose challenges for model choice and model validation. In the random effects setting, frequentist strategies for model assessment and model diagnosis are complex and not easily implemented and have several limitations. Therefore, it is of interest to explore Bayesian alternatives which provide the needed decision support to finalize a SAP. We focus on generalized linear mixed models (GLMMs) for the analysis of longitudinal count data. A series of distributions with over- and under-dispersion is considered. Additionally, the structure of the variance components is modified. We perform a simulation study to investigate the discriminatory power of Bayesian tools for model criticism in different scenarios derived from the model setting. We apply the findings to the data from an open clinical trial on vertigo attacks. These data are seen as pilot data for an ongoing phase III trial. To fit GLMMs we use a novel Bayesian computational approach based on integrated nested Laplace approximations (INLAs). The INLA methodology enables the direct computation of leave-one-out predictive distributions. These distributions are crucial for Bayesian model assessment. We evaluate competing GLMMs for longitudinal count data according to the deviance information criterion (DIC) or probability integral transform (PIT), and by using proper scoring rules (e.g. the logarithmic score). The instruments under study provide excellent tools for preparing decisions

  1. Sensitivity of submersed freshwater macrophytes and endpoints in laboratory toxicity tests

    International Nuclear Information System (INIS)

    Arts, Gertie H.P.; Belgers, J. Dick M.; Hoekzema, Conny H.; Thissen, Jac T.N.M.

    2008-01-01

    The toxicological sensitivity and variability of a range of macrophyte endpoints were statistically tested with data from chronic, non-axenic, macrophyte toxicity tests. Five submersed freshwater macrophytes, four pesticides/biocides and 13 endpoints were included in the statistical analyses. Root endpoints, reflecting root growth, were most sensitive in the toxicity tests, while endpoints relating to biomass, growth and shoot length were less sensitive. The endpoints with the lowest coefficients of variation were not necessarily the endpoints, which were toxicologically most sensitive. Differences in sensitivity were in the range of 10-1000 for different macrophyte-specific endpoints. No macrophyte species was consistently the most sensitive. Criteria to select endpoints in macrophyte toxicity tests should include toxicological sensitivity, variance and ecological relevance. Hence, macrophyte toxicity tests should comprise an array of endpoints, including very sensitive endpoints like those relating to root growth. - A range of endpoints is more representative of macrophyte fitness than biomass and growth only

  2. Shared Contract-Obedient Endpoints

    Directory of Open Access Journals (Sweden)

    Étienne Lozes

    2012-12-01

    Full Text Available Most of the existing verification techniques for message-passing programs suppose either that channel endpoints are used in a linear fashion, where at most one thread may send or receive from an endpoint at any given time, or that endpoints may be used arbitrarily by any number of threads. The former approach usually forbids the sharing of channels while the latter limits what is provable about programs. In this paper we propose a midpoint between these techniques by extending a proof system based on separation logic to allow sharing of endpoints. We identify two independent mechanisms for supporting sharing: an extension of fractional shares to endpoints, and a new technique based on what we call reflexive ownership transfer. We demonstrate on a number of examples that a linear treatment of sharing is possible.

  3. Clinical problems of multiple primary cancers including head and neck cancers. From the viewpoint of radiotherapy

    International Nuclear Information System (INIS)

    Nishio, Masamichi; Myojin, Miyako; Nishiyama, Noriaki; Taguchi, Hiroshi; Takagi, Masaru; Tanaka, Katsuhiko

    2003-01-01

    A total of 2144 head and neck cancers were treated by radiotherapy at the National Sapporo Hospital between 1974 and 2001. Of these, 313 (14.6%) were found to have other primary cancers besides head and neck cancer, in which double cancers were 79% and triple or more cancers were 21%. Frequency according to primary site of the first head and neck cancer was oral cavity: 107/603 (17.7%), epipharynx cancer: 7/117 (6.0%), oropharyngeal cancer: 63/257 (24.5%), hypopharyngeal cancer: 65/200 (32.5%), laryngeal cancer: 114/558 (20.4%), and nose/paranasal sinus: 4.9% respectively. Esophageal cancer, head and neck cancer, lung cancer and gastric cancer were very frequent as other primary sites combined with the head and neck. The first onset region was the head and neck in 233 out of 313 cases with multiple primary cancers. The five-year survival rate from the onset of head and neck cancers is 52%, 10-year: 30%, and 5-year cause-specific survival rate 82%, and 10-year: 78%, respectively. The treatment possibilities in multiple primary cancers tend to be limited because the treatment areas are sometimes overlapped. New approaches to the treatment of multiple primary cancers should be considered in the future. (author)

  4. Specialists meeting on properties of primary circuit structural materials including environmental effects

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1977-07-01

    The Specialists Meeting on Properties of Primary Circuit Structural Materials of LMFBRs covered the following topics: overview of materials program in different countries; mechanical properties of materials in air; fracture mechanics studies - component related activities; impact of environmental influences on mechanical properties; relationship of material properties and design methods. The purpose of the meeting was to provide a forum for exchange of information on structural materials behaviour in primary circuit of fast breeder reactors. Special emphasis was placed on environmental effects such as influence of sodium and irradiation on mechanical properties of reactor materials.

  5. Specialists meeting on properties of primary circuit structural materials including environmental effects

    International Nuclear Information System (INIS)

    1977-01-01

    The Specialists Meeting on Properties of Primary Circuit Structural Materials of LMFBRs covered the following topics: overview of materials program in different countries; mechanical properties of materials in air; fracture mechanics studies - component related activities; impact of environmental influences on mechanical properties; relationship of material properties and design methods. The purpose of the meeting was to provide a forum for exchange of information on structural materials behaviour in primary circuit of fast breeder reactors. Special emphasis was placed on environmental effects such as influence of sodium and irradiation on mechanical properties of reactor materials

  6. Calorimetry end-point predictions

    International Nuclear Information System (INIS)

    Fox, M.A.

    1981-01-01

    This paper describes a portion of the work presently in progress at Rocky Flats in the field of calorimetry. In particular, calorimetry end-point predictions are outlined. The problems associated with end-point predictions and the progress made in overcoming these obstacles are discussed. The two major problems, noise and an accurate description of the heat function, are dealt with to obtain the most accurate results. Data are taken from an actual calorimeter and are processed by means of three different noise reduction techniques. The processed data are then utilized by one to four algorithms, depending on the accuracy desired to determined the end-point

  7. Planning and analyzing clinical trials with composite endpoints

    CERN Document Server

    Rauch, Geraldine; Kieser, Meinhard

    2017-01-01

    This book addresses the most important aspects of how to plan and evaluate clinical trials with a composite primary endpoint to guarantee a clinically meaningful and valid interpretation of the results. Composite endpoints are often used as primary efficacy variables for clinical trials, particularly in the fields of oncology and cardiology. These endpoints combine several variables of interest within a single composite measure, and as a result, all variables that are of major clinical relevance can be considered in the primary analysis without the need to adjust for multiplicity. Moreover, composite endpoints are intended to increase the size of the expected effects thus making clinical trials more powerful. The book offers practical advice for statisticians and medical experts involved in the planning and analysis of clinical trials. For readers who are mainly interested in the application of the methods, all the approaches are illustrated with real-world clinical trial examples, and the software codes requ...

  8. Muscle layer histopathology and manometry pattern of primary esophageal motility disorders including achalasia.

    Science.gov (United States)

    Nakajima, N; Sato, H; Takahashi, K; Hasegawa, G; Mizuno, K; Hashimoto, S; Sato, Y; Terai, S

    2017-03-01

    Histopathology of muscularis externa in primary esophageal motility disorders has been characterized previously. We aimed to correlate the results of high-resolution manometry with those of histopathology. During peroral endoscopic myotomy, peroral esophageal muscle biopsy was performed in patients with primary esophageal motility disorders. Immunohistochemical staining for c-kit was performed to assess the interstitial cells of Cajal (ICCs). Hematoxylin Eosin and Azan-Mallory staining were used to detect muscle atrophy, inflammation, and fibrosis, respectively. Slides from 30 patients with the following motility disorders were analyzed: achalasia (type I: 14, type II: 5, type III: 3), one diffuse esophageal spasm (DES), two outflow obstruction (OO), four jackhammer esophagus (JE), and one nutcracker esophagus (NE). ICCs were preserved in high numbers in type III achalasia (n=9.4±1.2 cells/high power field [HPF]), compared to types I (n=3.7±0.3 cells/HPF) and II (n=3.5±1.0 cells/HPF). Moreover, severe fibrosis was only observed in type I achalasia and not in other types of achalasia, OO, or DES. Four of five patients with JE and NE had severe inflammation with eosinophilic infiltration of the esophageal muscle layer (73.8±50.3 eosinophils/HPF) with no epithelial eosinophils. One patient with JE showed a visceral myopathy pattern. Compared to types I and II, type III achalasia showed preserved ICCs, with variable data regarding DES and OO. In disorders considered as primary esophageal motility disorders, a disease category exists, which shows eosinophilic infiltration in the esophageal muscle layer with no eosinophils in the epithelium. © 2016 John Wiley & Sons Ltd.

  9. Subretinal Pigment Epithelial Deposition of Drusen Components Including Hydroxyapatite in a Primary Cell Culture Model.

    Science.gov (United States)

    Pilgrim, Matthew G; Lengyel, Imre; Lanzirotti, Antonio; Newville, Matt; Fearn, Sarah; Emri, Eszter; Knowles, Jonathan C; Messinger, Jeffrey D; Read, Russell W; Guidry, Clyde; Curcio, Christine A

    2017-02-01

    Extracellular deposits containing hydroxyapatite, lipids, proteins, and trace metals that form between the basal lamina of the RPE and the inner collagenous layer of Bruch's membrane are hallmarks of early AMD. We examined whether cultured RPE cells could produce extracellular deposits containing all of these molecular components. Retinal pigment epithelium cells isolated from freshly enucleated porcine eyes were cultured on Transwell membranes for up to 6 months. Deposit composition and structure were characterized using light, fluorescence, and electron microscopy; synchrotron x-ray diffraction and x-ray fluorescence; secondary ion mass spectroscopy; and immunohistochemistry. Apparently functional primary RPE cells, when cultured on 10-μm-thick inserts with 0.4-μm-diameter pores, can produce sub-RPE deposits that contain hydroxyapatite, lipids, proteins, and trace elements, without outer segment supplementation, by 12 weeks. The data suggest that sub-RPE deposit formation is initiated, and probably regulated, by the RPE, as well as the loss of permeability of the Bruch's membrane and choriocapillaris complex associated with age and early AMD. This cell culture model of early AMD lesions provides a novel system for testing new therapeutic interventions against sub-RPE deposit formation, an event occurring well in advance of the onset of vision loss.

  10. Sample size determination in clinical trials with multiple endpoints

    CERN Document Server

    Sozu, Takashi; Hamasaki, Toshimitsu; Evans, Scott R

    2015-01-01

    This book integrates recent methodological developments for calculating the sample size and power in trials with more than one endpoint considered as multiple primary or co-primary, offering an important reference work for statisticians working in this area. The determination of sample size and the evaluation of power are fundamental and critical elements in the design of clinical trials. If the sample size is too small, important effects may go unnoticed; if the sample size is too large, it represents a waste of resources and unethically puts more participants at risk than necessary. Recently many clinical trials have been designed with more than one endpoint considered as multiple primary or co-primary, creating a need for new approaches to the design and analysis of these clinical trials. The book focuses on the evaluation of power and sample size determination when comparing the effects of two interventions in superiority clinical trials with multiple endpoints. Methods for sample size calculation in clin...

  11. The value of including spirometry in health checks - a randomized controlled study in primary health care

    DEFF Research Database (Denmark)

    Ørts, Lene Maria; Ottesen, Anders Løkke; Bjerregaard, Anne-Louise

    Background Lung diseases are among the most frequent and most serious ailments in Denmark. Preventive health checks including spirometry can be used to detect lung diseases earlier. Over time the attendance at preventive health checks has decreased and at present the response rate is approximately...... 50%. Little is known about initiatives that can influence the attendance rate. Objectives To examine whether focused information on spirometry in the invitation material will influence the attendance in preventive health checks. Materiel/Methods Design: A randomized controlled study on information...... on spirometry embedded in “Check your health Prevention Program, CHPP” from 2015-16. CHPP is a house-hold cluster randomized controlled trial offering a preventive health check to 30-49 year olds in a Danish municipality during the years 2012 through to 2017 (n= 26,216), carried out in collaboration between...

  12. Fatigue evaluation including environmental effects for primary circuit components in nuclear power plants

    International Nuclear Information System (INIS)

    Seichter, Johannes; Reese, Sven H.; Klucke, Dietmar

    2013-01-01

    The influence of LWR coolant environment to the lifetime of materials in Nuclear Power Plants is in discussion internationally. Environmental phenomena were investigated in laboratory tests and published in recent years. The discussion is mainly focused both on the transition from laboratory to real plant components and on numerical calculation procedures. Since publishing of the NUREG/CR-6909 report in 2007, formulae for calculating the Fen factors have been modified several times. Various calculation procedures like the so called 'Strain-integrated Method' and 'Simplified Approach' have been published while each approach yields to different results. The recent revision of the calculation procedure, proposed by ANL in 2012, is presented and discussed with regard to possible variations in the results depending on the assumptions made. In German KTA Rules the effect of environmentally assisted fatigue (EAF) is taken into account by means of so called attention thresholds. If the threshold value is exceeded, further measures like NDT, in-service inspections including fracture mechanical evaluations or detailed assessment procedures have to be performed. One way to handle those measures is to apply sophisticated procedures and to show that the calculated CUF is below the defined attention thresholds. On the basis of a practical example, methods and approaches will be discussed and recommendations in terms of avoiding over-conservatism and misinterpretation will be presented.

  13. Fatigue evaluation including environmental effects for primary circuit components in nuclear power plants

    Energy Technology Data Exchange (ETDEWEB)

    Seichter, Johannes [Siempelkamp Pruef- und Gutachter-Gesellschaft mbH, Dresden (Germany); Reese, Sven H.; Klucke, Dietmar [Component Technology Global Unit Generation, E.ON Kernkraft GmbH, Hannover (Germany)

    2013-05-15

    The influence of LWR coolant environment to the lifetime of materials in Nuclear Power Plants is in discussion internationally. Environmental phenomena were investigated in laboratory tests and published in recent years. The discussion is mainly focused both on the transition from laboratory to real plant components and on numerical calculation procedures. Since publishing of the NUREG/CR-6909 report in 2007, formulae for calculating the Fen factors have been modified several times. Various calculation procedures like the so called 'Strain-integrated Method' and 'Simplified Approach' have been published while each approach yields to different results. The recent revision of the calculation procedure, proposed by ANL in 2012, is presented and discussed with regard to possible variations in the results depending on the assumptions made. In German KTA Rules the effect of environmentally assisted fatigue (EAF) is taken into account by means of so called attention thresholds. If the threshold value is exceeded, further measures like NDT, in-service inspections including fracture mechanical evaluations or detailed assessment procedures have to be performed. One way to handle those measures is to apply sophisticated procedures and to show that the calculated CUF is below the defined attention thresholds. On the basis of a practical example, methods and approaches will be discussed and recommendations in terms of avoiding over-conservatism and misinterpretation will be presented.

  14. Emergency response facilities including primary and secondary prevention strategies across 79 professional football clubs in England.

    Science.gov (United States)

    Malhotra, Aneil; Dhutia, Harshil; Gati, Sabiha; Yeo, Tee-Joo; Finocchiaro, Gherardo; Keteepe-Arachi, Tracey; Richards, Thomas; Walker, Mike; Birt, Robin; Stuckey, David; Robinson, Laurence; Tome, Maite; Beasley, Ian; Papadakis, Michael; Sharma, Sanjay

    2017-06-14

    To assess the emergency response planning and prevention strategies for sudden cardiac arrest (SCA) across a wide range of professional football clubs in England. A written survey was sent to all professional clubs in the English football league, namely the Premiership, Championship, League 1 and League 2. Outcomes included: (1) number of clubs performing cardiac screening and frequency of screening; (2) emergency planning and documentation; (3) automated external defibrillator (AED) training and availability; and (4) provision of emergency services at sporting venues. 79 clubs (86%) responded to the survey. 100% clubs participated in cardiac screening. All clubs had AEDs available on match days and during training sessions. 100% Premiership clubs provided AED training to designated staff. In contrast, 30% of lower division clubs with AEDs available did not provide formal training. Most clubs (n=66; 83%) reported the existence of an emergency action plan for SCA but formal documentation was variable. All clubs in the Premiership and League 1 provided an ambulance equipped for medical emergencies on match days compared with 75% of clubs in the Championship and 66% in League 2. The majority of football clubs in England have satisfactory prevention strategies and emergency response planning in line with European recommendations. Additional improvements such as increasing awareness of European guidelines for emergency planning, AED training and mentorship with financial support to lower division clubs are necessary to further enhance cardiovascular safety of athletes and spectators and close the gap between the highest and lower divisions. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  15. Undergraduate Students' Perceptions of the Mathematics Courses Included in the Primary School Teacher Education Program

    Science.gov (United States)

    Serin, Mehmet Koray; Incikabi, Semahat

    2017-01-01

    Mathematics educators have reported on many issues regarding students' mathematical education, particularly students who received mathematics education at different departments such as engineering, science or primary school, including their difficulties with mathematical concepts, their understanding of and preferences for mathematical concepts.…

  16. Endpoint-based parallel data processing in a parallel active messaging interface of a parallel computer

    Science.gov (United States)

    Archer, Charles J.; Blocksome, Michael A.; Ratterman, Joseph D.; Smith, Brian E.

    2014-08-12

    Endpoint-based parallel data processing in a parallel active messaging interface (`PAMI`) of a parallel computer, the PAMI composed of data communications endpoints, each endpoint including a specification of data communications parameters for a thread of execution on a compute node, including specifications of a client, a context, and a task, the compute nodes coupled for data communications through the PAMI, including establishing a data communications geometry, the geometry specifying, for tasks representing processes of execution of the parallel application, a set of endpoints that are used in collective operations of the PAMI including a plurality of endpoints for one of the tasks; receiving in endpoints of the geometry an instruction for a collective operation; and executing the instruction for a collective operation through the endpoints in dependence upon the geometry, including dividing data communications operations among the plurality of endpoints for one of the tasks.

  17. Confirmatory versus explorative endpoint analysis: Decision-making on the basis of evidence available from market authorization and early benefit assessment for oncology drugs.

    Science.gov (United States)

    Niehaus, Ines; Dintsios, Charalabos-Markos

    2018-03-26

    The early benefit assessment of pharmaceuticals in Germany and their preceding market authorization pursue different objectives. This is reflected by the inclusion of varying confirmatory endpoints within the evaluation of oncology drugs in early benefit assessment versus market authorization, with both relying on the same evidence. Data from assessments up to July 2015 are used to estimate the impact of explorative in comparison to confirmatory endpoints on market authorization and early benefit assessment by contrasting the benefit-risk ratio of EMA and the benefit-harm balance of the HTA jurisdiction. Agreement between market authorization and early benefit assessment is examined by Cohen's kappa (k). 21 of 41 assessments were considered in the analysis. Market authorization is more confirmatory than early benefit assessment because it includes a higher proportion of primary endpoints. The latter implies a primary endpoint to be relevant for the benefit-harm balance in only 67% of cases (0.078). Explorative mortality endpoints reached the highest agreement regarding the mutual consideration for the risk-benefit ratio and the benefit-harm balance (0.000). For explorative morbidity endpoints (-0.600), quality of life (-0.600) and side effects (-0.949) no agreement is ascertainable. To warrant a broader confirmatory basis for decisions supported by HTA, closer inter-institutional cooperation of approval authorities and HTA jurisdictions by means of reliable joint advice for manufacturers regarding endpoint definition would be favorable. Copyright © 2018 Elsevier B.V. All rights reserved.

  18. Improved Endpoints for Cancer Immunotherapy Trials

    Science.gov (United States)

    Eggermont, Alexander M. M.; Janetzki, Sylvia; Hodi, F. Stephen; Ibrahim, Ramy; Anderson, Aparna; Humphrey, Rachel; Blumenstein, Brent; Wolchok, Jedd

    2010-01-01

    Unlike chemotherapy, which acts directly on the tumor, cancer immunotherapies exert their effects on the immune system and demonstrate new kinetics that involve building a cellular immune response, followed by changes in tumor burden or patient survival. Thus, adequate design and evaluation of some immunotherapy clinical trials require a new development paradigm that includes reconsideration of established endpoints. Between 2004 and 2009, several initiatives facilitated by the Cancer Immunotherapy Consortium of the Cancer Research Institute and partner organizations systematically evaluated an immunotherapy-focused clinical development paradigm and created the principles for redefining trial endpoints. On this basis, a body of clinical and laboratory data was generated that supports three novel endpoint recommendations. First, cellular immune response assays generate highly variable results. Assay harmonization in multicenter trials may minimize variability and help to establish cellular immune response as a reproducible biomarker, thus allowing investigation of its relationship with clinical outcomes. Second, immunotherapy may induce novel patterns of antitumor response not captured by Response Evaluation Criteria in Solid Tumors or World Health Organization criteria. New immune-related response criteria were defined to more comprehensively capture all response patterns. Third, delayed separation of Kaplan–Meier curves in randomized immunotherapy trials can affect results. Altered statistical models describing hazard ratios as a function of time and recognizing differences before and after separation of curves may allow improved planning of phase III trials. These recommendations may improve our tools for cancer immunotherapy trials and may offer a more realistic and useful model for clinical investigation. PMID:20826737

  19. Gastroenterological endpoints in drug trials for cystic fibrosis

    NARCIS (Netherlands)

    Bodewes, Frank A. J. A.; Verkade, Henkjan J.; Wilschanski, Micheal

    2016-01-01

    The phenotype of cystic fibrosis includes a wide variety of clinical and biochemical gastrointestinal presentations. These gastrointestinal characteristics of the disease have come under renewed interest as potential outcome measures and clinical endpoints for therapeutic trials in cystic fibrosis.

  20. Factors affecting the local control of stereotactic body radiotherapy for lung tumors including primary lung cancer and metastatic lung tumors

    International Nuclear Information System (INIS)

    Hamamoto, Yasushi; Kataoka, Masaaki; Yamashita, Motohiro

    2012-01-01

    The purpose of this study was to identify factors affecting local control of stereotactic body radiotherapy (SBRT) for lung tumors including primary lung cancer and metastatic lung tumors. Between June 2006 and June 2009, 159 lung tumors in 144 patients (primary lung cancer, 128; metastatic lung tumor, 31) were treated with SBRT with 48-60 Gy (mean 50.1 Gy) in 4-5 fractions. Higher doses were given to larger tumors and metastatic tumors in principle. Assessed factors were age, gender, tumor origin (primary vs. metastatic), histological subtype, tumor size, tumor appearance (solid vs. ground glass opacity), maximum standardized uptake value of positron emission tomography using 18 F-fluoro-2-deoxy-D-glucose, and SBRT doses. Follow-up time was 1-60 months (median 18 months). The 1-, 2-, and 3-year local failure-free rates of all lesions were 90, 80, and 77%, respectively. On univariate analysis, metastatic tumors (p<0.0001), solid tumors (p=0.0246), and higher SBRT doses (p=0.0334) were the statistically significant unfavorable factors for local control. On multivariate analysis, only tumor origin was statistically significant (p=0.0027). The 2-year local failure-free rates of primary lung cancer and metastatic lung tumors were 87 and 50%, respectively. A metastatic tumor was the only independently significant unfavorable factor for local control after SBRT. (author)

  1. Helicopter EMS: Research Endpoints and Potential Benefits

    Directory of Open Access Journals (Sweden)

    Stephen H. Thomas

    2012-01-01

    Full Text Available Patients, EMS systems, and healthcare regions benefit from Helicopter EMS (HEMS utilization. This article discusses these benefits in terms of specific endpoints utilized in research projects. The endpoint of interest, be it primary, secondary, or surrogate, is important to understand in the deployment of HEMS resources or in planning further HEMS outcomes research. The most important outcomes are those which show potential benefits to the patients, such as functional survival, pain relief, and earlier ALS care. Case reports are also important “outcomes” publications. The benefits of HEMS in the rural setting is the ability to provide timely access to Level I or Level II trauma centers and in nontrauma, interfacility transport of cardiac, stroke, and even sepsis patients. Many HEMS crews have pharmacologic and procedural capabilities that bring a different level of care to a trauma scene or small referring hospital, especially in the rural setting. Regional healthcare and EMS system's benefit from HEMS by their capability to extend the advanced level of care throughout a region, provide a “backup” for areas with limited ALS coverage, minimize transport times, make available direct transport to specialized centers, and offer flexibility of transport in overloaded hospital systems.

  2. Enhanced peripheral visual processing in congenitally deaf humans is supported by multiple brain regions, including primary auditory cortex

    Directory of Open Access Journals (Sweden)

    Gregory D. Scott

    2014-03-01

    Full Text Available Brain reorganization associated with altered sensory experience clarifies the critical role of neuroplasticity in development. An example is enhanced peripheral visual processing associated with congenital deafness, but the neural systems supporting this have not been fully characterized. A gap in our understanding of deafness-enhanced peripheral vision is the contribution of primary auditory cortex. Previous studies of auditory cortex that use anatomical normalization across participants were limited by inter-subject variability of Heschl’s gyrus. In addition to reorganized auditory cortex (cross-modal plasticity, a second gap in our understanding is the contribution of altered modality-specific cortices (visual intramodal plasticity in this case, as well as supramodal and multisensory cortices, especially when target detection is required across contrasts. Here we address these gaps by comparing fMRI signal change for peripheral versus perifoveal visual stimulation (11-15° vs. 2°-7° in congenitally deaf and hearing participants in a blocked experimental design with two analytical approaches: a Heschl’s gyrus region of interest analysis and a whole brain analysis. Our results using individually-defined primary auditory cortex (Heschl’s gyrus indicate that fMRI signal change for more peripheral stimuli was greater than perifoveal in deaf but not in hearing participants. Whole-brain analyses revealed differences between deaf and hearing participants for peripheral versus perifoveal visual processing in extrastriate visual cortex including primary auditory cortex, MT+/V5, superior-temporal auditory and multisensory and/or supramodal regions, such as posterior parietal cortex, frontal eye fields, anterior cingulate, and supplementary eye fields. Overall, these data demonstrate the contribution of neuroplasticity in multiple systems including primary auditory cortex, supramodal and multisensory regions, to altered visual processing in

  3. Ecosystem services as assessment endpoints for ecological risk assessment.

    Science.gov (United States)

    Munns, Wayne R; Rea, Anne W; Suter, Glenn W; Martin, Lawrence; Blake-Hedges, Lynne; Crk, Tanja; Davis, Christine; Ferreira, Gina; Jordan, Steve; Mahoney, Michele; Barron, Mace G

    2016-07-01

    Ecosystem services are defined as the outputs of ecological processes that contribute to human welfare or have the potential to do so in the future. Those outputs include food and drinking water, clean air and water, and pollinated crops. The need to protect the services provided by natural systems has been recognized previously, but ecosystem services have not been formally incorporated into ecological risk assessment practice in a general way in the United States. Endpoints used conventionally in ecological risk assessment, derived directly from the state of the ecosystem (e.g., biophysical structure and processes), and endpoints based on ecosystem services serve different purposes. Conventional endpoints are ecologically important and susceptible entities and attributes that are protected under US laws and regulations. Ecosystem service endpoints are a conceptual and analytical step beyond conventional endpoints and are intended to complement conventional endpoints by linking and extending endpoints to goods and services with more obvious benefit to humans. Conventional endpoints can be related to ecosystem services even when the latter are not considered explicitly during problem formulation. To advance the use of ecosystem service endpoints in ecological risk assessment, the US Environmental Protection Agency's Risk Assessment Forum has added generic endpoints based on ecosystem services (ES-GEAE) to the original 2003 set of generic ecological assessment endpoints (GEAEs). Like conventional GEAEs, ES-GEAEs are defined by an entity and an attribute. Also like conventional GEAEs, ES-GEAEs are broadly described and will need to be made specific when applied to individual assessments. Adoption of ecosystem services as a type of assessment endpoint is intended to improve the value of risk assessment to environmental decision making, linking ecological risk to human well-being, and providing an improved means of communicating those risks. Integr Environ Assess Manag

  4. Endpoint behavior of high-energy scattering cross sections

    International Nuclear Information System (INIS)

    Chay, Junegone; Kim, Chul

    2010-01-01

    In high-energy processes near the endpoint, there emerge new contributions associated with spectator interactions. Away from the endpoint region, these new contributions are suppressed compared to the leading contribution, but the leading contribution becomes suppressed as we approach the endpoint and the new contributions become comparable. We present how the new contributions scale as we reach the endpoint and show that they are comparable to the suppressed leading contributions in deep inelastic scattering by employing a power-counting analysis. The hadronic tensor in deep inelastic scattering is shown to factorize including the spectator interactions, and it can be expressed in terms of the light cone distribution amplitudes of initial hadrons. We also consider the contribution of the spectator contributions in Drell-Yan processes. Here the spectator interactions are suppressed compared to double parton annihilation according to the power counting.

  5. Protocol of the Definition for the Assessment of Time-to-event Endpoints in CANcer trials (DATECAN) project: formal consensus method for the development of guidelines for standardised time-to-event endpoints' definitions in cancer clinical trials.

    Science.gov (United States)

    Bellera, Carine A; Pulido, Marina; Gourgou, Sophie; Collette, Laurence; Doussau, Adélaïde; Kramar, Andrew; Dabakuyo, Tienhan Sandrine; Ouali, Monia; Auperin, Anne; Filleron, Thomas; Fortpied, Catherine; Le Tourneau, Christophe; Paoletti, Xavier; Mauer, Murielle; Mathoulin-Pélissier, Simone; Bonnetain, Franck

    2013-03-01

    In randomised phase III cancer clinical trials, the most objectively defined and only validated time-to-event endpoint is overall survival (OS). The appearance of new types of treatments and the multiplication of lines of treatment have resulted in the use of surrogate endpoints for overall survival such as progression-free survival (PFS), or time-to-treatment failure. Their development is strongly influenced by the necessity of reducing clinical trial duration, cost and number of patients. However, while these endpoints are frequently used, they are often poorly defined and definitions can differ between trials which may limit their use as primary endpoints. Moreover, this variability of definitions can impact on the trial's results by affecting estimation of treatments' effects. The aim of the Definition for the Assessment of Time-to-event Endpoints in CANcer trials (DATECAN) project is to provide recommendations for standardised definitions of time-to-event endpoints in randomised cancer clinical trials. We will use a formal consensus methodology based on experts' opinions which will be obtained in a systematic manner. Definitions will be independently developed for several cancer sites, including pancreatic, breast, head and neck and colon cancer, as well as sarcomas and gastrointestinal stromal tumours (GISTs). The DATECAN project should lead to the elaboration of recommendations that can then be used as guidelines by researchers participating in clinical trials. This process should lead to a standardisation of the definitions of commonly used time-to-event endpoints, enabling appropriate comparisons of future trials' results. Copyright © 2012 Elsevier Ltd. All rights reserved.

  6. Preferences for Depression Treatment Including Internet-Based Interventions: Results From a Large Sample of Primary Care Patients

    Directory of Open Access Journals (Sweden)

    Marie Dorow

    2018-05-01

    Full Text Available Background: To date, little is known about treatment preferences for depression concerning new media. This study aims to (1 investigate treatment preferences for depression including internet-based interventions and (2 examine subgroup differences concerning age, gender and severity of depression as well as patient-related factors associated with treatment preferences.Methods: Data were derived from the baseline assessment of the @ktiv-trial. Depression treatment preferences were assessed from n = 641 primary care patients with mild to moderate depression regarding the following treatments: medication, psychotherapy, combined treatment, alternative treatment, talking to friends and family, exercise, self-help literature, and internet-based interventions. Depression severity was specified by GPs according to ICD-10 criteria. Ordinal logistic regression models were conducted to identify associated factors of treatment preferences.Results: Patients had a mean age of 43.9 years (SD = 13.8 and more than two thirds (68.6% were female. About 43% of patients had mild depression while 57% were diagnosed with moderate depression. The majority of patients reported strong preferences for psychotherapy, talking to friends and family, and exercise. About one in five patients was very likely to consider internet-based interventions in case of depression. Younger patients expressed significantly stronger treatment preferences for psychotherapy and internet-based interventions than older patients. The most salient factors associated with treatment preferences were the patients' education and perceived self-efficacy.Conclusions: Patients with depression report individually different treatment preferences.Our results underline the importance of shared decision-making within primary care. Future studies should investigate treatment preferences for different types of internet-based interventions.

  7. Should All Patients Be Included in Alternative Payment Models for Primary Total Hip Arthroplasty and Total Knee Arthroplasty?

    Science.gov (United States)

    Rozell, Joshua C; Courtney, Paul M; Dattilo, Jonathan R; Wu, Chia H; Lee, Gwo-Chin

    2016-09-01

    Alternative payment models in total joint replacement incentivize cost effective health care delivery and reward reductions in length of stay (LOS), complications, and readmissions. If not adjusted for patient comorbidities, they may encourage restrictive access to health care. We prospectively evaluated 802 consecutive primary total hip arthroplasty and total knee arthroplasty patients evaluating comorbidities associated with increased LOS and readmissions. During this 9-month period, 115 patients (14.3%) required hospitalization >3 days and 16 (1.99%) were readmitted within 90 days. Univariate analysis demonstrated that preoperative narcotic use, heart failure, stroke, chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), and liver disease were more likely to require hospitalization >3 days. In multivariate analysis, CKD and COPD were independent risk factors for LOS >3 days. A Charlson comorbidity index >5 points was associated with increased LOS and readmissions. Patients with CKD, COPD, and Charlson comorbidity index >5 points should not be included in alternative payment model for THA and TKA. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. Extracting gluino endpoints with event topology patterns

    Energy Technology Data Exchange (ETDEWEB)

    Pietsch, N. [Hamburg Univ. (Germany). Inst. fuer Experimentalphysik; Reuter, J.; Sakurai, K.; Wiesler, D. [Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany)

    2012-06-15

    In this paper we study the gluino dijet mass edge measurement at the LHC in a realistic situation including both SUSY and combinatorical backgrounds together with effects of initial and final state radiation as well as a finite detector resolution. Three benchmark scenarios are examined in which the dominant SUSY production process and also the decay modes are different. Several new kinematical variables are proposed to minimize the impact of SUSY and combinatorial backgrounds in the measurement. By selecting events with a particular number of jets and leptons, we attempt to measure two distinct gluino dijet mass edges originating from wino g {yields} jjW and bino g {yields}jjB decay modes, separately. We determine the endpoints of distributions of proposed and existing variables and show that those two edges can be disentangled and measured within good accuracy, irrespective of the presence of ISR, FSR, and detector effects.

  9. Prognostic factors for head and neck cancer of unknown primary including the impact of human papilloma virus infection.

    Science.gov (United States)

    Axelsson, Lars; Nyman, Jan; Haugen-Cange, Hedda; Bove, Mogens; Johansson, Leif; De Lara, Shahin; Kovács, Anikó; Hammerlid, Eva

    2017-06-10

    Head and neck cancer of unknown primary (HNCUP) is rare and prospective studies are lacking. The impact of different prognostic factors such as age and N stage is not completely known, the optimal treatment is not yet established, and the reported survival rates vary. In the last decade, human papilloma virus (HPV) has been identified as a common cause of and important prognostic factor in oropharyngeal cancer, and there is now growing interest in the importance of HPV for HNCUP. The aim of the present study on curatively treated HNCUP was to investigate the prognostic importance of different factors, including HPV status, treatment, and overall survival. A search for HNCUP was performed in the Swedish Cancer Registry, Western health district, between the years 1992-2009. The medical records were reviewed, and only patients with squamous cell carcinoma or undifferentiated carcinoma treated with curative intent were included. The tumor specimens were retrospectively analyzed for HPV with p16 immunostaining. Sixty-eight patients were included. The mean age was 59 years. The majority were males, and had N2 tumors. Sixty-nine percent of the tumors were HPV positive using p16 staining. Patients who were older than 70 years, patients with N3-stage tumors, and patients with tumors that were p16 negative had a significantly worse prognosis. The overall 5-year survival rate for patients with p16-positive tumors was 88% vs 61% for p16-negative tumors. Treatment with neck dissection and postoperative radiation or (chemo) radiation had 81 and 88% 5-year survival rates, respectively. The overall and disease-free 5-year survival rates for all patients in the study were 82 and 74%. Curatively treated HNCUP had good survival. HPV infection was common. Independent prognostic factors for survival were age over 70 years, HPV status and N3 stage. We recommend that HPV analysis should be performed routinely for HNCUP. Treatment with neck dissection and postoperative radiation or

  10. Adhesion kinetics of human primary monocytes, dendritic cells, and macrophages: Dynamic cell adhesion measurements with a label-free optical biosensor and their comparison with end-point assays.

    Science.gov (United States)

    Orgovan, Norbert; Ungai-Salánki, Rita; Lukácsi, Szilvia; Sándor, Noémi; Bajtay, Zsuzsa; Erdei, Anna; Szabó, Bálint; Horvath, Robert

    2016-09-01

    obtained with the high-temporal-resolution Epic BT, but could only provide end-point data. In contrast, complex, nonmonotonic cell adhesion kinetics measured by the high-throughput optical biosensor is expected to open a window on the hidden background of the immune cell-extracellular matrix interactions.

  11. Sensitive endpoints in extended one-generation reproductive toxicity study versus two generation?

    DEFF Research Database (Denmark)

    Christiansen, Sofie

    . The protocol includes assessment of novel endpoints of concern and developmental landmarks such as anogenital distance, nipple retention (both sensitive endpoints for anti-androgenic effects in male offspring) and mammary gland development (sensitive endpoint for oestrogen action) and may also include...... during critical period of development in contrast to the parental generation. Retrospective analysis of available two-generation studies, however, indicate that the assessment included in the study of other endpoints in the male offspring such as histopathology of reproductive organs and semen quality...

  12. Surrogate Endpoint Evaluation: Principal Stratification Criteria and the Prentice Definition.

    Science.gov (United States)

    Gilbert, Peter B; Gabriel, Erin E; Huang, Ying; Chan, Ivan S F

    2015-09-01

    A common problem of interest within a randomized clinical trial is the evaluation of an inexpensive response endpoint as a valid surrogate endpoint for a clinical endpoint, where a chief purpose of a valid surrogate is to provide a way to make correct inferences on clinical treatment effects in future studies without needing to collect the clinical endpoint data. Within the principal stratification framework for addressing this problem based on data from a single randomized clinical efficacy trial, a variety of definitions and criteria for a good surrogate endpoint have been proposed, all based on or closely related to the "principal effects" or "causal effect predictiveness (CEP)" surface. We discuss CEP-based criteria for a useful surrogate endpoint, including (1) the meaning and relative importance of proposed criteria including average causal necessity (ACN), average causal sufficiency (ACS), and large clinical effect modification; (2) the relationship between these criteria and the Prentice definition of a valid surrogate endpoint; and (3) the relationship between these criteria and the consistency criterion (i.e., assurance against the "surrogate paradox"). This includes the result that ACN plus a strong version of ACS generally do not imply the Prentice definition nor the consistency criterion, but they do have these implications in special cases. Moreover, the converse does not hold except in a special case with a binary candidate surrogate. The results highlight that assumptions about the treatment effect on the clinical endpoint before the candidate surrogate is measured are influential for the ability to draw conclusions about the Prentice definition or consistency. In addition, we emphasize that in some scenarios that occur commonly in practice, the principal strata sub-populations for inference are identifiable from the observable data, in which cases the principal stratification framework has relatively high utility for the purpose of effect

  13. Surrogate Endpoint Evaluation: Principal Stratification Criteria and the Prentice Definition

    Science.gov (United States)

    Gilbert, Peter B.; Gabriel, Erin E.; Huang, Ying; Chan, Ivan S.F.

    2015-01-01

    A common problem of interest within a randomized clinical trial is the evaluation of an inexpensive response endpoint as a valid surrogate endpoint for a clinical endpoint, where a chief purpose of a valid surrogate is to provide a way to make correct inferences on clinical treatment effects in future studies without needing to collect the clinical endpoint data. Within the principal stratification framework for addressing this problem based on data from a single randomized clinical efficacy trial, a variety of definitions and criteria for a good surrogate endpoint have been proposed, all based on or closely related to the “principal effects” or “causal effect predictiveness (CEP)” surface. We discuss CEP-based criteria for a useful surrogate endpoint, including (1) the meaning and relative importance of proposed criteria including average causal necessity (ACN), average causal sufficiency (ACS), and large clinical effect modification; (2) the relationship between these criteria and the Prentice definition of a valid surrogate endpoint; and (3) the relationship between these criteria and the consistency criterion (i.e., assurance against the “surrogate paradox”). This includes the result that ACN plus a strong version of ACS generally do not imply the Prentice definition nor the consistency criterion, but they do have these implications in special cases. Moreover, the converse does not hold except in a special case with a binary candidate surrogate. The results highlight that assumptions about the treatment effect on the clinical endpoint before the candidate surrogate is measured are influential for the ability to draw conclusions about the Prentice definition or consistency. In addition, we emphasize that in some scenarios that occur commonly in practice, the principal strata sub-populations for inference are identifiable from the observable data, in which cases the principal stratification framework has relatively high utility for the purpose of

  14. Computation of aquatic primary production: Extended formalism to include effect of angular and spectral distribution of light

    Digital Repository Service at National Institute of Oceanography (India)

    Sathyendranath, S.; Platt, T.

    and utilization by algal cells. Neglecting the effect of angular distribution on the light absorbed by phytoplankton can lead to underestimation of primary production. For the stations studied as examples, the minimum correction required is 5-l3% for daily, column...

  15. Inconsistent selection and definition of local and regional endpoints in breast cancer research.

    Science.gov (United States)

    Moossdorff, M; van Roozendaal, L M; Schipper, R-J; Strobbe, L J A; Voogd, A C; Tjan-Heijnen, V C G; Smidt, M L

    2014-12-01

    Results in breast cancer research are reported using study endpoints. Most are composite endpoints (such as locoregional recurrence), consisting of several components (for example local recurrence) that are in turn composed of specific events (such as skin recurrence). Inconsistent endpoint selection and definition might lead to unjustified conclusions when comparing study outcomes. This study aimed to determine which locoregional endpoints are used in breast cancer studies, and how these endpoints and their components are defined. PubMed was searched for breast cancer studies published in nine leading journals in 2011. Articles using endpoints with a local or regional component were included and definitions were compared. Twenty-three different endpoints with a local or regional component were extracted from 44 articles. Most frequently used were disease-free survival (25 articles), recurrence-free survival (7), local control (4), locoregional recurrence-free survival (3) and event-free survival (3). Different endpoints were used for similar outcomes. Of 23 endpoints, five were not defined and 18 were defined only partially. Of these, 16 contained a local and 13 a regional component. Included events were not specified in 33 of 57 (local) and 27 of 50 (regional) cases. Definitions of local components inconsistently included carcinoma in situ and skin and chest wall recurrences. Regional components inconsistently included specific nodal sites and skin and chest wall recurrences. Breast cancer studies use many different endpoints with a locoregional component. Definitions of endpoints and events are either not provided or vary between trials. To improve transparency, facilitate trial comparison and avoid unjustified conclusions, authors should report detailed definitions of all endpoints. © 2014 BJS Society Ltd. Published by John Wiley & Sons Ltd.

  16. Enhanced peripheral visual processing in congenitally deaf humans is supported by multiple brain regions, including primary auditory cortex

    OpenAIRE

    Scott, Gregory D.; Karns, Christina M.; Dow, Mark W.; Stevens, Courtney; Neville, Helen J.

    2014-01-01

    Brain reorganization associated with altered sensory experience clarifies the critical role of neuroplasticity in development. An example is enhanced peripheral visual processing associated with congenital deafness, but the neural systems supporting this have not been fully characterized. A gap in our understanding of deafness-enhanced peripheral vision is the contribution of primary auditory cortex. Previous studies of auditory cortex that use anatomical normalization across participants wer...

  17. Modeling hard clinical end-point data in economic analyses.

    Science.gov (United States)

    Kansal, Anuraag R; Zheng, Ying; Palencia, Roberto; Ruffolo, Antonio; Hass, Bastian; Sorensen, Sonja V

    2013-11-01

    The availability of hard clinical end-point data, such as that on cardiovascular (CV) events among patients with type 2 diabetes mellitus, is increasing, and as a result there is growing interest in using hard end-point data of this type in economic analyses. This study investigated published approaches for modeling hard end-points from clinical trials and evaluated their applicability in health economic models with different disease features. A review of cost-effectiveness models of interventions in clinically significant therapeutic areas (CV diseases, cancer, and chronic lower respiratory diseases) was conducted in PubMed and Embase using a defined search strategy. Only studies integrating hard end-point data from randomized clinical trials were considered. For each study included, clinical input characteristics and modeling approach were summarized and evaluated. A total of 33 articles (23 CV, eight cancer, two respiratory) were accepted for detailed analysis. Decision trees, Markov models, discrete event simulations, and hybrids were used. Event rates were incorporated either as constant rates, time-dependent risks, or risk equations based on patient characteristics. Risks dependent on time and/or patient characteristics were used where major event rates were >1%/year in models with fewer health states (Models of infrequent events or with numerous health states generally preferred constant event rates. The detailed modeling information and terminology varied, sometimes requiring interpretation. Key considerations for cost-effectiveness models incorporating hard end-point data include the frequency and characteristics of the relevant clinical events and how the trial data is reported. When event risk is low, simplification of both the model structure and event rate modeling is recommended. When event risk is common, such as in high risk populations, more detailed modeling approaches, including individual simulations or explicitly time-dependent event rates, are

  18. Practice makes perfect: the neural substrates of tactile discrimination by Mah-Jong experts include the primary visual cortex

    Directory of Open Access Journals (Sweden)

    Honda Manabu

    2006-12-01

    Full Text Available Abstract Background It has yet to be determined whether visual-tactile cross-modal plasticity due to visual deprivation, particularly in the primary visual cortex (V1, is solely due to visual deprivation or if it is a result of long-term tactile training. Here we conducted an fMRI study with normally-sighted participants who had undergone long-term training on the tactile shape discrimination of the two dimensional (2D shapes on Mah-Jong tiles (Mah-Jong experts. Eight Mah-Jong experts and twelve healthy volunteers who were naïve to Mah-Jong performed a tactile shape matching task using Mah-Jong tiles with no visual input. Furthermore, seven out of eight experts performed a tactile shape matching task with unfamiliar 2D Braille characters. Results When participants performed tactile discrimination of Mah-Jong tiles, the left lateral occipital cortex (LO and V1 were activated in the well-trained subjects. In the naïve subjects, the LO was activated but V1 was not activated. Both the LO and V1 of the well-trained subjects were activated during Braille tactile discrimination tasks. Conclusion The activation of V1 in subjects trained in tactile discrimination may represent altered cross-modal responses as a result of long-term training.

  19. Patients’ preferences for selection of endpoints in cardiovascular clinical trials

    Directory of Open Access Journals (Sweden)

    Robert D. Chow

    2014-02-01

    Full Text Available Background: To reduce the duration and overall costs of cardiovascular trials, use of the combined endpoints in trial design has become commonplace. Though this methodology may serve the needs of investigators and trial sponsors, the preferences of patients or potential trial subjects in the trial design process has not been studied. Objective: To determine the preferences of patients in the design of cardiovascular trials. Design: Participants were surveyed in a pilot study regarding preferences among various single endpoints commonly used in cardiovascular trials, preference for single vs. composite endpoints, and the likelihood of compliance with a heart medication if patients similar to them participated in the trial design process. Participants: One hundred adult English-speaking patients, 38% male, from a primary care ambulatory practice located in an urban setting. Key results: Among single endpoints, participants rated heart attack as significantly more important than death from other causes (4.53 vs. 3.69, p=0.004 on a scale of 1–6. Death from heart disease was rated as significantly more important than chest pain (4.73 vs. 2.47, p<0.001, angioplasty/PCI/CABG (4.73 vs. 2.43, p<0.001, and stroke (4.73 vs. 2.43, p<0.001. Participants also expressed a slight preference for combined endpoints over single endpoint (43% vs. 57%, incorporation of the opinions of the study patient population into the design of trials (48% vs. 41% for researchers, and a greater likelihood of medication compliance if patient preferences were considered during trial design (67% indicated a significant to major effect. Conclusions: Patients are able to make judgments and express preferences regarding trial design. They prefer that the opinions of the study population rather than the general population be incorporated into the design of the study. This novel approach to study design would not only incorporate patient preferences into medical decision making, but

  20. A summation free β+-endpoint spectrometer

    International Nuclear Information System (INIS)

    Keller, H.; Kirchner, R.; Klepper, O.; Roeckl, E.; Schardt, D.; Simon, R.S.; Kleinheinz, P.; Liang, C.F.; Paris, P.

    1990-08-01

    A β + -endpoint spectrometer is described, where positrons are observed in an 11-mm thick silicon detector in coincidence with subsequent γ-rays meausred in a germanium detector, and where the summing of the positron energy with the annihilation radiation is prevented by detecting both 511-keV quanta in opposite segments of a BGO ring surrounding the silicon detector. The procedure of measuring and analyzing the data is outlined for the decay of the 11/2 - -isomer of 149 Tb; its endpoint energy is determined to be 1853(10) keV, in agreement with the literature. The accuracy and reliability of β + -endpoint measurements is discussed in comparison to the EC/β + -ratio method. (orig.)

  1. End-point sharpness in thermometric titrimetry.

    Science.gov (United States)

    Tyrrell, H J

    1967-07-01

    It is shown that the sharpness of an end-point in a thermometric titration where the simple reaction A + B right harpoon over left harpoon AB takes place, depends on Kc(A') where K is the equilibrium constant for the reaction, and c(A') is the total concentration of the titrand (A) in the reaction mixture. The end-point is sharp if, (i) the enthalpy change in the reaction is not negligible, and (ii) Kc(A') > 10(3). This shows that it should, for example, be possible to titrate 0.1 M acid, pK(A) = 10, using a thennometric end-point. Some aspects of thermometric titrimetry when Kc(A') < 10(3) are also considered.

  2. Biomechanical constraints on the feedforward regulation of endpoint stiffness.

    Science.gov (United States)

    Hu, Xiao; Murray, Wendy M; Perreault, Eric J

    2012-10-01

    Although many daily tasks tend to destabilize arm posture, it is still possible to have stable interactions with the environment by regulating the multijoint mechanics of the arm in a task-appropriate manner. For postural tasks, this regulation involves the appropriate control of endpoint stiffness, which represents the stiffness of the arm at the hand. Although experimental studies have been used to evaluate endpoint stiffness control, including the orientation of maximal stiffness, the underlying neural strategies remain unknown. Specifically, the relative importance of feedforward and feedback mechanisms has yet to be determined due to the difficulty separately identifying the contributions of these mechanisms in human experiments. This study used a previously validated three-dimensional musculoskeletal model of the arm to quantify the degree to which the orientation of maximal endpoint stiffness could be changed using only steady-state muscle activations, used to represent feedforward motor commands. Our hypothesis was that the feedforward control of endpoint stiffness orientation would be significantly constrained by the biomechanical properties of the musculoskeletal system. Our results supported this hypothesis, demonstrating substantial biomechanical constraints on the ability to regulate endpoint stiffness throughout the workspace. The ability to regulate stiffness orientation was further constrained by additional task requirements, such as the need to support the arm against gravity or exert forces on the environment. Together, these results bound the degree to which slowly varying feedforward motor commands can be used to regulate the orientation of maximum arm stiffness and provide a context for better understanding conditions in which feedback control may be needed.

  3. Forecasting interest rates with shifting endpoints

    DEFF Research Database (Denmark)

    Van Dijk, Dick; Koopman, Siem Jan; Wel, Michel van der

    2014-01-01

    We consider forecasting the term structure of interest rates with the assumption that factors driving the yield curve are stationary around a slowly time-varying mean or ‘shifting endpoint’. The shifting endpoints are captured using either (i) time series methods (exponential smoothing) or (ii......) long-range survey forecasts of either interest rates or inflation and output growth, or (iii) exponentially smoothed realizations of these macro variables. Allowing for shifting endpoints in yield curve factors provides substantial and significant gains in out-of-sample predictive accuracy, relative...... to stationary and random walk benchmarks. Forecast improvements are largest for long-maturity interest rates and for long-horizon forecasts....

  4. Observations on Three Endpoint Properties and Their Relationship to Regulatory Outcomes of European Oncology Marketing Applications.

    Science.gov (United States)

    Liberti, Lawrence; Stolk, Pieter; McAuslane, James Neil; Schellens, Jan; Breckenridge, Alasdair M; Leufkens, Hubert

    2015-06-01

    Guidance and exploratory evidence indicate that the type of endpoints and the magnitude of their outcome can define a therapy's clinical activity; however, little empirical evidence relates specific endpoint properties with regulatory outcomes. We explored the relationship of 3 endpoint properties to regulatory outcomes by assessing 50 oncology marketing authorization applications (MAAs; reviewed from 2009 to 2013). Overall, 16 (32%) had a negative outcome. The most commonly used hard endpoints were overall survival (OS) and the duration of response or stable disease. OS was a component of 91% approved and 63% failed MAAs. The most commonly used surrogate endpoints were progression-free survival (PFS), response rate, and health-related quality of life assessments. There was no difference (p = .3801) between the approved and failed MAA cohorts in the proportion of hard endpoints used. A mean of slightly more than four surrogate endpoints were used per approved MAA compared with slightly more than two for failed MAAs. Longer OS and PFS duration outcomes were generally associated with approvals, often when not statistically significant. The approved cohort was associated with a preponderance of statistically significant (p < .05) improvements in primary endpoints (p < .0001 difference between the approved and failed groups). Three key endpoint properties (type of endpoint [hard/surrogate], magnitude of an endpoint outcome, and its statistical significance) are consistent with the European Medicines Agency guidance and, notwithstanding the contribution of unique disease-specific circumstances, are associated with a predictable positive outcome for oncology MAAs. Regulatory decisions made by the European Medicines Agency determine which new medicines will be available to European prescribers and for which therapeutic indications. Regulatory success or failure can be influenced by many factors. This study assessed three key properties of endpoints used in

  5. Cost-Effectiveness of Including a Nurse Specialist in the Treatment of Urinary Incontinence in Primary Care in the Netherlands.

    Directory of Open Access Journals (Sweden)

    K M Holtzer-Goor

    Full Text Available Incontinence is an important health problem. Effectively treating incontinence could lead to important health gains in patients and caregivers. Management of incontinence is currently suboptimal, especially in elderly patients. To optimise the provision of incontinence care a global optimum continence service specification (OCSS was developed. The current study evaluates the costs and effects of implementing this OCSS for community-dwelling patients older than 65 years with four or more chronic diseases in the Netherlands.A decision analytic model was developed comparing the current care pathway for urinary incontinence in the Netherlands with the pathway as described in the OCSS. The new care strategy was operationalised as the appointment of a continence nurse specialist (NS located with the general practitioner (GP. This was assumed to increase case detection and to include initial assessment and treatment by the NS. The analysis used a societal perspective, including medical costs, containment products (out-of-pocket and paid by insurer, home care, informal care, and implementation costs.With the new care strategy a QALY gain of 0.005 per patient is achieved while saving €402 per patient over a 3 year period from a societal perspective. In interpreting these findings it is important to realise that many patients are undetected, even in the new care situation (36%, or receive care for containment only. In both of these groups no health gains were achieved.Implementing the OCSS in the Netherlands by locating a NS in the GP practice is likely to reduce incontinence, improve quality of life, and reduce costs. Furthermore, the study also highlighted that various areas of the continence care process lack data, which would be valuable to collect through the introduction of the NS in a study setting.

  6. Pulmonary Endpoints in Duchenne Muscular Dystrophy. A Workshop Summary.

    Science.gov (United States)

    Finder, Jonathan; Mayer, Oscar Henry; Sheehan, Daniel; Sawnani, Hemant; Abresch, R Ted; Benditt, Joshua; Birnkrant, David J; Duong, Tina; Henricson, Erik; Kinnett, Kathi; McDonald, Craig M; Connolly, Anne M

    2017-08-15

    Development of novel therapeutics for treatment of Duchenne muscular dystrophy (DMD) has led to clinical trials that include pulmonary endpoints that allow assessment of respiratory muscle status, especially in nonambulatory subjects. Parent Project Muscular Dystrophy (PPMD) convened a workshop in Bethesda, Maryland, on April 14 and 15, 2016, to summarize published respiratory data in DMD and give guidance to clinical researchers assessing the effect of interventions on pulmonary outcomes in DMD.

  7. The Effects of a Family Support Program Including Respite Care on Parenting Stress and Family Quality of Life Perceived by Primary Caregivers of Children with Disabilities in Korea

    Science.gov (United States)

    Sung, Minjung; Park, Jiyeon

    2012-01-01

    In this study, a family support program was carried out for primary caregivers of children with disabilities. The program included respite care, recreation programs, counseling, and social support coordination based on individual needs of each family. In order to verify the intervention effects, parenting stress and family quality of life were…

  8. Trial endpoints for drug approval in oncology: Chemoprevention.

    Science.gov (United States)

    Beitz, J

    2001-04-01

    As with other drugs, new drug applications for marketing approval of chemopreventive drugs must include data from adequate and well-controlled clinical trials that demonstrate effectiveness and safety for the intended use. This article summarizes the regulatory requirements for traditional marketing approval, as well as for approval under the accelerated approval regulations. Unlike traditional approval, accelerated approval is based on a surrogate endpoint that is reasonably likely to predict clinical benefit. Discussions with the Food and Drug Administration (FDA) regarding the validity of trial endpoints that may serve as surrogates for clinical benefit for accelerated approval should take place as early as possible in drug development. Meetings with the FDA to discuss these issues may be requested throughout the clinical development of a new drug.

  9. Choice of futility boundaries for group sequential designs with two endpoints

    Directory of Open Access Journals (Sweden)

    Svenja Schüler

    2017-08-01

    Full Text Available Abstract Background In clinical trials, the opportunity for an early stop during an interim analysis (either for efficacy or for futility may relevantly save time and financial resources. This is especially important, if the planning assumptions required for power calculation are based on a low level of evidence. For example, when including two primary endpoints in the confirmatory analysis, the power of the trial depends on the effects of both endpoints and on their correlation. Assessing the feasibility of such a trial is therefore difficult, as the number of parameter assumptions to be correctly specified is large. For this reason, so-called ‘group sequential designs’ are of particular importance in this setting. Whereas the choice of adequate boundaries to stop a trial early for efficacy has been broadly discussed in the literature, the choice of optimal futility boundaries has not been investigated so far, although this may have serious consequences with respect to performance characteristics. Methods In this work, we propose a general method to construct ‘optimal’ futility boundaries according to predefined criteria. Further, we present three different group sequential designs for two endpoints applying these futility boundaries. Our methods are illustrated by a real clinical trial example and by Monte-Carlo simulations. Results By construction, the provided method of choosing futility boundaries maximizes the probability to correctly stop in case of small or opposite effects while limiting the power loss and the probability of stopping the study ‘wrongly’. Our results clearly demonstrate the benefit of using such ‘optimal’ futility boundaries, especially compared to futility boundaries commonly applied in practice. Conclusions As the properties of futility boundaries are often not considered in practice and unfavorably chosen futility boundaries may imply bad properties of the study design, we recommend assessing the

  10. Overview of Biomarkers and Surrogate Endpoints in Drug Development

    Directory of Open Access Journals (Sweden)

    John A. Wagner

    2002-01-01

    Full Text Available There are numerous factors that recommend the use of biomarkers in drug development including the ability to provide a rational basis for selection of lead compounds, as an aid in determining or refining mechanism of action or pathophysiology, and the ability to work towards qualification and use of a biomarker as a surrogate endpoint. Examples of biomarkers come from many different means of clinical and laboratory measurement. Total cholesterol is an example of a clinically useful biomarker that was successfully qualified for use as a surrogate endpoint. Biomarkers require validation in most circumstances. Validation of biomarker assays is a necessary component to delivery of high-quality research data necessary for effective use of biomarkers. Qualification is necessary for use of a biomarker as a surrogate endpoint. Putative biomarkers are typically identified because of a relationship to known or hypothetical steps in a pathophysiologic cascade. Biomarker discovery can also be effected by expression profiling experiment using a variety of array technologies and related methods. For example, expression profiling experiments enabled the discovery of adipocyte related complement protein of 30 kD (Acrp30 or adiponectin as a biomarker for in vivo activation of peroxisome proliferator-activated receptors (PPAR γ activity.

  11. Biomarkers and correlative endpoints for immunotherapy trials.

    Science.gov (United States)

    Morse, Michael A; Osada, Takuya; Hobeika, Amy; Patel, Sandip; Lyerly, H Kim

    2013-01-01

    Immunotherapies for lung cancer are reaching phase III clinical trial, but the ultimate success likely will depend on developing biomarkers to guide development and choosing patient populations most likely to benefit. Because the immune response to cancer involves multiple cell types and cytokines, some spatially and temporally separated, it is likely that multiple biomarkers will be required to fully characterize efficacy of the vaccine and predict eventual benefit. Peripheral blood markers of response, such as the ELISPOT assay and cytokine flow cytometry analyses of peripheral blood mononuclear cells following immunotherapy, remain the standard approach, but it is increasingly important to obtain tissue to study the immune response at the site of the tumor. Earlier clinical endpoints such as response rate and progression-free survival do not correlate with overall survival demonstrated for some immunotherapies, suggesting the need to develop other intermediary clinical endpoints. Insofar as all these biomarkers and surrogate endpoints are relevant in multiple malignancies, it may be possible to extrapolate findings to immunotherapy of lung cancer.

  12. A data-driven weighting scheme for multivariate phenotypic endpoints recapitulates zebrafish developmental cascades

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Guozhu, E-mail: gzhang6@ncsu.edu [Bioinformatics Research Center, North Carolina State University, Raleigh, NC (United States); Roell, Kyle R., E-mail: krroell@ncsu.edu [Bioinformatics Research Center, North Carolina State University, Raleigh, NC (United States); Truong, Lisa, E-mail: lisa.truong@oregonstate.edu [Department of Environmental and Molecular Toxicology, Sinnhuber Aquatic Research Laboratory, Oregon State University, Corvallis, OR (United States); Tanguay, Robert L., E-mail: robert.tanguay@oregonstate.edu [Department of Environmental and Molecular Toxicology, Sinnhuber Aquatic Research Laboratory, Oregon State University, Corvallis, OR (United States); Reif, David M., E-mail: dmreif@ncsu.edu [Bioinformatics Research Center, North Carolina State University, Raleigh, NC (United States); Department of Biological Sciences, Center for Human Health and the Environment, North Carolina State University, Raleigh, NC (United States)

    2017-01-01

    Zebrafish have become a key alternative model for studying health effects of environmental stressors, partly due to their genetic similarity to humans, fast generation time, and the efficiency of generating high-dimensional systematic data. Studies aiming to characterize adverse health effects in zebrafish typically include several phenotypic measurements (endpoints). While there is a solid biomedical basis for capturing a comprehensive set of endpoints, making summary judgments regarding health effects requires thoughtful integration across endpoints. Here, we introduce a Bayesian method to quantify the informativeness of 17 distinct zebrafish endpoints as a data-driven weighting scheme for a multi-endpoint summary measure, called weighted Aggregate Entropy (wAggE). We implement wAggE using high-throughput screening (HTS) data from zebrafish exposed to five concentrations of all 1060 ToxCast chemicals. Our results show that our empirical weighting scheme provides better performance in terms of the Receiver Operating Characteristic (ROC) curve for identifying significant morphological effects and improves robustness over traditional curve-fitting approaches. From a biological perspective, our results suggest that developmental cascade effects triggered by chemical exposure can be recapitulated by analyzing the relationships among endpoints. Thus, wAggE offers a powerful approach for analysis of multivariate phenotypes that can reveal underlying etiological processes. - Highlights: • Introduced a data-driven weighting scheme for multiple phenotypic endpoints. • Weighted Aggregate Entropy (wAggE) implies differential importance of endpoints. • Endpoint relationships reveal developmental cascade effects triggered by exposure. • wAggE is generalizable to multi-endpoint data of different shapes and scales.

  13. Transforming primary healthcare by including the stakeholders involved in delivering care to people living in poverty: EQUIhealThY study protocol.

    Science.gov (United States)

    Loignon, Christine; Hudon, Catherine; Boudreault-Fournier, Alexandrine; Dupéré, Sophie; Macaulay, Ann C; Pluye, Pierre; Gaboury, Isabelle; Haggerty, Jeannie L; Fortin, Martin; Goulet, Émilie; Lambert, Mireille; Pelissier-Simard, Luce; Boyer, Sophie; de Laat, Marianne; Lemire, Francine; Champagne, Louise; Lemieux, Martin

    2013-03-11

    Ensuring access to timely and appropriate primary healthcare for people living in poverty is an issue facing all countries, even those with universal healthcare systems. The transformation of healthcare practices and organization could be improved by involving key stakeholders from the community and the healthcare system in the development of research interventions. The aim of this project is to stimulate changes in healthcare organizations and practices by encouraging collaboration between care teams and people living in poverty. Our objectives are twofold: 1) to identify actions required to promote the adoption of professional practices oriented toward social competence in primary care teams; and 2) to examine factors that would encourage the inclusion of people living in poverty in the process of developing social competence in healthcare organizations. This study will use a participatory action research design applied in healthcare organizations. Participatory research is an increasingly recognized approach that is helpful for involving the people for whom the research results are intended. Our research team consists of 19 non-academic researchers, 11 academic researchers and six partners. A steering committee composed of academic researchers and stakeholders will have a decision-making role at each step, including knowledge dissemination and recommendations for new interventions. In this project we will adopt a multiphase approach and will use a variety of methods, including photovoice, group discussions and interviews. The proposed study will be one of only a few using participatory research in primary care to foster changes aimed at enhancing quality and access to care for people living in poverty. To our knowledge this will be the first study to use photovoice in healthcare organizations to promote new interventions. Our project includes partners who are targeted for practice changes and improvements in delivering primary care to persons living in poverty

  14. A comparison of chemoembolization endpoints using angiographic versus transcatheter intraarterial perfusion/MR imaging monitoring.

    Science.gov (United States)

    Lewandowski, Robert J; Wang, Dingxin; Gehl, James; Atassi, Bassel; Ryu, Robert K; Sato, Kent; Nemcek, Albert A; Miller, Frank H; Mulcahy, Mary F; Kulik, Laura; Larson, Andrew C; Salem, Riad; Omary, Reed A

    2007-10-01

    Transcatheter arterial chemoembolization (TACE) is an established treatment for unresectable liver cancer. This study was conducted to test the hypothesis that angiographic endpoints during TACE are measurable and reproducible by comparing subjective angiographic versus objective magnetic resonance (MR) endpoints of TACE. The study included 12 consecutive patients who presented for TACE for surgically unresectable HCC or progressive hepatic metastases despite chemotherapy. All procedures were performed with a dedicated imaging system. Angiographic series before and after TACE were reviewed independently by three board-certified interventional radiologists. A subjective angiographic chemoembolization endpoint (SACE) classification scheme, modified from an established angiographic grading system in the cardiology literature, was designed to assist in reproducibly classifying angiographic endpoints. Reproducibility in SACE classification level was compared among operators, and MR imaging perfusion reduction was compared with SACE levels for each observer. Twelve patients successfully underwent 15 separate TACE sessions. SACE levels ranged from I through IV. There was moderate agreement in SACE classification (kappa = 0.46 +/- 0.12). There was no correlation between SACE level and MR perfusion reduction (r = 0.16 for one operator and 0.02 for the other two). Angiographic endpoints during TACE vary widely, have moderate reproducibility among operators, and do not correlate with functional MR imaging perfusion endpoints. Future research should aim to determine ideal angiographic and functional MR imaging endpoints for TACE according to outcome measures such as imaging response, pathologic response, and survival.

  15. Endpoint singularities in unintegrated parton distributions

    CERN Document Server

    Hautmann, F

    2007-01-01

    We examine the singular behavior from the endpoint region x -> 1 in parton distributions unintegrated in both longitudinal and transverse momenta. We identify and regularize the singularities by using the subtraction method, and compare this with the cut-off regularization method. The counterterms for the distributions with subtractive regularization are given in coordinate space by compact all-order expressions in terms of eikonal-line operators. We carry out an explicit calculation at one loop for the unintegrated quark distribution. We discuss the relation of the unintegrated parton distributions in subtractive regularization with the ordinary parton distributions.

  16. Alternative Endpoints and Approaches for the Remediation of Contaminated Groundwater at Complex Sites - 13426

    Energy Technology Data Exchange (ETDEWEB)

    Deeb, Rula A.; Hawley, Elisabeth L. [ARCADIS, U.S., 2000 Powell St., 7th Floor, Emeryville, California 94608 (United States)

    2013-07-01

    The goal of United States (U.S.) Department of Energy's (DOE)'s environmental remediation programs is to restore groundwater to beneficial use, similar to many other Federal and state environmental cleanup programs. Based on past experience, groundwater remediation to pre-contamination conditions (i.e., drinking water standards or non-detectable concentrations) can be successfully achieved at many sites. At a subset of the most complex sites, however, complete restoration is not likely achievable within the next 50 to 100 years using today's technology. This presentation describes several approaches used at complex sites in the face of these technical challenges. Many complex sites adopted a long-term management approach, whereby contamination was contained within a specified area using active or passive remediation techniques. Consistent with the requirements of their respective environmental cleanup programs, several complex sites selected land use restrictions and used risk management approaches to accordingly adopt alternative cleanup goals (alternative endpoints). Several sites used long-term management designations and approaches in conjunction with the alternative endpoints. Examples include various state designations for groundwater management zones, technical impracticability (TI) waivers or greater risk waivers at Superfund sites, and the use of Monitored Natural Attenuation (MNA) or other passive long-term management approaches over long time frames. This presentation will focus on findings, statistics, and case studies from a recently-completed report for the Department of Defense's Environmental Security Technology Certification Program (ESTCP) (Project ER-0832) on alternative endpoints and approaches for groundwater remediation at complex sites under a variety of Federal and state cleanup programs. The primary objective of the project was to provide environmental managers and regulators with tools, metrics, and information needed

  17. Alternative Endpoints and Approaches for the Remediation of Contaminated Groundwater at Complex Sites - 13426

    International Nuclear Information System (INIS)

    Deeb, Rula A.; Hawley, Elisabeth L.

    2013-01-01

    The goal of United States (U.S.) Department of Energy's (DOE)'s environmental remediation programs is to restore groundwater to beneficial use, similar to many other Federal and state environmental cleanup programs. Based on past experience, groundwater remediation to pre-contamination conditions (i.e., drinking water standards or non-detectable concentrations) can be successfully achieved at many sites. At a subset of the most complex sites, however, complete restoration is not likely achievable within the next 50 to 100 years using today's technology. This presentation describes several approaches used at complex sites in the face of these technical challenges. Many complex sites adopted a long-term management approach, whereby contamination was contained within a specified area using active or passive remediation techniques. Consistent with the requirements of their respective environmental cleanup programs, several complex sites selected land use restrictions and used risk management approaches to accordingly adopt alternative cleanup goals (alternative endpoints). Several sites used long-term management designations and approaches in conjunction with the alternative endpoints. Examples include various state designations for groundwater management zones, technical impracticability (TI) waivers or greater risk waivers at Superfund sites, and the use of Monitored Natural Attenuation (MNA) or other passive long-term management approaches over long time frames. This presentation will focus on findings, statistics, and case studies from a recently-completed report for the Department of Defense's Environmental Security Technology Certification Program (ESTCP) (Project ER-0832) on alternative endpoints and approaches for groundwater remediation at complex sites under a variety of Federal and state cleanup programs. The primary objective of the project was to provide environmental managers and regulators with tools, metrics, and information needed to evaluate

  18. Mechanisms of growth inhibition of primary prostate epithelial cells following gamma irradiation or photodynamic therapy include senescence, necrosis, and autophagy, but not apoptosis

    International Nuclear Information System (INIS)

    Frame, Fiona M.; Savoie, Huguette; Bryden, Francesca; Giuntini, Francesca; Mann, Vincent M.; Simms, Matthew S.; Boyle, Ross W.; Maitland, Norman J.

    2015-01-01

    In comparison to more differentiated cells, prostate cancer stem-like cells are radioresistant, which could explain radio-recurrent prostate cancer. Improvement of radiotherapeutic efficacy may therefore require combination therapy. We have investigated the consequences of treating primary prostate epithelial cells with gamma irradiation and photodynamic therapy (PDT), both of which act through production of reactive oxygen species (ROS). Primary prostate epithelial cells were cultured from patient samples of benign prostatic hyperplasia and prostate cancer prior to treatment with PDT or gamma irradiation. Cell viability was measured using MTT and alamar blue assay, and cell recovery by colony-forming assays. Immunofluorescence of gamma-H2AX foci was used to quantify DNA damage, and autophagy and apoptosis were assessed using Western blots. Necrosis and senescence were measured by propidium iodide staining and beta-galactosidase staining, respectively. Both PDT and gamma irradiation reduced the colony-forming ability of primary prostate epithelial cells. PDT reduced the viability of all types of cells in the cultures, including stem-like cells and more differentiated cells. PDT induced necrosis and autophagy, whereas gamma irradiation induced senescence, but neither treatment induced apoptosis. PDT and gamma irradiation therefore inhibit cell growth by different mechanisms. We suggest these treatments would be suitable for use in combination as sequential treatments against prostate cancer

  19. Effectiveness of a structured motivational intervention including smoking cessation advice and spirometry information in the primary care setting: the ESPITAP study

    Directory of Open Access Journals (Sweden)

    Martin-Lujan Francisco

    2011-11-01

    Full Text Available Abstract Background There is current controversy about the efficacy of smoking cessation interventions that are based on information obtained by spirometry. The objective of this study is to evaluate the effectiveness in the primary care setting of structured motivational intervention to achieve smoking cessation, compared with usual clinical practice. Methods Design Multicentre randomized clinical trial with an intervention and a control group. Setting 12 primary care centres in the province of Tarragona (Spain. Subjects of study 600 current smokers aged between 35 and 70 years with a cumulative habit of more than 10 packs of cigarettes per year, attended in primary care for any reason and who did not meet any of the exclusion criteria for the study, randomly assigned to structured intervention or standard clinical attention. Intervention Usual advice to quit smoking by a general practitioner as well as a 20-minute personalized visit to provide detailed information about spirometry results, during which FEV1, FVC, FEF 25-75% and PEF measurements were discussed and interpreted in terms of theoretical values. Additional information included the lung age index (defined as the average age of a non-smoker with the same FEV1 as the study participant, comparing this with the chronological age to illustrate the pulmonary deterioration that results from smoking. Measurements Spirometry during the initial visit. Structured interview questionnaire administered at the primary care centre at the initial visit and at 12-month follow-up. Telephone follow-up interview at 6 months. At 12-month follow-up, expired CO was measured in patients who claimed to have quit smoking. Main variables Smoking cessation at 12 months. Analysis Data will be analyzed on the basis of "intention to treat" and the unit of analysis will be the individual smoker. Expected results Among active smokers treated in primary care we anticipate significantly higher smoking cessation in the

  20. Serum urate as surrogate endpoint for flares in people with gout

    DEFF Research Database (Denmark)

    Stamp, Lisa K; Birger Morillon, Melanie; Taylor, William J

    2018-01-01

    Objectives The primary efficacy outcome in trials of urate lowering therapy (ULT) for gout is serum urate (SU). The aim of this study was to examine the strength of the relationship between SU and patient-important outcomes to determine whether SU is an adequate surrogate endpoint for clinical tr...

  1. Incidence of primary hypothyroidism in patients exposed to therapeutic external beam radiation, where radiation portals include a part or whole of the thyroid gland

    Directory of Open Access Journals (Sweden)

    B A Laway

    2012-01-01

    Full Text Available Introduction: Hypothyroidism is a known consequence of external-beam radiotherapy to the neck encompassing a part or whole of the thyroid gland. In this non-randomized prospective study, we have tried to evaluate the response of the thyroid gland to radiation by assessing thyroid function before irradiation and at regular intervals after irradiation. Aims and Objectives: The aim of this study were to assess in the cancer patients, who were exposed to the therapeutic external beam radiation, where radiation portals include a part or whole of the thyroid gland: the incidence of primary hypothyroidism, the time required to become hypothyroid, any relation between the total dose for the development of hypothyroidism, and whether there are any patient or treatment-related factors that are predictive for the development of hypothyroidism, including the use of concurrent chemotherapy. Materials and Methods: This non-randomized, prospective study was conducted for a period of 2 years in which thyroid function was assessed in 59 patients (cases of head and neck cancer, breast cancer, lymphoma patients and other malignancies, who had received radiotherapy to the neck region. 59 euthyroid healthy patients (controls were also taken, who had not received the neck irradiation. These patients/controls were assessed periodically for 2 years. Results: The incidence of hypothyroidism after external beam radiation therapy (EBRT to neck where radiation portals include part or whole of the thyroid gland was 16.94%, seven cases had subclinical hypothyroidism (11.86% and three cases had clinical hypothyroidism (5.08%. Mean time for development of hypothyroidism was 4.5 months. There was no effect of age, gender, primary tumor site, radiation dose and chemotherapy, whether neoadjuvant or concurrent with the development of hypothyroidism. Conclusion: In summary, we found that thyroid dysfunction is a prevalent, yet easily treatable source of morbidity in patients

  2. Reporting and evaluation of HIV-related clinical endpoints in two multicenter international clinical trials

    DEFF Research Database (Denmark)

    Lifson, A; Rhame, F; Bellosa, W

    2006-01-01

    adjudication between reviewers before diagnostic certainty was assigned. CONCLUSION: Important requirements for HIV trials using clinical endpoints include objective definitions of "confirmed" and "probable," a formal reporting process with adequate information and supporting source documentation, evaluation......PURPOSE: The processes for reporting and review of progression of HIV disease clinical endpoints are described for two large phase III international clinical trials. METHOD: SILCAAT and ESPRIT are multicenter randomized HIV trials evaluating the impact of interleukin-2 on disease progression...... and death in HIV-infected patients receiving antiretroviral therapy. We report definitions used for HIV progression of disease endpoints, procedures for site reporting of such events, processes for independent review of reported events by an Endpoint Review Committee (ERC), and the procedure...

  3.  Alkaline phosphatase normalization is a biomarker of improved survival in primary sclerosing cholangitis.

    Science.gov (United States)

    Hilscher, Moira; Enders, Felicity B; Carey, Elizabeth J; Lindor, Keith D; Tabibian, James H

    2016-01-01

     Introduction. Recent studies suggest that serum alkaline phosphatase may represent a prognostic biomarker in patients with primary sclerosing cholangitis. However, this association remains poorly understood. Therefore, the aim of this study was to investigate the prognostic significance and clinical correlates of alkaline phosphatase normalization in primary sclerosing cholangitis. This was a retrospective cohort study of patients with a new diagnosis of primary sclerosing cholangitis made at an academic medical center. The primary endpoint was time to hepatobiliaryneoplasia, liver transplantation, or liver-related death. Secondary endpoints included occurrence of and time to alkaline phosphatase normalization. Patients who did and did not achieve normalization were compared with respect to clinical characteristics and endpoint-free survival, and the association between normalization and the primary endpoint was assessed with univariate and multivariate Cox proportional-hazards analyses. Eighty six patients were included in the study, with a total of 755 patient-years of follow-up. Thirty-eight patients (44%) experienced alkaline phosphatase normalization within 12 months of diagnosis. Alkaline phosphatase normalization was associated with longer primary endpoint-free survival (p = 0.0032) and decreased risk of requiring liver transplantation (p = 0.033). Persistent normalization was associated with even fewer adverse endpoints as well as longer survival. In multivariate analyses, alkaline phosphatase normalization (adjusted hazard ratio 0.21, p = 0.012) and baseline bilirubin (adjusted hazard ratio 4.87, p = 0.029) were the only significant predictors of primary endpoint-free survival. Alkaline phosphatase normalization, particularly if persistent, represents a robust biomarker of improved long-term survival and decreased risk of requiring liver transplantation in patients with primary sclerosing cholangitis.

  4. Secondary efficacy endpoints of the pentavalent rotavirus vaccine against gastroenteritis in sub-Saharan Africa.

    Science.gov (United States)

    Tapia, Milagritos D; Armah, George; Breiman, Robert F; Dallas, Michael J; Lewis, Kristen D C; Sow, Samba O; Rivers, Stephen B; Levine, Myron M; Laserson, Kayla F; Feikin, Daniel R; Victor, John C; Ciarlet, Max; Neuzil, Kathleen M; Steele, A Duncan

    2012-04-27

    The efficacy of the pentavalent rotavirus vaccine (PRV), RotaTeq(®), was evaluated in a double-blind, placebo-controlled, multicenter Phase III clinical trial conducted (April 2007-March 2009) in 3 low-income countries in Africa: Ghana, Kenya, and Mali. In total, 5468 infants were randomized 1:1 to receive 3 doses of PRV/placebo at approximately 6, 10, and 14 weeks of age; concomitant administration with routine EPI vaccines, including OPV, was allowed. HIV-infected infants were not excluded. The primary endpoint, vaccine efficacy (VE) against severe-rotavirus gastroenteritis (RVGE), as measured by Vesikari scoring system (VSS, score ≥11), from ≥14 days following Dose 3 through a follow-up period of nearly 2 years in the combined 3 African countries, and secondary endpoints by total follow-up period have been previously reported. In this study, we report post hoc subgroup analyses on secondary endpoints of public health importance. VE against RVGE of any severity was 49.2% (95%CI: 29.9, 63.5) through the first year of life and 30.5% (95%CI: 16.7, 42.2) through the complete follow-up period. VE against severe-gastroenteritis of any etiology was 21.5% (95%CI: vaccine-contained G and P types (G1-G4, P1A[8]), (ii) non-vaccine G types (G8, G9, G10), and (iii) non-vaccine P types (P1B[4], P2A[6]) was 34.0% (95%CI:11.2, 51.2), 81.8% (95%CI:16.5, 98.0) and 40.7% (95%CI:8.4, 62.1), respectively. There was a trend towards higher VE with higher disease severity, although in some cases the numbers were small. In African countries with high under-5 mortality rates, PRV significantly reduced RVGE through nearly 2 years of follow-up; more modest reductions were observed against gastroenteritis of any etiology. PRV provides protection against severe-RVGE caused by diverse rotavirus genotypes, including those not contained in the vaccine. Copyright © 2012 Elsevier Ltd. All rights reserved.

  5. Cost-effectiveness of collaborative care including PST and an antidepressant treatment algorithm for the treatment of major depressive disorder in primary care; a randomised clinical trial

    Directory of Open Access Journals (Sweden)

    Beekman Aartjan TF

    2007-03-01

    Full Text Available Abstract Background Depressive disorder is currently one of the most burdensome disorders worldwide. Evidence-based treatments for depressive disorder are already available, but these are used insufficiently, and with less positive results than possible. Earlier research in the USA has shown good results in the treatment of depressive disorder based on a collaborative care approach with Problem Solving Treatment and an antidepressant treatment algorithm, and research in the UK has also shown good results with Problem Solving Treatment. These treatment strategies may also work very well in the Netherlands too, even though health care systems differ between countries. Methods/design This study is a two-armed randomised clinical trial, with randomization on patient-level. The aim of the trial is to evaluate the treatment of depressive disorder in primary care in the Netherlands by means of an adapted collaborative care framework, including contracting and adherence-improving strategies, combined with Problem Solving Treatment and antidepressant medication according to a treatment algorithm. Forty general practices will be randomised to either the intervention group or the control group. Included will be patients who are diagnosed with moderate to severe depression, based on DSM-IV criteria, and stratified according to comorbid chronic physical illness. Patients in the intervention group will receive treatment based on the collaborative care approach, and patients in the control group will receive care as usual. Baseline measurements and follow up measures (3, 6, 9 and 12 months are assessed using questionnaires and an interview. The primary outcome measure is severity of depressive symptoms, according to the PHQ9. Secondary outcome measures are remission as measured with the PHQ9 and the IDS-SR, and cost-effectiveness measured with the TiC-P, the EQ-5D and the SF-36. Discussion In this study, an American model to enhance care for patients with a

  6. Development of Cardiovascular and Neurodevelopmental Metrics as Sublethal Endpoints for the Fish Embryo Toxicity Test.

    Science.gov (United States)

    Krzykwa, Julie C; Olivas, Alexis; Jeffries, Marlo K Sellin

    2018-06-19

    The fathead minnow fish embryo toxicity (FET) test has been proposed as a more humane alternative to current toxicity testing methods, as younger organisms are thought to experience less distress during toxicant exposure. However, the FET test protocol does not include endpoints that allow for the prediction of sublethal adverse outcomes, limiting its utility relative to other test types. Researchers have proposed the development of sublethal endpoints for the FET test to increase its utility. The present study 1) developed methods for previously unmeasured sublethal metrics in fathead minnows (i.e., spontaneous contraction frequency and heart rate) and 2) investigated the responsiveness of several sublethal endpoints related to growth (wet weight, length, and growth-related gene expression), neurodevelopment (spontaneous contraction frequency, and neurodevelopmental gene expression), and cardiovascular function and development (pericardial area, eye size and cardiovascular related gene expression) as additional FET test metrics using the model toxicant 3,4-dichloroaniline. Of the growth, neurological and cardiovascular endpoints measured, length, eye size and pericardial area were found to more responsive than the other endpoints, respectively. Future studies linking alterations in these endpoints to longer-term adverse impacts are needed to fully evaluate the predictive power of these metrics in chemical and whole effluent toxicity testing. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  7. The intermediate endpoint effect in logistic and probit regression

    Science.gov (United States)

    MacKinnon, DP; Lockwood, CM; Brown, CH; Wang, W; Hoffman, JM

    2010-01-01

    Background An intermediate endpoint is hypothesized to be in the middle of the causal sequence relating an independent variable to a dependent variable. The intermediate variable is also called a surrogate or mediating variable and the corresponding effect is called the mediated, surrogate endpoint, or intermediate endpoint effect. Clinical studies are often designed to change an intermediate or surrogate endpoint and through this intermediate change influence the ultimate endpoint. In many intermediate endpoint clinical studies the dependent variable is binary, and logistic or probit regression is used. Purpose The purpose of this study is to describe a limitation of a widely used approach to assessing intermediate endpoint effects and to propose an alternative method, based on products of coefficients, that yields more accurate results. Methods The intermediate endpoint model for a binary outcome is described for a true binary outcome and for a dichotomization of a latent continuous outcome. Plots of true values and a simulation study are used to evaluate the different methods. Results Distorted estimates of the intermediate endpoint effect and incorrect conclusions can result from the application of widely used methods to assess the intermediate endpoint effect. The same problem occurs for the proportion of an effect explained by an intermediate endpoint, which has been suggested as a useful measure for identifying intermediate endpoints. A solution to this problem is given based on the relationship between latent variable modeling and logistic or probit regression. Limitations More complicated intermediate variable models are not addressed in the study, although the methods described in the article can be extended to these more complicated models. Conclusions Researchers are encouraged to use an intermediate endpoint method based on the product of regression coefficients. A common method based on difference in coefficient methods can lead to distorted

  8. Imaging biomarkers as surrogate endpoints for drug development

    International Nuclear Information System (INIS)

    Richter, Wolf S.

    2006-01-01

    The employment of biomarkers (including imaging biomarkers, especially PET) in drug development has gained increasing attention during recent years. This has been partly stimulated by the hope that the integration of biomarkers into drug development programmes may be a means to increase the efficiency and effectiveness of the drug development process by early identification of promising drug candidates - thereby counteracting the rising costs of drug development. More importantly, however, the interest in biomarkers for drug development is the logical consequence of recent advances in biosciences and medicine which are leading to target-specific treatments in the framework of ''personalised medicine''. A considerable proportion of target-specific drugs will show effects in subgroups of patients only. Biomarkers are a means to identify potential responders, or patient subgroups at risk for specific side-effects. Biomarkers are used in early drug development in the context of translational medicine to gain information about the drug's potential in different patient groups and disease states. The information obtained at this stage is mainly important for designing subsequent clinical trials and to identify promising drug candidates. Biomarkers in later phases of clinical development may - if properly validated - serve as surrogate endpoints for clinical outcomes. Regulatory agencies in the EU and the USA have facilitated the use of biomarkers early in the development process. The validation of biomarkers as surrogate endpoints is part of FDA's ''critical path initiative''. (orig.)

  9. The primary immune response to Vaccinia virus vaccination includes cells with a distinct cytotoxic effector CD4 T-cell phenotype.

    Science.gov (United States)

    Munier, C Mee Ling; van Bockel, David; Bailey, Michelle; Ip, Susanna; Xu, Yin; Alcantara, Sheilajen; Liu, Sue Min; Denyer, Gareth; Kaplan, Warren; Suzuki, Kazuo; Croft, Nathan; Purcell, Anthony; Tscharke, David; Cooper, David A; Kent, Stephen J; Zaunders, John J; Kelleher, Anthony D

    2016-10-17

    Smallpox was eradicated by a global program of inoculation with Vaccinia virus (VV). Robust VV-specific CD4 T-cell responses during primary infection are likely essential to controlling VV replication. Although there is increasing interest in cytolytic CD4 T-cells across many viral infections, the importance of these cells during acute VV infection is unclear. We undertook a detailed functional and genetic characterization of CD4 T-cells during acute VV-infection of humans. VV-specific T-cells were identified by up-regulation of activation markers directly ex vivo and through cytokine and co-stimulatory molecule expression. At day-13-post primary inoculation with VV, CD38highCD45RO+ CD4 T-cells were purified by cell sorting, RNA isolated and analysed by microarray. Differential expression of up-regulated genes in activated CD4 T-cells was confirmed at the mRNA and protein levels. We compared analyses of VV-specific CD4 T-cells to studies on 12 subjects with primary HIV infection (PHI). VV-specific T-cells lines were established from PBMCs collected post vaccination and checked for cytotoxicity potential. A median 11.9% CD4 T-cells were CD38highCD45RO+ at day-13 post-VV inoculation, compared to 3.0% prior and 10.4% during PHI. Activated CD4 T-cells had an up-regulation of genes related to cytolytic function, including granzymes K and A, perforin, granulysin, TIA-1, and Rab27a. No difference was seen between CD4 T-cell expression of perforin or TIA-1 to VV and PHI, however granzyme k was more dominant in the VV response. At 25:1 effector to target ratio, two VV-specific T-cell lines exhibited 62% and 30% cytotoxicity respectively and CD107a degranulation. We show for the first time that CD4 CTL are prominent in the early response to VV. Understanding the role of CD4 CTL in the generation of an effective anti-viral memory may help develop more effective vaccines for diseases such as HIV. Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.

  10. Endpoint distinctiveness facilitates analogical mapping in pigeons.

    Science.gov (United States)

    Hagmann, Carl Erick; Cook, Robert G

    2015-03-01

    Analogical thinking necessitates mapping shared relations across two separate domains. We investigated whether pigeons could learn faster with ordinal mapping of relations across two physical dimensions (circle size & choice spatial position) relative to random mapping of these relations. Pigeons were trained to relate six circular samples of different sizes to horizontally positioned choice locations in a six alternative matching-to-sample task. Three pigeons were trained in a mapped condition in which circle size mapped directly onto choice spatial position. Three other pigeons were trained in a random condition in which the relations between size and choice position were arbitrarily assigned. The mapped group showed an advantage over the random group in acquiring this task. In a subsequent second phase, relations between the dimensions were ordinally reversed for the mapped group and re-randomized for the random group. There was no difference in how quickly matching accuracy re-emerged in the two groups, although the mapped group eventually performed more accurately. Analyses suggested this mapped advantage was likely due to endpoint distinctiveness and the benefits of proximity errors during choice responding rather than a conceptual or relational advantage attributable to the common or ordinal mapping of the two dimensions. This potential difficulty in mapping relations across dimensions may limit the pigeons' capacity for more advanced types of analogical reasoning. This article is part of a Special Issue entitled: Tribute to Tom Zentall. Copyright © 2014 Elsevier B.V. All rights reserved.

  11. Endpoint Distinctiveness Facilitates Analogical Mapping in Pigeons

    Science.gov (United States)

    Hagmann, Carl Erick; Cook, Robert G.

    2015-01-01

    Analogical thinking necessitates mapping shared relations across two separate domains. We investigated whether pigeons could learn faster with ordinal mapping of relations across two physical dimensions (circle size & choice spatial position) relative to random mapping of these relations. Pigeons were trained to relate six circular samples of different sizes to horizontally positioned choice locations in a six alternative matching-to-sample task. Three pigeons were trained in a mapped condition in which circle size mapped directly onto choice spatial position. Three other pigeons were trained in a random condition in which the relations between size and choice position were arbitrarily assigned. The mapped group showed an advantage over the random group in acquiring this task. In a subsequent second phase, reassignment, relations between the dimensions were ordinally reversed for the mapped group and re-randomized for the random group. There was no difference in how quickly matching accuracy re-emerged in the two groups, although the mapped group eventually performed more accurately. Analyses suggested this mapped advantage was likely due endpoint distinctiveness and the benefits of proximity errors during choice responding rather than a conceptual or relational advantage attributable to the common or ordinal map of the two dimensions. This potential difficulty in mapping relations across dimensions may limit the pigeons’ capacity for more advanced types of analogical reasoning. PMID:25447511

  12. Correlation of Hip Fracture with Other Fracture Types: Toward a Rational Composite Hip Fracture Endpoint

    Science.gov (United States)

    Colón-Emeric, Cathleen; Pieper, Carl F.; Grubber, Janet; Van Scoyoc, Lynn; Schnell, Merritt L; Van Houtven, Courtney Harold; Pearson, Megan; Lafleur, Joanne; Lyles, Kenneth W.; Adler, Robert A.

    2016-01-01

    Purpose With ethical requirements to the enrollment of lower risk subjects, osteoporosis trials are underpowered to detect reduction in hip fractures. Different skeletal sites have different levels of fracture risk and response to treatment. We sought to identify fracture sites which cluster with hip fracture at higher than expected frequency; if these sites respond to treatment similarly, then a composite fracture endpoint could provide a better estimate of hip fracture reduction. Methods Cohort study using Veterans Affairs and Medicare administrative data. Male Veterans (n=5,036,536) aged 50-99 years receiving VA primary care between1999-2009 were included. Fractures were ascertained using ICD9 and CPT codes and classified by skeletal site. Pearson correlation coefficients, logistic regression and kappa statistics, were used to describe the correlation between each fracture type and hip fracture within individuals, without regards to the timing of the events. Results 595,579 (11.8%) men suffered 1 or more fractures and 179,597 (3.6%) suffered 2 or more fractures during the time under study. Of those with one or more fractures, rib was the most common site (29%), followed by spine (22%), hip (21%) and femur (20%). The fracture types most highly correlated with hip fracture were pelvic/acetabular (Pearson correlation coefficient 0.25, p<0.0001), femur (0.15, p<0.0001), and shoulder (0.11, p<0.0001). Conclusions Pelvic, acetabular, femur, and shoulder fractures cluster with hip fractures within individuals at greater than expected frequency. If we observe similar treatment risk reductions within that cluster, subsequent trials could consider use of a composite endpoint to better estimate hip fracture risk. PMID:26151123

  13. Sample size determination for equivalence assessment with multiple endpoints.

    Science.gov (United States)

    Sun, Anna; Dong, Xiaoyu; Tsong, Yi

    2014-01-01

    Equivalence assessment between a reference and test treatment is often conducted by two one-sided tests (TOST). The corresponding power function and sample size determination can be derived from a joint distribution of the sample mean and sample variance. When an equivalence trial is designed with multiple endpoints, it often involves several sets of two one-sided tests. A naive approach for sample size determination in this case would select the largest sample size required for each endpoint. However, such a method ignores the correlation among endpoints. With the objective to reject all endpoints and when the endpoints are uncorrelated, the power function is the production of all power functions for individual endpoints. With correlated endpoints, the sample size and power should be adjusted for such a correlation. In this article, we propose the exact power function for the equivalence test with multiple endpoints adjusted for correlation under both crossover and parallel designs. We further discuss the differences in sample size for the naive method without and with correlation adjusted methods and illustrate with an in vivo bioequivalence crossover study with area under the curve (AUC) and maximum concentration (Cmax) as the two endpoints.

  14. Ordered kinematic endpoints for 5-body cascade decays

    Energy Technology Data Exchange (ETDEWEB)

    Klimek, Matthew D. [Theory Group, Department of Physics and Texas Cosmology Center,University of Texas at Austin, 2515 Speedway, Stop C1608, Austin, TX, 78712 (United States)

    2016-12-23

    We present expressions for the kinematic endpoints of 5-body cascade decay chains proceeding through all possible combinations of 2-body and 3-body decays, with one stable invisible particle in the final decay stage. When an invariant mass can be formed in multiple ways by choosing different final state particles from a common vertex, we introduce techniques for finding the sub-leading endpoints for all indistinguishable versions of the invariant mass. In contrast to short decay chains, where sub-leading endpoints are linearly related to the leading endpoints, we find that in 5-body decays, they provide additional independent constraints on the mass spectrum.

  15. A web-based endpoint adjudication system for interim analyses in clinical trials.

    Science.gov (United States)

    Nolen, Tracy L; Dimmick, Bill F; Ostrosky-Zeichner, Luis; Kendrick, Amy S; Sable, Carole; Ngai, Angela; Wallace, Dennis

    2009-02-01

    A data monitoring committee (DMC) is often employed to assess trial progress and review safety data and efficacy endpoints throughout a trail. Interim analyses performed for the DMC should use data that are as complete and verified as possible. Such analyses are complicated when data verification involves subjective study endpoints or requires clinical expertise to determine each subject's status with respect to the study endpoint. Therefore, procedures are needed to obtain adjudicated data for interim analyses in an efficient manner. In the past, methods for handling such data included using locally reported results as surrogate endpoints, adjusting analysis methods for unadjudicated data, or simply performing the adjudication as rapidly as possible. These methods all have inadequacies that make their sole usage suboptimal. For a study of prophylaxis for invasive candidiasis, adjudication of both study eligibility criteria and clinical endpoints prior to two interim analyses was required. Because the study was expected to enroll at a moderate rate and the sponsor required adjudicated endpoints to be used for interim analyses, an efficient process for adjudication was required. We created a web-based endpoint adjudication system (WebEAS) that allows for expedited review by the endpoint adjudication committee (EAC). This system automatically identifies when a subject's data are complete, creates a subject profile from the study data, and assigns EAC reviewers. The reviewers use the WebEAS to review the subject profile and submit their completed review form. The WebEAS then compares the reviews, assigns an additional review as a tiebreaker if needed, and stores the adjudicated data. The study for which this system was originally built was administratively closed after 10 months with only 38 subjects enrolled. The adjudication process was finalized and the WebEAS system activated prior to study closure. Some website accessibility issues presented initially. However

  16. Gene expression profiles in auricle skin as a possible additional endpoint for determination of sensitizers: A multi-endpoint evaluation of the local lymph node assay.

    Science.gov (United States)

    Tsuchiyama, Hiromi; Maeda, Akihisa; Nakajima, Mayumi; Kitsukawa, Mika; Takahashi, Kei; Miyoshi, Tomoya; Mutsuga, Mayu; Asaoka, Yoshiji; Miyamoto, Yohei; Oshida, Keiyu

    2017-10-05

    The murine local lymph node assay (LLNA) is widely used to test chemicals to induce skin sensitization. Exposure of mouse auricle skin to a sensitizer results in proliferation of local lymph node T cells, which has been measured by in vivo incorporation of H 3 -methyl thymidine or 5-bromo-2'-deoxyuridine (BrdU). The stimulation index (SI), the ratio of the mean proliferation in each treated group to that in the concurrent vehicle control group, is frequently used as a regulatory-authorized endpoint for LLNA. However, some non-sensitizing irritants, such as sodium dodecyl sulfate (SDS) or methyl salicylate (MS), have been reported as false-positives by this endpoint. In search of a potential endpoint to enhance the specificity of existing endpoints, we evaluated 3 contact sensitizers; (hexyl cinnamic aldehyde [HCA], oxazolone [OXA], and 2,4-dinitrochlorobenzene [DNCB]), 1 respiratory sensitizer (toluene 2,4-diisocyanate [TDI]), and 2 non-sensitizing irritants (MS and SDS) by several endpoints in LLNA. Each test substance was applied to both ears of female CBA/Ca mice daily for 3 consecutive days. The ears and auricle lymph node cells were analyzed on day 5 for endpoints including the SI value, lymph node cell count, cytokine release from lymph node cells, and histopathological changes and gene expression profiles in auricle skin. The SI values indicated that all the test substances induced significant proliferation of lymph node cells. The lymph node cell counts showed no significant changes by the non-sensitizers assessed. The inflammatory findings of histopathology were similar among the auricle skins treated by sensitizers and irritants. Gene expression profiles of cytokines IFN-γ, IL-4, and IL-17 in auricle skin were similar to the cytokine release profiles in draining lymph node cells. In addition, the gene expression of the chemokine CXCL1 and/or CXCL2 showed that it has the potential to discriminate sensitizers and non-sensitizing irritants. Our results

  17. Defining an EPOR- regulated transcriptome for primary progenitors, including Tnfr-sf13c as a novel mediator of EPO- dependent erythroblast formation.

    Directory of Open Access Journals (Sweden)

    Seema Singh

    Full Text Available Certain concepts concerning EPO/EPOR action modes have been challenged by in vivo studies: Bcl-x levels are elevated in maturing erythroblasts, but not in their progenitors; truncated EPOR alleles that lack a major p85/PI3K recruitment site nonetheless promote polycythemia; and Erk1 disruption unexpectedly bolsters erythropoiesis. To discover novel EPO/EPOR action routes, global transcriptome analyses presently are applied to interrogate EPO/EPOR effects on primary bone marrow-derived CFUe-like progenitors. Overall, 160 EPO/EPOR target transcripts were significantly modulated 2-to 21.8-fold. A unique set of EPO-regulated survival factors included Lyl1, Gas5, Pim3, Pim1, Bim, Trib3 and Serpina 3g. EPO/EPOR-modulated cell cycle mediators included Cdc25a, Btg3, Cyclin-d2, p27-kip1, Cyclin-g2 and CyclinB1-IP-1. EPO regulation of signal transduction factors was also interestingly complex. For example, not only Socs3 plus Socs2 but also Spred2, Spred1 and Eaf1 were EPO-induced as negative-feedback components. Socs2, plus five additional targets, further proved to comprise new EPOR/Jak2/Stat5 response genes (which are important for erythropoiesis during anemia. Among receptors, an atypical TNF-receptor Tnfr-sf13c was up-modulated >5-fold by EPO. Functionally, Tnfr-sf13c ligation proved to both promote proerythroblast survival, and substantially enhance erythroblast formation. The EPOR therefore engages a sophisticated set of transcriptome response circuits, with Tnfr-sf13c deployed as one novel positive regulator of proerythroblast formation.

  18. Comparison of RNA-seq and microarray-based models for clinical endpoint prediction.

    Science.gov (United States)

    Zhang, Wenqian; Yu, Ying; Hertwig, Falk; Thierry-Mieg, Jean; Zhang, Wenwei; Thierry-Mieg, Danielle; Wang, Jian; Furlanello, Cesare; Devanarayan, Viswanath; Cheng, Jie; Deng, Youping; Hero, Barbara; Hong, Huixiao; Jia, Meiwen; Li, Li; Lin, Simon M; Nikolsky, Yuri; Oberthuer, André; Qing, Tao; Su, Zhenqiang; Volland, Ruth; Wang, Charles; Wang, May D; Ai, Junmei; Albanese, Davide; Asgharzadeh, Shahab; Avigad, Smadar; Bao, Wenjun; Bessarabova, Marina; Brilliant, Murray H; Brors, Benedikt; Chierici, Marco; Chu, Tzu-Ming; Zhang, Jibin; Grundy, Richard G; He, Min Max; Hebbring, Scott; Kaufman, Howard L; Lababidi, Samir; Lancashire, Lee J; Li, Yan; Lu, Xin X; Luo, Heng; Ma, Xiwen; Ning, Baitang; Noguera, Rosa; Peifer, Martin; Phan, John H; Roels, Frederik; Rosswog, Carolina; Shao, Susan; Shen, Jie; Theissen, Jessica; Tonini, Gian Paolo; Vandesompele, Jo; Wu, Po-Yen; Xiao, Wenzhong; Xu, Joshua; Xu, Weihong; Xuan, Jiekun; Yang, Yong; Ye, Zhan; Dong, Zirui; Zhang, Ke K; Yin, Ye; Zhao, Chen; Zheng, Yuanting; Wolfinger, Russell D; Shi, Tieliu; Malkas, Linda H; Berthold, Frank; Wang, Jun; Tong, Weida; Shi, Leming; Peng, Zhiyu; Fischer, Matthias

    2015-06-25

    Gene expression profiling is being widely applied in cancer research to identify biomarkers for clinical endpoint prediction. Since RNA-seq provides a powerful tool for transcriptome-based applications beyond the limitations of microarrays, we sought to systematically evaluate the performance of RNA-seq-based and microarray-based classifiers in this MAQC-III/SEQC study for clinical endpoint prediction using neuroblastoma as a model. We generate gene expression profiles from 498 primary neuroblastomas using both RNA-seq and 44 k microarrays. Characterization of the neuroblastoma transcriptome by RNA-seq reveals that more than 48,000 genes and 200,000 transcripts are being expressed in this malignancy. We also find that RNA-seq provides much more detailed information on specific transcript expression patterns in clinico-genetic neuroblastoma subgroups than microarrays. To systematically compare the power of RNA-seq and microarray-based models in predicting clinical endpoints, we divide the cohort randomly into training and validation sets and develop 360 predictive models on six clinical endpoints of varying predictability. Evaluation of factors potentially affecting model performances reveals that prediction accuracies are most strongly influenced by the nature of the clinical endpoint, whereas technological platforms (RNA-seq vs. microarrays), RNA-seq data analysis pipelines, and feature levels (gene vs. transcript vs. exon-junction level) do not significantly affect performances of the models. We demonstrate that RNA-seq outperforms microarrays in determining the transcriptomic characteristics of cancer, while RNA-seq and microarray-based models perform similarly in clinical endpoint prediction. Our findings may be valuable to guide future studies on the development of gene expression-based predictive models and their implementation in clinical practice.

  19. Living conditions, including life style, in primary-care patients with nonacute, nonspecific spinal pain compared with a population-based sample: a cross-sectional study

    Directory of Open Access Journals (Sweden)

    Odd Lindell

    2010-11-01

    Full Text Available Odd Lindell, Sven-Erik Johansson, Lars-Erik Strender1Center for Family and Community Medicine, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, SwedenBackground: Nonspecific spinal pain (NSP, comprising back and/or neck pain, is one of the leading disorders behind long-term sick-listing, including disability pensions. Early interventions to prevent long-term sick-listing require the identification of patients at risk. The aim of this study was to compare living conditions associated with long-term sick-listing for NSP in patients with nonacute NSP, with a nonpatient population-based sample. Nonacute NSP is pain that leads to full-time sick-listing>3 weeks.Methods: One hundred and twenty-five patients with nonacute NSP, 2000–2004, were included in a randomized controlled trial in Stockholm County with the objective of comparing cognitive–behavioral rehabilitation with traditional primary care. For these patients, a cross-sectional study was carried out with baseline data. Living conditions were compared between the patients and 338 nonpatients by logistic regression. The conditions from univariate analyses were included in a multivariate analysis. The nonsignificant variables were excluded sequentially to yield a model comprising only the significant factors (P <0.05. The results are shown as odds ratios (OR with 95% confidence intervals.Results: In the univariate analyses, 13 of the 18 living conditions had higher odds for the patients with a dominance of physical work strains and Indication of alcohol over-consumption, odds ratio (OR 14.8 (95% confidence interval [CI] 3.2–67.6. Five conditions qualified for the multivariate model: High physical workload, OR 13.7 (CI 5.9–32.2; Hectic work tempo, OR 8.4 (CI 2.5–28.3; Blue-collar job, OR 4.5 (CI 1.8–11.4; Obesity, OR 3.5 (CI 1.2–10.2; and Low education, OR 2.7 (CI 1.1–6.8.Conclusions: As most of the living conditions have previously been

  20. Hippeastrum hybridum anthocyanins as indicators of endpoint in acid

    African Journals Online (AJOL)

    Anthocyanins from Hippeastrum hybridum (Amaryllis) were investigated as indicators of endpoint in acid- base titrations. Extraction of the anthocyanins was done using distilled water, methanol and methanol containing 0.5% acetic acid. The extracts were used in determination of endpoint in titrations between strong.

  1. Hippeastrum hybridum anthocyanins as indicators of endpoint in ...

    African Journals Online (AJOL)

    Anthocyanins from Hippeastrum hybridum (Amaryllis) were investigated as indicators of endpoint in acid- base titrations. Extraction of the anthocyanins was done using distilled water, methanol and methanol containing 0.5% acetic acid. The extracts were used in determination of endpoint in titrations between strong ...

  2. The impact of endpoint measures in rheumatoid arthritis clinical trials

    NARCIS (Netherlands)

    van der Heide, A.; Jacobs, J. W.; Dinant, H. J.; Bijlsma, J. W.

    1992-01-01

    In clinical trials on the effectiveness of disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA), it is common to apply a large number of endpoint measures. This practice has several disadvantages. To determine which endpoint measures are most valuable, reports of

  3. Synthesis and evaluation of the potential deleterious effects of ZnO nanomaterials (nanoneedles and nanoflowers) on blood components, including albumin, erythrocytes and human isolated primary neutrophils

    Energy Technology Data Exchange (ETDEWEB)

    Pastrello, Bruna [São Paulo State University (UNESP), Department of Chemistry, Faculty of Sciences (Brazil); Paracatu, Luana Chiquetto [São Paulo State University (UNESP), Department of Clinical Analysis, School of Pharmaceutical Sciences (Brazil); Carvalho Bertozo, Luiza de [São Paulo State University (UNESP), Department of Chemistry, Faculty of Sciences (Brazil); Paino, Iêda Maria Martinez [University of São Paulo (USP), Nanomedicine and Nanotoxicology Group, Physics Institute of São Carlos (IFSC) (Brazil); Lisboa-Filho, Paulo Noronha [São Paulo State University (UNESP), Department of Physics, Faculty of Sciences (Brazil); Ximenes, Valdecir Farias, E-mail: vfximenes@fc.unesp.br [São Paulo State University (UNESP), Department of Chemistry, Faculty of Sciences (Brazil)

    2016-07-15

    The application of zinc oxide (ZnO) nanoparticles in biomaterials has increased significantly in the recent years. Here, we aimed to study the potential deleterious effects of ZnO on blood components, including human serum albumin (HSA), erythrocytes and human isolated primary neutrophils. To test the influence of the morphology of the nanomaterials, ZnO nanoneedles (ZnO-nn) and nanoflowers (ZnO-nf) were synthesized. The zeta potential and mean size of ZnO-nf and ZnO-nn suspensions in phosphate-buffered saline were −10.73 mV and 3.81 nm and −5.27 mV and 18.26 nm, respectively. The incubation of ZnO with HSA did not cause its denaturation as verified by the absence of significant alterations in the intrinsic and extrinsic fluorescence and in the circular dichroism spectrum of the protein. The capacity of HSA as a drug carrier was not affected as verified by employing site I and II fluorescent markers. Neither type of ZnO was able to provoke the activation of neutrophils, as verified by lucigenin- and luminol-dependent chemiluminescence and by the extracellular release of hydrogen peroxide. ZnO-nf, but not ZnO-nn, induced the haemolysis of erythrocytes. In conclusion, our results reinforce the concept that ZnO nanomaterials are relatively safe for usage in biomaterials. A potential exception is the capacity of ZnO-nf to promote the lysis of erythrocytes, a discovery that shows the importance of the morphology in the toxicity of nanoparticles.

  4. Bioremediation of hydrocarbon-contaminated soils: are treatability and ecotoxicity endpoints related?

    International Nuclear Information System (INIS)

    Visser, S.

    1999-01-01

    To determine if there is a relationship between biotreatability and ecotoxicity endpoints in a wide range of hydrocarbon-contaminated soils, including medium and heavy crude oil-contaminated flare pit wastes and lubrication oil contaminated soil, research was conducted. Each test material was analyzed for pH, water repellency, electrical conductivity, available N and P, total extractable hydrocarbons, oil and grease, and toxicity to seedling emergence, root elongation in barley, lettuce and canola, earthworm survival and luminescent bacteria (Microtox), prior to, and following three months of bioremediation in the laboratory. By monitoring soil respiration, progress of the bioremediation process and determination of a treatment endpoint were assessed. The time required to attain a treatment endpoint under laboratory conditions can range from 30 days to 100 days depending on the concentration of hydrocarbons and degree of weathering. Most flare pits are biotreatable, averaging a loss of 25-30% of hydrocarbons during bioremediation. Once a treatment endpoint is achieved, residual hydrocarbons contents almost always exceeds Alberta Tier I criteria for mineral oil and grease. As a result of bioremediation treatments, hydrophobicity is often reduced from severe to low. Many flare pit materials are still moderately to extremely toxic after reaching a treatment endpoint. (Abstract only)

  5. Deep inelastic scattering near the endpoint in soft-collinear effective theory

    International Nuclear Information System (INIS)

    Chay, Junegone; Kim, Chul

    2007-01-01

    We apply the soft-collinear effective theory to deep inelastic scattering near the endpoint region. The forward scattering amplitude and the structure functions are shown to factorize as a convolution of the Wilson coefficients, the jet functions, and the parton distribution functions. The behavior of the parton distribution functions near the endpoint region is considered. It turns out that it evolves with the Altarelli-Parisi kernel even in the endpoint region, and the parton distribution function can be factorized further into a collinear part and the soft Wilson line. The factorized form for the structure functions is obtained by the two-step matching, and the radiative corrections or the evolution for each factorized part can be computed in perturbation theory. We present the radiative corrections of each factorized part to leading order in α s , including the zero-bin subtraction for the collinear part

  6. Endpoint-based parallel data processing with non-blocking collective instructions in a parallel active messaging interface of a parallel computer

    Science.gov (United States)

    Archer, Charles J; Blocksome, Michael A; Cernohous, Bob R; Ratterman, Joseph D; Smith, Brian E

    2014-11-11

    Endpoint-based parallel data processing with non-blocking collective instructions in a PAMI of a parallel computer is disclosed. The PAMI is composed of data communications endpoints, each including a specification of data communications parameters for a thread of execution on a compute node, including specifications of a client, a context, and a task. The compute nodes are coupled for data communications through the PAMI. The parallel application establishes a data communications geometry specifying a set of endpoints that are used in collective operations of the PAMI by associating with the geometry a list of collective algorithms valid for use with the endpoints of the geometry; registering in each endpoint in the geometry a dispatch callback function for a collective operation; and executing without blocking, through a single one of the endpoints in the geometry, an instruction for the collective operation.

  7. Rheumatoid factor testing in Spanish primary care: A population-based cohort study including 4.8 million subjects and almost half a million measurements.

    Science.gov (United States)

    Morsley, Klara; Miller, Anne; Luqmani, Raashid; Fina-Aviles, Francesc; Javaid, Muhammad Kassim; Edwards, Christopher J; Pinedo-Villanueva, Rafael; Medina, Manuel; Calero, Sebastian; Cooper, Cyrus; Arden, Nigel; Prieto-Alhambra, Daniel

    2018-02-26

    Rheumatoid factor (RF) testing is used in primary care in the diagnosis of rheumatoid arthritis (RA); however a positive RF may occur without RA. Incorrect use of RF testing may lead to increased costs and delayed diagnoses. The aim was to assess the performance of RF as a test for RA and to estimate the costs associated with its use in a primary care setting. A retrospective cohort study using the Information System for the Development of Research in Primary Care database (contains primary care records and laboratory results of >80% of the Catalonian population, Spain). Participants were patients ≥18 years with ≥1 RF test performed between 01/01/2006 and 31/12/2011, without a pre-existing diagnosis of RA. Outcome measures were an incident diagnosis of RA within 1 year of testing, and the cost of testing per case of RA. 495,434/4,796,498 (10.3%) patients were tested at least once. 107,362 (21.7%) of those tested were sero-positive of which 2768 (2.6%) were diagnosed with RA within 1 year as were 1141/388,072 (0.3%) sero-negative participants. The sensitivity of RF was 70.8% (95% CI 69.4-72.2), specificity 78.7% (78.6-78.8), and positive and negative predictive values 2.6% (2.5-2.7) and 99.7% (99.6-99.7) respectively. Approximately €3,963,472 was spent, with a cost of €1432 per true positive case. Although 10% of patients were tested for RF, most did not have RA. Limiting testing to patients with a higher pre-test probability would significantly reduce the cost of testing. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

  8. A systematic comparison of recurrent event models for application to composite endpoints.

    Science.gov (United States)

    Ozga, Ann-Kathrin; Kieser, Meinhard; Rauch, Geraldine

    2018-01-04

    Many clinical trials focus on the comparison of the treatment effect between two or more groups concerning a rarely occurring event. In this situation, showing a relevant effect with an acceptable power requires the observation of a large number of patients over a long period of time. For feasibility issues, it is therefore often considered to include several event types of interest, non-fatal or fatal, and to combine them within a composite endpoint. Commonly, a composite endpoint is analyzed with standard survival analysis techniques by assessing the time to the first occurring event. This approach neglects that an individual may experience more than one event which leads to a loss of information. As an alternative, composite endpoints could be analyzed by models for recurrent events. There exists a number of such models, e.g. regression models based on count data or Cox-based models such as the approaches of Andersen and Gill, Prentice, Williams and Peterson or, Wei, Lin and Weissfeld. Although some of the methods were already compared within the literature there exists no systematic investigation for the special requirements regarding composite endpoints. Within this work a simulation-based comparison of recurrent event models applied to composite endpoints is provided for different realistic clinical trial scenarios. We demonstrate that the Andersen-Gill model and the Prentice- Williams-Petersen models show similar results under various data scenarios whereas the Wei-Lin-Weissfeld model delivers effect estimators which can considerably deviate under commonly met data scenarios. Based on the conducted simulation study, this paper helps to understand the pros and cons of the investigated methods in the context of composite endpoints and provides therefore recommendations for an adequate statistical analysis strategy and a meaningful interpretation of results.

  9. Efficacy and prospects for cryopreserved thyroid gland transplantation as a method for treatment of different forms of primary hypothyroidism including postradiation

    International Nuclear Information System (INIS)

    Karachentsev, Yu.I.; Lyakh, I.A.; Khasiev, V.V.

    1999-01-01

    It was established that auto-and allo transplantation of cryopreserved thyroid is a physiologically well grounded technique of treatment and can be an alternative to substitution hormonotherapy of hypothyroidism and can be a main method of treatment in cases when hormone treatment is not effective or is contraindicated.Talking into account the efficiency of cryopreserved thyroid transplantation in patients with primary hypothyroidism,it is possible to predict its positive effect for c postradiation hypothyroidism treatment,if substitution hormonotherapy is not effective

  10. Immunofluorescence Microscopy and mRNA Analysis of Human Embryonic Stem Cells (hESCs) Including Primary Cilia Associated Signaling Pathways

    DEFF Research Database (Denmark)

    Vestergaard, Maj Linea; Awan, Aashir; Warzecha, Caroline Becker

    2016-01-01

    onto 16-well glass chambers, and continuing with the general IFM and qPCR anlysis. The techniques are illustrated with results on cellular localization of transcriptional factors and components of the Hedgehog, Wnt, PDGF, and TGFβ signaling pathways to primary cilia in stem cell maintenance......This chapter describes the procedures for immunofluorescence microscopy (IFM) and quantitative PCR (qPCR) analyses of human embryonic stem cells (hESCs) grown specifically under feeder-free conditions. A detailed protocol is provided outlining the steps from initially growing the cells, passaging...

  11. Deep vadose zone remediation: technical and policy challenges, opportunities, and progress in achieving cleanup endpoints

    International Nuclear Information System (INIS)

    Wellman, D.M.; Freshley, M.D.; Truex, M.J.; Lee, M.H.

    2013-01-01

    Current requirements for site remediation and closure are standards-based and are often overly conservative, costly, and in some cases, technically impractical. Use of risk-informed alternate endpoints provides a means to achieve remediation goals that are permitted by regulations and are protective of human health and the environment. Alternate endpoints enable the establishment of a path for cleanup that may include intermediate remedial milestones and transition points and/or regulatory alternatives to standards-based remediation. A framework is presented that is centered around developing and refining conceptual models in conjunction with assessing risks and potential endpoints as part of a system-based assessment that integrates site data with scientific understanding of processes that control the distribution and transport of contaminants in the subsurface and pathways to receptors. This system-based assessment and subsequent implementation of the remediation strategy with appropriate monitoring are targeted at providing a holistic approach to addressing risks to human health and the environment. This holistic approach also enables effective predictive analysis of contaminant behavior to provide defensible criteria and data for making long-term decisions. Developing and implementing an alternate endpoint-based approach for remediation and waste site closure presents a number of challenges and opportunities. Categories of these challenges include scientific and technical, regulatory, institutional, and budget and resource allocation issues. Opportunities exist for developing and implementing systems-based approaches with respect to supportive characterization, monitoring, predictive modeling, and remediation approaches. (authors)

  12. Alternate Endpoints for Deep Vadose Zone Environments: Challenges, Opportunities, and Progress - 13036

    International Nuclear Information System (INIS)

    Wellman, Dawn M.; Freshley, Mark D.; Truex, Michael J.; Lee, M. Hope

    2013-01-01

    Current requirements for site remediation and closure are standards-based and are often overly conservative, costly, and in some cases, technically impractical to achieve. Use of risk-informed alternate endpoints provide a means to achieve remediation goals that are permitted by regulations and are protective of human health and the environment. Alternate endpoints enable establishing a path for cleanup that may include intermediate remedial milestones and transition points and/or regulatory alternatives to standards-based remediation. A framework is presented that is centered around developing and refining conceptual models in conjunction with assessing risks and potential endpoints as part of a system-based assessment that integrates site data with scientific understanding of processes that control the distribution and transport of contaminants in the subsurface and pathways to receptors. This system-based assessment and subsequent implementation of the remediation strategy with appropriate monitoring are targeted at providing a holistic approach to addressing risks to human health and the environment. This holistic approach also enables effective predictive analysis of contaminant behavior to provide defensible criteria and data for making long-term decisions. Developing and implementing an alternate endpoint-based approach for remediation and waste site closure presents a number of challenges and opportunities. Categories of these challenges include scientific and technical, regulatory, institutional, and budget and resource allocation issues. Opportunities exist for developing and implementing systems-based approaches with respect to supportive characterization, monitoring, predictive modeling, and remediation approaches. (authors)

  13. Alternate Endpoints for Deep Vadose Zone Environments: Challenges, Opportunities, and Progress - 13036

    Energy Technology Data Exchange (ETDEWEB)

    Wellman, Dawn M.; Freshley, Mark D.; Truex, Michael J.; Lee, M. Hope [Pacific Northwest National Laboratory, 902 Battelle Blvd, Richland, WA, 99352 (United States)

    2013-07-01

    Current requirements for site remediation and closure are standards-based and are often overly conservative, costly, and in some cases, technically impractical to achieve. Use of risk-informed alternate endpoints provide a means to achieve remediation goals that are permitted by regulations and are protective of human health and the environment. Alternate endpoints enable establishing a path for cleanup that may include intermediate remedial milestones and transition points and/or regulatory alternatives to standards-based remediation. A framework is presented that is centered around developing and refining conceptual models in conjunction with assessing risks and potential endpoints as part of a system-based assessment that integrates site data with scientific understanding of processes that control the distribution and transport of contaminants in the subsurface and pathways to receptors. This system-based assessment and subsequent implementation of the remediation strategy with appropriate monitoring are targeted at providing a holistic approach to addressing risks to human health and the environment. This holistic approach also enables effective predictive analysis of contaminant behavior to provide defensible criteria and data for making long-term decisions. Developing and implementing an alternate endpoint-based approach for remediation and waste site closure presents a number of challenges and opportunities. Categories of these challenges include scientific and technical, regulatory, institutional, and budget and resource allocation issues. Opportunities exist for developing and implementing systems-based approaches with respect to supportive characterization, monitoring, predictive modeling, and remediation approaches. (authors)

  14. Deep vadose zone remediation: technical and policy challenges, opportunities, and progress in achieving cleanup endpoints

    Energy Technology Data Exchange (ETDEWEB)

    Wellman, D.M.; Freshley, M.D.; Truex, M.J.; Lee, M.H. [Pacific Northwest National Laboratory, Richland, Washington (United States)

    2013-07-01

    Current requirements for site remediation and closure are standards-based and are often overly conservative, costly, and in some cases, technically impractical. Use of risk-informed alternate endpoints provides a means to achieve remediation goals that are permitted by regulations and are protective of human health and the environment. Alternate endpoints enable the establishment of a path for cleanup that may include intermediate remedial milestones and transition points and/or regulatory alternatives to standards-based remediation. A framework is presented that is centered around developing and refining conceptual models in conjunction with assessing risks and potential endpoints as part of a system-based assessment that integrates site data with scientific understanding of processes that control the distribution and transport of contaminants in the subsurface and pathways to receptors. This system-based assessment and subsequent implementation of the remediation strategy with appropriate monitoring are targeted at providing a holistic approach to addressing risks to human health and the environment. This holistic approach also enables effective predictive analysis of contaminant behavior to provide defensible criteria and data for making long-term decisions. Developing and implementing an alternate endpoint-based approach for remediation and waste site closure presents a number of challenges and opportunities. Categories of these challenges include scientific and technical, regulatory, institutional, and budget and resource allocation issues. Opportunities exist for developing and implementing systems-based approaches with respect to supportive characterization, monitoring, predictive modeling, and remediation approaches. (authors)

  15. Traditional and new composite endpoints in heart failure clinical trials : facilitating comprehensive efficacy assessments and improving trial efficiency

    NARCIS (Netherlands)

    Anker, Stefan D. t; Schroeder, Stefan; Atar, Dan; Bax, Jeroen J.; Ceconi, Claudio; Cowie, Martin R.; AdamCrisp,; Dominjon, Fabienne; Ford, Ian; Ghofrani, Hossein-Ardeschir; Gropper, Savion; Hindricks, Gerhard; Hlatky, Mark A.; Holcomb, Richard; Honarpour, Narimon; Jukema, J. Wouter; Kim, Albert M.; Kunz, Michael; Lefkowitz, Martin; Le Floch, Chantal; Landmesser, Ulf; McDonagh, Theresa A.; McMurray, John J.; Merkely, Bela; Packer, Milton; Prasad, Krishna; Revkin, James; Rosano, Giuseppe M. C.; Somaratne, Ransi; Stough, Wendy Gattis; Voors, Adriaan A.; Ruschitzka, Frank

    Composite endpoints are commonly used as the primary measure of efficacy in heart failure clinical trials to assess the overall treatment effect and to increase the efficiency of trials. Clinical trials still must enrol large numbers of patients to accrue a sufficient number of outcome events and

  16. Tropism and Infectivity of Influenza Virus, Including Highly Pathogenic Avian H5N1 Virus, in Ferret Tracheal Differentiated Primary Epithelial Cell Cultures

    Science.gov (United States)

    Zeng, Hui; Goldsmith, Cynthia S.; Maines, Taronna R.; Belser, Jessica A.; Gustin, Kortney M.; Pekosz, Andrew; Zaki, Sherif R.; Katz, Jacqueline M.

    2013-01-01

    Tropism and adaptation of influenza viruses to new hosts is partly dependent on the distribution of the sialic acid (SA) receptors to which the viral hemagglutinin (HA) binds. Ferrets have been established as a valuable in vivo model of influenza virus pathogenesis and transmission because of similarities to humans in the distribution of HA receptors and in clinical signs of infection. In this study, we developed a ferret tracheal differentiated primary epithelial cell culture model that consisted of a layered epithelium structure with ciliated and nonciliated cells on its apical surface. We found that human-like (α2,6-linked) receptors predominated on ciliated cells, whereas avian-like (α2,3-linked) receptors, which were less abundant, were presented on nonciliated cells. When we compared the tropism and infectivity of three human (H1 and H3) and two avian (H1 and H5) influenza viruses, we observed that the human influenza viruses primarily infected ciliated cells and replicated efficiently, whereas a highly pathogenic avian H5N1 virus (A/Vietnam/1203/2004) replicated efficiently within nonciliated cells despite a low initial infection rate. Furthermore, compared to other influenza viruses tested, VN/1203 virus replicated more efficiently in cells isolated from the lower trachea and at a higher temperature (37°C) compared to a lower temperature (33°C). VN/1203 virus infection also induced higher levels of immune mediator genes and cell death, and virus was recovered from the basolateral side of the cell monolayer. This ferret tracheal differentiated primary epithelial cell culture system provides a valuable in vitro model for studying cellular tropism, infectivity, and the pathogenesis of influenza viruses. PMID:23255802

  17. Impact of confinement housing on study end-points in the calf model of cryptosporidiosis.

    Science.gov (United States)

    Graef, Geneva; Hurst, Natalie J; Kidder, Lance; Sy, Tracy L; Goodman, Laura B; Preston, Whitney D; Arnold, Samuel L M; Zambriski, Jennifer A

    2018-04-01

    Diarrhea is the second leading cause of death in children confinement housing, and Interval Collection (IC), which permits use of box stalls. CFC mimics human challenge model methodology but it is unknown if confinement housing impacts study end-points and if data gathered via this method is suitable for generalization to human populations. Using a modified crossover study design we compared CFC and IC and evaluated the impact of housing on study end-points. At birth, calves were randomly assigned to confinement (n = 14) or box stall housing (n = 9), or were challenged with 5 x 107 C. parvum oocysts, and followed for 10 days. Study end-points included fecal oocyst shedding, severity of diarrhea, degree of dehydration, and plasma cortisol. Calves in confinement had no significant differences in mean log oocysts enumerated per gram of fecal dry matter between CFC and IC samples (P = 0.6), nor were there diurnal variations in oocyst shedding (P = 0.1). Confinement housed calves shed significantly more oocysts (P = 0.05), had higher plasma cortisol (P = 0.001), and required more supportive care (P = 0.0009) than calves in box stalls. Housing method confounds study end-points in the calf model of cryptosporidiosis. Due to increased stress data collected from calves in confinement housing may not accurately estimate the efficacy of chemotherapeutics targeting C. parvum.

  18. In vitro systems: standardization of endpoints

    International Nuclear Information System (INIS)

    Dewey, W.C.

    1979-01-01

    Principles are discussed for utilizing cell culture systems to assay for interactions between drugs and radiation. Emphasis is based on the necessity of using synchronous cultures to determine whether the interaction is independent, additive, or synergistic, and to determine the effect of drugs on recovery from sublethal x-ray damage (SLD). Furthermore, in studies of drug effects on SLD, adequate controls must be included to distinguish between effects associated with the interaction of 2 x-ray doses and the effects associated with interaction of a second x-ray dose with prior drug exposure. Finally, different methods of expressing drug exposure are reviewed, and associated problems related to predicting in vivo effects from in vitro results are mentioned

  19. Guidelines for time-to-event end-point definitions in trials for pancreatic cancer. Results of the DATECAN initiative (Definition for the Assessment of Time-to-event End-points in CANcer trials).

    Science.gov (United States)

    Bonnetain, Franck; Bonsing, Bert; Conroy, Thierry; Dousseau, Adelaide; Glimelius, Bengt; Haustermans, Karin; Lacaine, François; Van Laethem, Jean Luc; Aparicio, Thomas; Aust, Daniela; Bassi, Claudio; Berger, Virginie; Chamorey, Emmanuel; Chibaudel, Benoist; Dahan, Laeticia; De Gramont, Aimery; Delpero, Jean Robert; Dervenis, Christos; Ducreux, Michel; Gal, Jocelyn; Gerber, Erich; Ghaneh, Paula; Hammel, Pascal; Hendlisz, Alain; Jooste, Valérie; Labianca, Roberto; Latouche, Aurelien; Lutz, Manfred; Macarulla, Teresa; Malka, David; Mauer, Muriel; Mitry, Emmanuel; Neoptolemos, John; Pessaux, Patrick; Sauvanet, Alain; Tabernero, Josep; Taieb, Julien; van Tienhoven, Geertjan; Gourgou-Bourgade, Sophie; Bellera, Carine; Mathoulin-Pélissier, Simone; Collette, Laurence

    2014-11-01

    Using potential surrogate end-points for overall survival (OS) such as Disease-Free- (DFS) or Progression-Free Survival (PFS) is increasingly common in randomised controlled trials (RCTs). However, end-points are too often imprecisely defined which largely contributes to a lack of homogeneity across trials, hampering comparison between them. The aim of the DATECAN (Definition for the Assessment of Time-to-event End-points in CANcer trials)-Pancreas project is to provide guidelines for standardised definition of time-to-event end-points in RCTs for pancreatic cancer. Time-to-event end-points currently used were identified from a literature review of pancreatic RCT trials (2006-2009). Academic research groups were contacted for participation in order to select clinicians and methodologists to participate in the pilot and scoring groups (>30 experts). A consensus was built after 2 rounds of the modified Delphi formal consensus approach with the Rand scoring methodology (range: 1-9). For pancreatic cancer, 14 time to event end-points and 25 distinct event types applied to two settings (detectable disease and/or no detectable disease) were considered relevant and included in the questionnaire sent to 52 selected experts. Thirty experts answered both scoring rounds. A total of 204 events distributed over the 14 end-points were scored. After the first round, consensus was reached for 25 items; after the second consensus was reached for 156 items; and after the face-to-face meeting for 203 items. The formal consensus approach reached the elaboration of guidelines for standardised definitions of time-to-event end-points allowing cross-comparison of RCTs in pancreatic cancer. Copyright © 2014 Elsevier Ltd. All rights reserved.

  20. Plasma TIMP-1 and CEA as markers for detection of primary colorectal cancer

    DEFF Research Database (Denmark)

    Christensen, Ib Jarle; Brünner, Nils; Dowell, Barry

    2015-01-01

    endoscopy were prospectively included (N=1965). Baseline data and co-morbidity were recorded. The primary end-point was the detection of CRC. Plasma was obtained before endoscopy and TIMP-1 and CEA levels were determined using an automated analysis platform when all samples were collected. RESULTS: CRC...

  1. Root length of aquatic plant, Lemna minor L., as an optimal toxicity endpoint for biomonitoring of mining effluents.

    Science.gov (United States)

    Gopalapillai, Yamini; Vigneault, Bernard; Hale, Beverley A

    2014-10-01

    Lemna minor, a free-floating macrophyte, is used for biomonitoring of mine effluent quality under the Metal Mining Effluent Regulations (MMER) of the Environmental Effects Monitoring (EEM) program in Canada and is known to be sensitive to trace metals commonly discharged in mine effluents such as Ni. Environment Canada's standard toxicity testing protocol recommends frond count (FC) and dry weight (DW) as the 2 required toxicity endpoints-this is similar to other major protocols such as those by the US Environmental Protection Agency (USEPA) and the Organisation for Economic Co-operation and Development (OECD)-that both require frond growth or biomass endpoints. However, we suggest that similar to terrestrial plants, average root length (RL) of aquatic plants will be an optimal and relevant endpoint. As expected, results demonstrate that RL is the ideal endpoint based on the 3 criteria: accuracy (i.e., toxicological sensitivity to contaminant), precision (i.e., lowest variance), and ecological relevance (metal mining effluents). Roots are known to play a major role in nutrient uptake in conditions of low nutrient conditions-thus having ecological relevance to freshwater from mining regions. Root length was the most sensitive and precise endpoint in this study where water chemistry varied greatly (pH and varying concentrations of Ca, Mg, Na, K, dissolved organic carbon, and an anthropogenic organic contaminant, sodium isopropyl xanthates) to match mining effluent ranges. Although frond count was a close second, dry weight proved to be an unreliable endpoint. We conclude that toxicity testing for the floating macrophyte should require average RL measurement as a primary endpoint. © 2014 SETAC.

  2. Population modelling to compare chronic external radiotoxicity between individual and population endpoints in four taxonomic groups.

    Science.gov (United States)

    Alonzo, Frédéric; Hertel-Aas, Turid; Real, Almudena; Lance, Emilie; Garcia-Sanchez, Laurent; Bradshaw, Clare; Vives I Batlle, Jordi; Oughton, Deborah H; Garnier-Laplace, Jacqueline

    2016-02-01

    In this study, we modelled population responses to chronic external gamma radiation in 12 laboratory species (including aquatic and soil invertebrates, fish and terrestrial mammals). Our aim was to compare radiosensitivity between individual and population endpoints and to examine how internationally proposed benchmarks for environmental radioprotection protected species against various risks at the population level. To do so, we used population matrix models, combining life history and chronic radiotoxicity data (derived from laboratory experiments and described in the literature and the FREDERICA database) to simulate changes in population endpoints (net reproductive rate R0, asymptotic population growth rate λ, equilibrium population size Neq) for a range of dose rates. Elasticity analyses of models showed that population responses differed depending on the affected individual endpoint (juvenile or adult survival, delay in maturity or reduction in fecundity), the considered population endpoint (R0, λ or Neq) and the life history of the studied species. Among population endpoints, net reproductive rate R0 showed the lowest EDR10 (effective dose rate inducing 10% effect) in all species, with values ranging from 26 μGy h(-1) in the mouse Mus musculus to 38,000 μGy h(-1) in the fish Oryzias latipes. For several species, EDR10 for population endpoints were lower than the lowest EDR10 for individual endpoints. Various population level risks, differing in severity for the population, were investigated. Population extinction (predicted when radiation effects caused population growth rate λ to decrease below 1, indicating that no population growth in the long term) was predicted for dose rates ranging from 2700 μGy h(-1) in fish to 12,000 μGy h(-1) in soil invertebrates. A milder risk, that population growth rate λ will be reduced by 10% of the reduction causing extinction, was predicted for dose rates ranging from 24 μGy h(-1) in mammals to 1800 μGy h(-1) in

  3. Eco-efficient production of spring barley in a changed climate: A Life Cycle Assessment including primary data from future climate scenarios

    DEFF Research Database (Denmark)

    Niero, Monia; Ingvordsen, Cathrine Heinz; Peltonen-Sainio, Pirjo

    2015-01-01

    The paper has two main objectives: (i) to assess the eco-efficiency of spring barley cultivation for malting in Denmark in a future changed climate (700 ppm [CO2] and +5 °C) through Life Cycle Assessment (LCA) and (ii) to compare alternative future cultivation scenarios, both excluding and includ......The paper has two main objectives: (i) to assess the eco-efficiency of spring barley cultivation for malting in Denmark in a future changed climate (700 ppm [CO2] and +5 °C) through Life Cycle Assessment (LCA) and (ii) to compare alternative future cultivation scenarios, both excluding...

  4. Population modelling to compare chronic external radiotoxicity between individual and population endpoints in four taxonomic groups

    International Nuclear Information System (INIS)

    Alonzo, Frédéric; Hertel-Aas, Turid; Real, Almudena; Lance, Emilie; Garcia-Sanchez, Laurent; Bradshaw, Clare; Vives i Batlle, Jordi; Oughton, Deborah H.; Garnier-Laplace, Jacqueline

    2016-01-01

    In this study, we modelled population responses to chronic external gamma radiation in 12 laboratory species (including aquatic and soil invertebrates, fish and terrestrial mammals). Our aim was to compare radiosensitivity between individual and population endpoints and to examine how internationally proposed benchmarks for environmental radioprotection protected species against various risks at the population level. To do so, we used population matrix models, combining life history and chronic radiotoxicity data (derived from laboratory experiments and described in the literature and the FREDERICA database) to simulate changes in population endpoints (net reproductive rate R_0, asymptotic population growth rate λ, equilibrium population size N_e_q) for a range of dose rates. Elasticity analyses of models showed that population responses differed depending on the affected individual endpoint (juvenile or adult survival, delay in maturity or reduction in fecundity), the considered population endpoint (R_0, λ or N_e_q) and the life history of the studied species. Among population endpoints, net reproductive rate R_0 showed the lowest EDR_1_0 (effective dose rate inducing 10% effect) in all species, with values ranging from 26 μGy h"−"1 in the mouse Mus musculus to 38,000 μGy h"−"1 in the fish Oryzias latipes. For several species, EDR_1_0 for population endpoints were lower than the lowest EDR_1_0 for individual endpoints. Various population level risks, differing in severity for the population, were investigated. Population extinction (predicted when radiation effects caused population growth rate λ to decrease below 1, indicating that no population growth in the long term) was predicted for dose rates ranging from 2700 μGy h"−"1 in fish to 12,000 μGy h"−"1 in soil invertebrates. A milder risk, that population growth rate λ will be reduced by 10% of the reduction causing extinction, was predicted for dose rates ranging from 24 μGy h"−"1

  5. Surrogate endpoints for overall survival in digestive oncology trials: which candidates? A questionnaires survey among clinicians and methodologists

    Directory of Open Access Journals (Sweden)

    Bonnetain Franck

    2010-06-01

    , were ranked first, with a frequency of more than 69% in 20 out of 22 settings. PFS was proposed in association with QoL in metastatic primary liver and stomach cancers (both 81%. This composite endpoint was ranked second in metastatic oesophageal (69%, colorectal (56% and anal (56% cancers, whereas QoL alone was also suggested in most metastatic situations. Other endpoints frequently suggested were R0 resection in the neoadjuvant settings (oesophagus (69%, stomach (56%, pancreas (75% and biliary tract (63% and response. An unexpected endpoint was metastatic PFS in non operable oesophageal (31% and pancreatic (44% cancers. Quality and results of surgical procedures like sphincter preservation were also cited as eligible surrogate endpoints in rectal (19% and anal (50% in case of localized disease cancers. Except for alpha-FP kinetic in hepatocellular carcinoma (13% and CA19-9 decline (6% in pancreas, few endpoints based on biological or tumour markers were proposed. Conclusion The overall results should help prioritise the endpoints to be statistically evaluated as surrogate for OS, so that trialists and clinicians can rely on endpoints that ensure relevant clinical benefit to the patient.

  6. Surrogate endpoints for overall survival in digestive oncology trials: which candidates? A questionnaires survey among clinicians and methodologists

    International Nuclear Information System (INIS)

    Methy, Nicolas; Bedenne, Laurent; Bonnetain, Franck

    2010-01-01

    69% in 20 out of 22 settings. PFS was proposed in association with QoL in metastatic primary liver and stomach cancers (both 81%). This composite endpoint was ranked second in metastatic oesophageal (69%), colorectal (56%) and anal (56%) cancers, whereas QoL alone was also suggested in most metastatic situations. Other endpoints frequently suggested were R0 resection in the neoadjuvant settings (oesophagus (69%), stomach (56%), pancreas (75%) and biliary tract (63%)) and response. An unexpected endpoint was metastatic PFS in non operable oesophageal (31%) and pancreatic (44%) cancers. Quality and results of surgical procedures like sphincter preservation were also cited as eligible surrogate endpoints in rectal (19%) and anal (50% in case of localized disease) cancers. Except for alpha-FP kinetic in hepatocellular carcinoma (13%) and CA19-9 decline (6%) in pancreas, few endpoints based on biological or tumour markers were proposed. The overall results should help prioritise the endpoints to be statistically evaluated as surrogate for OS, so that trialists and clinicians can rely on endpoints that ensure relevant clinical benefit to the patient

  7. Surrogate endpoints for overall survival in digestive oncology trials: which candidates? A questionnaires survey among clinicians and methodologists.

    Science.gov (United States)

    Methy, Nicolas; Bedenne, Laurent; Bonnetain, Franck

    2010-06-10

    % in 20 out of 22 settings. PFS was proposed in association with QoL in metastatic primary liver and stomach cancers (both 81%). This composite endpoint was ranked second in metastatic oesophageal (69%), colorectal (56%) and anal (56%) cancers, whereas QoL alone was also suggested in most metastatic situations.Other endpoints frequently suggested were R0 resection in the neoadjuvant settings (oesophagus (69%), stomach (56%), pancreas (75%) and biliary tract (63%)) and response. An unexpected endpoint was metastatic PFS in non operable oesophageal (31%) and pancreatic (44%) cancers. Quality and results of surgical procedures like sphincter preservation were also cited as eligible surrogate endpoints in rectal (19%) and anal (50% in case of localized disease) cancers. Except for alpha-FP kinetic in hepatocellular carcinoma (13%) and CA19-9 decline (6%) in pancreas, few endpoints based on biological or tumour markers were proposed. The overall results should help prioritise the endpoints to be statistically evaluated as surrogate for OS, so that trialists and clinicians can rely on endpoints that ensure relevant clinical benefit to the patient.

  8. The role of natural gas as a primary fuel in the near future, including comparisons of acquisition, transmission and waste handling costs of as with competitive alternatives

    Science.gov (United States)

    2012-01-01

    Natural gas comprises about a quarter of the United States’ energy use. It is more environmentally friendly than oil and coal due to lower carbon dioxide (CO2) emissions per unit, less costly per unit of energy and more readily available domestically in abundant supply. However, due to a number of barriers in the political, infrastructural, pricing and other arenas, the use of natural gas as a significant energy source in the United States has been limited. In our paper, we highlight the favorable qualities of natural gas and its benefits for the consumer, producer, and environment, having compared the costs of the various components of the natural gas business such as drilling and transport to that of coal and oil. Moreover, we touch upon the major issues that have prevented a more prevalent use of the gas, such as the fact that the infrastructure of natural gas is more costly since it is transported though pipelines whereas other energy sources such as oil and coal have flexible systems that use trains, trucks and ships. In addition, the powerful lobbies of the coal and oil businesses, along with the inertia in the congress to pass a national climate change bill further dampens incentives for these industries to invest in natural gas, despite its various attractive qualities. We also include discussions of policy proposals to incentive greater use of natural gas in the future. PMID:22540989

  9. Epigenetics targeted protein-vorinostat nanomedicine inducing apoptosis in heterogeneous population of primary acute myeloid leukemia cells including refractory and relapsed cases.

    Science.gov (United States)

    Chandran, Parwathy; Kavalakatt, Anu; Malarvizhi, Giridharan Loghanathan; Vasanthakumari, Divya Rani Vikraman Nair; Retnakumari, Archana Payickattu; Sidharthan, Neeraj; Pavithran, Keechilat; Nair, Shantikumar; Koyakutty, Manzoor

    2014-05-01

    Aberrant epigenetics play a key role in the onset and progression of acute myeloid leukemia (AML). Herein we report in silico modelling based development of a novel, protein-vorinostat nanomedicine exhibiting selective and superior anti-leukemic activity against heterogeneous population of AML patient samples (n=9), including refractory and relapsed cases, and three representative cell lines expressing CD34(+)/CD38(-) stem cell phenotype (KG-1a), promyelocytic phenotype (HL-60) and FLT3-ITD mutation (MV4-11). Nano-vorinostat having ~100nm size exhibited enhanced cellular uptake rendering significantly lower IC50 in AML cell lines and patient samples, and induced enhanced HDAC inhibition, oxidative injury, cell cycle arrest and apoptosis compared to free vorinostat. Most importantly, nanomedicine showed exceptional single-agent activity against the clonogenic proliferative capability of bone marrow derived leukemic progenitors, while remaining non-toxic to healthy bone marrow cells. Collectively, this epigenetics targeted nanomedicine appears to be a promising therapeutic strategy against various French-American-British (FAB) classes of AML. Through the use of a protein-vorinostat agent, exceptional single-agent activity was demonstrated against the clonogenic proliferative capability of bone marrow derived leukemic progenitors, while remaining non-toxic to healthy bone marrow cells. The studied epigenetics targeted nanomedicine approach is a promising therapeutic strategy against various French-American-British classes of acute myeloid leukemia. © 2014 Elsevier Inc. All rights reserved.

  10. Occurrence and impact of negative behaviour, including domestic violence and abuse, in men attending UK primary care health clinics: a cross-sectional survey.

    Science.gov (United States)

    Hester, M; Ferrari, G; Jones, S K; Williamson, E; Bacchus, L J; Peters, T J; Feder, G

    2015-05-19

    To measure the experience and perpetration of negative behaviour, including domestic violence and abuse (DVA), and investigate its associations with health conditions and behaviours in men attending general practice. Cross-sectional questionnaire-based study conducted between September 2010 and June 2011. 16 general practices in the south west of England. Male patients aged 18 or older, attending alone, who could read and write English. A total of 1403 of eligible patients (58%) participated in the survey and 1368 (56%) completed the questions relevant to this paper. 97% of respondents reported they were heterosexual. Lifetime occurrence of negative behaviour consistent with DVA, perceived health impact of negative behaviours, associations with anxiety and depression symptoms, and cannabis use in the past 12 months and binge drinking. 22.7% (95% CI 20.2% to 24.9%) of men reported ever experiencing negative behaviour (feeling frightened, physically hurt, forced sex, ask permission) from a partner. All negative behaviours were associated with a twofold to threefold increased odds of anxiety and depression symptoms in men experiencing or perpetrating negative behaviours or both. 34.9% (95% CI 28.7% to 41.7%) of men who reported experiencing negative behaviour from a partner, and 30.8% (95% CI 23.7% to 37.8%) of men who perpetrated negative behaviours said they had been in a domestically violent or abusive relationship. No associations with problematic drinking were found; there was a weak association with cannabis use. DVA is experienced or perpetrated by a large minority of men presenting to general practice, and these men were more likely to have current symptoms of depression and anxiety. Presentation of anxiety or depression to clinicians may be an indicator of male experience or perpetration of DVA victimisation. 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.

  11. Occurrence and impact of negative behaviour, including domestic violence and abuse, in men attending UK primary care health clinics: a cross-sectional survey

    Science.gov (United States)

    Hester, M; Ferrari, G; Jones, S K; Williamson, E; Bacchus, L J; Peters, T J; Feder, G

    2015-01-01

    Objective To measure the experience and perpetration of negative behaviour, including domestic violence and abuse (DVA), and investigate its associations with health conditions and behaviours in men attending general practice. Design Cross-sectional questionnaire-based study conducted between September 2010 and June 2011. Setting 16 general practices in the south west of England. Participants Male patients aged 18 or older, attending alone, who could read and write English. A total of 1403 of eligible patients (58%) participated in the survey and 1368 (56%) completed the questions relevant to this paper. 97% of respondents reported they were heterosexual. Main outcome measures Lifetime occurrence of negative behaviour consistent with DVA, perceived health impact of negative behaviours, associations with anxiety and depression symptoms, and cannabis use in the past 12 months and binge drinking. Results 22.7% (95% CI 20.2% to 24.9%) of men reported ever experiencing negative behaviour (feeling frightened, physically hurt, forced sex, ask permission) from a partner. All negative behaviours were associated with a twofold to threefold increased odds of anxiety and depression symptoms in men experiencing or perpetrating negative behaviours or both. 34.9% (95% CI 28.7% to 41.7%) of men who reported experiencing negative behaviour from a partner, and 30.8% (95% CI 23.7% to 37.8%) of men who perpetrated negative behaviours said they had been in a domestically violent or abusive relationship. No associations with problematic drinking were found; there was a weak association with cannabis use. Conclusions DVA is experienced or perpetrated by a large minority of men presenting to general practice, and these men were more likely to have current symptoms of depression and anxiety. Presentation of anxiety or depression to clinicians may be an indicator of male experience or perpetration of DVA victimisation. PMID:25991450

  12. Clinical endpoint adjudication in a contemporary all-comers coronary stent investigation: methodology and external validation.

    Science.gov (United States)

    Vranckx, Pascal; McFadden, Eugene; Cutlip, Donald E; Mehran, Roxana; Swart, Michael; Kint, P P; Zijlstra, Felix; Silber, Sigmund; Windecker, Stephan; Serruys, Patrick W C J

    2013-01-01

    Globalisation in coronary stent research calls for harmonization of clinical endpoint definitions and event adjudication. Little has been published about the various processes used for event adjudication or their impact on outcome reporting. We performed a validation of the clinical event committee (CEC) adjudication process on 100 suspected events in the RESOLUTE All-comers trial (Resolute-AC). Two experienced Clinical Research Organisations (CRO) that had already extensive internal validation processes in place, participated in the study. After initial adjudication by the primary-CEC, events were cross-adjudicated by an external-CEC using the same definitions. Major discrepancies affecting the primary end point of target-lesion failure (TLF), a composite of cardiac death, target vessel myocardial infarction (TV-MI), or clinically-indicated target-lesion revascularization (CI-TLR), were analysed by an independent oversight committee who provided recommendations for harmonization. Discordant adjudications were reconsidered by the primary CEC. Subsequently, the RAC database was interrogated for cases that based on these recommendations merited re-adjudication and these cases were also re-adjudicated by the primary CEC. Final discrepancies in adjudication of individual components of TLF occurred in 7 out of 100 events in 5 patients. Discrepancies for the (hierarchical) primary endpoint occurred in 5 events (2 cardiac deaths and 3 TV-MI). After application of harmonization recommendations to the overall RAC population (n=2292), the primary CEC adjudicated 3 additional clinical-TLRs and considered 1 TV-MI as no event. A harmonization process provided a high level of concordance for event adjudication and improved accuracy for final event reporting. These findings suggest it is feasible to pool clinical event outcome data across clinical trials even when different CECs are responsible for event adjudication. Copyright © 2012 Elsevier Inc. All rights reserved.

  13. The Asthma Control Questionnaire as a clinical trial endpoint

    DEFF Research Database (Denmark)

    Barnes, P J; Casale, T B; Dahl, Ronald

    2014-01-01

    these component endpoints; however, there is no consensus on the optimal instrument for use in clinical trials. The Asthma Control Questionnaire (ACQ) has been shown to be a valid, reliable instrument that allows accurate and reproducible assessment of asthma control that compares favourably with other commonly...

  14. An evaluation of culture results during treatment for tuberculosis as surrogate endpoints for treatment failure and relapse.

    Directory of Open Access Journals (Sweden)

    Patrick P J Phillips

    Full Text Available It is widely acknowledged that new regimens are urgently needed for the treatment of tuberculosis. The primary endpoint in the Phase III trials is a composite outcome of failure at the end of treatment or relapse after stopping treatment. Such trials are usually both long and expensive. Valid surrogate endpoints measured during or at the end of treatment could dramatically reduce both the time and cost of assessing the effectiveness of new regimens. The objective of this study was to evaluate sputum culture results on solid media during treatment as surrogate endpoints for poor outcome. Data were obtained from twelve randomised controlled trials conducted by the British Medical Research Council in the 1970s and 80s in East Africa and East Asia, consisting of 6974 participants and 49 different treatment regimens. The month two culture result was shown to be a poor surrogate in East Africa but a good surrogate in Hong Kong. In contrast, the month three culture was a good surrogate in trials conducted in East Africa but not in Hong Kong. As well as differences in location, ethnicity and probable strain of Mycobacteria tuberculosis, Hong Kong trials more often evaluated regimens with rifampicin throughout and intermittent regimens, and patients in East African trials more often presented with extensive cavitation and were slower to convert to culture negative during treatment. An endpoint that is a summary measure of the longitudinal profile of culture results over time or that is able to detect the presence of M. tuberculosis later in treatment is more likely to be a better endpoint for a phase II trial than a culture result at a single time point and may prove to be an acceptable surrogate. More data are needed before any endpoint can be used as a surrogate in a confirmatory phase III trial.

  15. Identification and content validation of wound therapy clinical endpoints relevant to clinical practice and patient values for FDA approval. Part 1. Survey of the wound care community.

    Science.gov (United States)

    Driver, Vickie R; Gould, Lisa J; Dotson, Peggy; Gibbons, Gary W; Li, William W; Ennis, William J; Kirsner, Robert S; Eaglstein, William H; Bolton, Laura L; Carter, Marissa J

    2017-05-01

    Wounds that exhibit delayed healing add extraordinary clinical, economic, and personal burdens to patients, as well as to increasing financial costs to health systems. New interventions designed to ease such burdens for patients with cancer, renal, or ophthalmologic conditions are often cleared for approval by the U.S. Food and Drug Administration (FDA) using multiple endpoints but the requirement of complete healing as a primary endpoint for wound products impedes FDA clearance of interventions that can provide other clinical or patient-centered benefits for persons with wounds. A multidisciplinary group of wound experts undertook an initiative, in collaboration with the FDA, to identify and content validate supporting FDA criteria for qualifying wound endpoints relevant to clinical practice (CP) and patient-centered outcomes (PCO) as primary outcomes in clinical trials. As part of the initiative, a research study was conducted involving 628 multidisciplinary expert wound clinicians and researchers from 4 different groups: the interdisciplinary core advisory team; attendees of the Spring 2015 Symposium on Advanced Wound Care (SAWC); clinicians employed by a national network of specialty clinics focused on comprehensive wound care; and Association for the Advancement of Wound Care (AAWC) and Wound Healing Society (WHS) members who had not previously completed the survey. The online survey assessed 28 literature-based wound care endpoints for their relevance and importance to clinical practice and clinical research. Fifteen of the endpoints were evaluated for their relevance to improving quality of life. Twenty-two endpoints had content validity indexes (CVI) ≥ 0.75, and 15 were selected as meriting potential inclusion as additional endpoints for FDA approval of future wound care interventions. This study represents an important first step in identifying and validating new measurable wound care endpoints for clinical research and practice and for regulatory

  16. Sperm count as a surrogate endpoint for male fertility control.

    Science.gov (United States)

    Benda, Norbert; Gerlinger, Christoph

    2007-11-30

    When assessing the effectiveness of a hormonal method of fertility control in men, the classical approach used for the assessment of hormonal contraceptives in women, by estimating the pregnancy rate or using a life-table analysis for the time to pregnancy, is difficult to apply in a clinical development program. The main reasons are the dissociation of the treated unit, i.e. the man, and the observed unit, i.e. his female partner, the high variability in the frequency of male intercourse, the logistical cost and ethical concerns related to the monitoring of the trial. A reasonable surrogate endpoint of the definite endpoint time to pregnancy is sperm count. In addition to the avoidance of the mentioned problems, trials that compare different treatments are possible with reasonable sample sizes, and study duration can be shorter. However, current products do not suppress sperm production to 100 per cent in all men and the sperm count is only observed with measurement error. Complete azoospermia might not be necessary in order to achieve an acceptable failure rate compared with other forms of male fertility control. Therefore, the use of sperm count as a surrogate endpoint must rely on the results of a previous trial in which both the definitive- and surrogate-endpoint results were assessed. The paper discusses different estimation functions of the mean pregnancy rate (corresponding to the cumulative hazard) that are based on the results of sperm count trial and a previous trial in which both sperm count and time to pregnancy were assessed, as well as the underlying assumptions. Sample size estimations are given for pregnancy rate estimation with a given precision.

  17. Gene expression profiling reveals multiple toxicity endpoints induced by hepatotoxicants

    Energy Technology Data Exchange (ETDEWEB)

    Huang Qihong; Jin Xidong; Gaillard, Elias T.; Knight, Brian L.; Pack, Franklin D.; Stoltz, James H.; Jayadev, Supriya; Blanchard, Kerry T

    2004-05-18

    Microarray technology continues to gain increased acceptance in the drug development process, particularly at the stage of toxicology and safety assessment. In the current study, microarrays were used to investigate gene expression changes associated with hepatotoxicity, the most commonly reported clinical liability with pharmaceutical agents. Acetaminophen, methotrexate, methapyrilene, furan and phenytoin were used as benchmark compounds capable of inducing specific but different types of hepatotoxicity. The goal of the work was to define gene expression profiles capable of distinguishing the different subtypes of hepatotoxicity. Sprague-Dawley rats were orally dosed with acetaminophen (single dose, 4500 mg/kg for 6, 24 and 72 h), methotrexate (1 mg/kg per day for 1, 7 and 14 days), methapyrilene (100 mg/kg per day for 3 and 7 days), furan (40 mg/kg per day for 1, 3, 7 and 14 days) or phenytoin (300 mg/kg per day for 14 days). Hepatic gene expression was assessed using toxicology-specific gene arrays containing 684 target genes or expressed sequence tags (ESTs). Principal component analysis (PCA) of gene expression data was able to provide a clear distinction of each compound, suggesting that gene expression data can be used to discern different hepatotoxic agents and toxicity endpoints. Gene expression data were applied to the multiplicity-adjusted permutation test and significantly changed genes were categorized and correlated to hepatotoxic endpoints. Repression of enzymes involved in lipid oxidation (acyl-CoA dehydrogenase, medium chain, enoyl CoA hydratase, very long-chain acyl-CoA synthetase) were associated with microvesicular lipidosis. Likewise, subsets of genes associated with hepatotocellular necrosis, inflammation, hepatitis, bile duct hyperplasia and fibrosis have been identified. The current study illustrates that expression profiling can be used to: (1) distinguish different hepatotoxic endpoints; (2) predict the development of toxic endpoints; and

  18. Exposing the cancer genome atlas as a SPARQL endpoint

    Science.gov (United States)

    Deus, Helena F.; Veiga, Diogo F.; Freire, Pablo R.; Weinstein, John N.; Mills, Gordon B.; Almeida, Jonas S.

    2011-01-01

    The Cancer Genome Atlas (TCGA) is a multidisciplinary, multi-institutional effort to characterize several types of cancer. Datasets from biomedical domains such as TCGA present a particularly challenging task for those interested in dynamically aggregating its results because the data sources are typically both heterogeneous and distributed. The Linked Data best practices offer a solution to integrate and discover data with those characteristics, namely through exposure of data as Web services supporting SPARQL, the Resource Description Framework query language. Most SPARQL endpoints, however, cannot easily be queried by data experts. Furthermore, exposing experimental data as SPARQL endpoints remains a challenging task because, in most cases, data must first be converted to Resource Description Framework triples. In line with those requirements, we have developed an infrastructure to expose clinical, demographic and molecular data elements generated by TCGA as a SPARQL endpoint by assigning elements to entities of the Simple Sloppy Semantic Database (S3DB) management model. All components of the infrastructure are available as independent Representational State Transfer (REST) Web services to encourage reusability, and a simple interface was developed to automatically assemble SPARQL queries by navigating a representation of the TCGA domain. A key feature of the proposed solution that greatly facilitates assembly of SPARQL queries is the distinction between the TCGA domain descriptors and data elements. Furthermore, the use of the S3DB management model as a mediator enables queries to both public and protected data without the need for prior submission to a single data source. PMID:20851208

  19. Congenital Adrenal Hyperplasia: Classification of Studies Employing Psychological Endpoints

    Directory of Open Access Journals (Sweden)

    Sandberg DavidE

    2010-08-01

    Full Text Available Psychological outcomes in persons with congenital adrenal hyperplasia (CAH have received substantial attention. The objectives of this paper were to (1 catalog psychological endpoints assessed in CAH outcome studies and (2 classify the conceptual/theoretical model shaping the research design and interpretation of CAH-related psychological effects. A total of 98 original research studies, published between 1955 and 2009, were categorized based on psychological endpoints examined as well as the research design and conceptual model guiding analysis and interpretation of data. The majority of studies (68% investigated endpoints related to psychosexual differentiation. The preponderance of studies (76% examined a direct relationship (i.e., inferring causality between prenatal androgen exposure and psychological outcomes. Findings are discussed in relation to the observed imbalance between theoretical interest in the role of prenatal androgens in shaping psychosexual differentiation and a broader conceptual model that examines the role of other potential factors in mediating or moderating the influence of CAH pathophysiology on psychological outcomes in both affected females and males. The latter approach offers to identify factors amenable to clinical intervention that enhance both health and quality of life outcomes in CAH as well as other disorders of sex development.

  20. Dependence of QSAR models on the selection of trial descriptor sets: a demonstration using nanotoxicity endpoints of decorated nanotubes.

    Science.gov (United States)

    Shao, Chi-Yu; Chen, Sing-Zuo; Su, Bo-Han; Tseng, Yufeng J; Esposito, Emilio Xavier; Hopfinger, Anton J

    2013-01-28

    Little attention has been given to the selection of trial descriptor sets when designing a QSAR analysis even though a great number of descriptor classes, and often a greater number of descriptors within a given class, are now available. This paper reports an effort to explore interrelationships between QSAR models and descriptor sets. Zhou and co-workers (Zhou et al., Nano Lett. 2008, 8 (3), 859-865) designed, synthesized, and tested a combinatorial library of 80 surface modified, that is decorated, multi-walled carbon nanotubes for their composite nanotoxicity using six endpoints all based on a common 0 to 100 activity scale. Each of the six endpoints for the 29 most nanotoxic decorated nanotubes were incorporated as the training set for this study. The study reported here includes trial descriptor sets for all possible combinations of MOE, VolSurf, and 4D-fingerprints (FP) descriptor classes, as well as including and excluding explicit spatial contributions from the nanotube. Optimized QSAR models were constructed from these multiple trial descriptor sets. It was found that (a) both the form and quality of the best QSAR models for each of the endpoints are distinct and (b) some endpoints are quite dependent upon 4D-FP descriptors of the entire nanotube-decorator complex. However, other endpoints yielded equally good models only using decorator descriptors with and without the decorator-only 4D-FP descriptors. Lastly, and most importantly, the quality, significance, and interpretation of a QSAR model were found to be critically dependent on the trial descriptor sets used within a given QSAR endpoint study.

  1. Exposing the cancer genome atlas as a SPARQL endpoint.

    Science.gov (United States)

    Deus, Helena F; Veiga, Diogo F; Freire, Pablo R; Weinstein, John N; Mills, Gordon B; Almeida, Jonas S

    2010-12-01

    The Cancer Genome Atlas (TCGA) is a multidisciplinary, multi-institutional effort to characterize several types of cancer. Datasets from biomedical domains such as TCGA present a particularly challenging task for those interested in dynamically aggregating its results because the data sources are typically both heterogeneous and distributed. The Linked Data best practices offer a solution to integrate and discover data with those characteristics, namely through exposure of data as Web services supporting SPARQL, the Resource Description Framework query language. Most SPARQL endpoints, however, cannot easily be queried by data experts. Furthermore, exposing experimental data as SPARQL endpoints remains a challenging task because, in most cases, data must first be converted to Resource Description Framework triples. In line with those requirements, we have developed an infrastructure to expose clinical, demographic and molecular data elements generated by TCGA as a SPARQL endpoint by assigning elements to entities of the Simple Sloppy Semantic Database (S3DB) management model. All components of the infrastructure are available as independent Representational State Transfer (REST) Web services to encourage reusability, and a simple interface was developed to automatically assemble SPARQL queries by navigating a representation of the TCGA domain. A key feature of the proposed solution that greatly facilitates assembly of SPARQL queries is the distinction between the TCGA domain descriptors and data elements. Furthermore, the use of the S3DB management model as a mediator enables queries to both public and protected data without the need for prior submission to a single data source. Copyright © 2010 Elsevier Inc. All rights reserved.

  2. BOP2: Bayesian optimal design for phase II clinical trials with simple and complex endpoints.

    Science.gov (United States)

    Zhou, Heng; Lee, J Jack; Yuan, Ying

    2017-09-20

    We propose a flexible Bayesian optimal phase II (BOP2) design that is capable of handling simple (e.g., binary) and complicated (e.g., ordinal, nested, and co-primary) endpoints under a unified framework. We use a Dirichlet-multinomial model to accommodate different types of endpoints. At each interim, the go/no-go decision is made by evaluating a set of posterior probabilities of the events of interest, which is optimized to maximize power or minimize the number of patients under the null hypothesis. Unlike other existing Bayesian designs, the BOP2 design explicitly controls the type I error rate, thereby bridging the gap between Bayesian designs and frequentist designs. In addition, the stopping boundary of the BOP2 design can be enumerated prior to the onset of the trial. These features make the BOP2 design accessible to a wide range of users and regulatory agencies and particularly easy to implement in practice. Simulation studies show that the BOP2 design has favorable operating characteristics with higher power and lower risk of incorrectly terminating the trial than some existing Bayesian phase II designs. The software to implement the BOP2 design is freely available at www.trialdesign.org. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

  3. Two-temperature LATE-PCR endpoint genotyping

    Directory of Open Access Journals (Sweden)

    Reis Arthur H

    2006-12-01

    Full Text Available Abstract Background In conventional PCR, total amplicon yield becomes independent of starting template number as amplification reaches plateau and varies significantly among replicate reactions. This paper describes a strategy for reconfiguring PCR so that the signal intensity of a single fluorescent detection probe after PCR thermal cycling reflects genomic composition. The resulting method corrects for product yield variations among replicate amplification reactions, permits resolution of homozygous and heterozygous genotypes based on endpoint fluorescence signal intensities, and readily identifies imbalanced allele ratios equivalent to those arising from gene/chromosomal duplications. Furthermore, the use of only a single colored probe for genotyping enhances the multiplex detection capacity of the assay. Results Two-Temperature LATE-PCR endpoint genotyping combines Linear-After-The-Exponential (LATE-PCR (an advanced form of asymmetric PCR that efficiently generates single-stranded DNA and mismatch-tolerant probes capable of detecting allele-specific targets at high temperature and total single-stranded amplicons at a lower temperature in the same reaction. The method is demonstrated here for genotyping single-nucleotide alleles of the human HEXA gene responsible for Tay-Sachs disease and for genotyping SNP alleles near the human p53 tumor suppressor gene. In each case, the final probe signals were normalized against total single-stranded DNA generated in the same reaction. Normalization reduces the coefficient of variation among replicates from 17.22% to as little as 2.78% and permits endpoint genotyping with >99.7% accuracy. These assays are robust because they are consistent over a wide range of input DNA concentrations and give the same results regardless of how many cycles of linear amplification have elapsed. The method is also sufficiently powerful to distinguish between samples with a 1:1 ratio of two alleles from samples comprised of

  4. Verification of models for ballistic movement time and endpoint variability.

    Science.gov (United States)

    Lin, Ray F; Drury, Colin G

    2013-01-01

    A hand control movement is composed of several ballistic movements. The time required in performing a ballistic movement and its endpoint variability are two important properties in developing movement models. The purpose of this study was to test potential models for predicting these two properties. Twelve participants conducted ballistic movements of specific amplitudes using a drawing tablet. The measured data of movement time and endpoint variability were then used to verify the models. This study was successful with Hoffmann and Gan's movement time model (Hoffmann, 1981; Gan and Hoffmann 1988) predicting more than 90.7% data variance for 84 individual measurements. A new theoretically developed ballistic movement variability model, proved to be better than Howarth, Beggs, and Bowden's (1971) model, predicting on average 84.8% of stopping-variable error and 88.3% of aiming-variable errors. These two validated models will help build solid theoretical movement models and evaluate input devices. This article provides better models for predicting end accuracy and movement time of ballistic movements that are desirable in rapid aiming tasks, such as keying in numbers on a smart phone. The models allow better design of aiming tasks, for example button sizes on mobile phones for different user populations.

  5. Time-dependent efficacy of longitudinal biomarker for clinical endpoint.

    Science.gov (United States)

    Kolamunnage-Dona, Ruwanthi; Williamson, Paula R

    2018-06-01

    Joint modelling of longitudinal biomarker and event-time processes has gained its popularity in recent years as they yield more accurate and precise estimates. Considering this modelling framework, a new methodology for evaluating the time-dependent efficacy of a longitudinal biomarker for clinical endpoint is proposed in this article. In particular, the proposed model assesses how well longitudinally repeated measurements of a biomarker over various time periods (0,t) distinguish between individuals who developed the disease by time t and individuals who remain disease-free beyond time t. The receiver operating characteristic curve is used to provide the corresponding efficacy summaries at various t based on the association between longitudinal biomarker trajectory and risk of clinical endpoint prior to each time point. The model also allows detecting the time period over which a biomarker should be monitored for its best discriminatory value. The proposed approach is evaluated through simulation and illustrated on the motivating dataset from a prospective observational study of biomarkers to diagnose the onset of sepsis.

  6. Cortical plasticity as a new endpoint measurement for chronic pain

    Directory of Open Access Journals (Sweden)

    Zhuo Min

    2011-07-01

    Full Text Available Abstract Animal models of chronic pain are widely used to investigate basic mechanisms of chronic pain and to evaluate potential novel drugs for treating chronic pain. Among the different criteria used to measure chronic pain, behavioral responses are commonly used as the end point measurements. However, not all chronic pain conditions can be easily measured by behavioral responses such as the headache, phantom pain and pain related to spinal cord injury. Here I propose that cortical indexes, that indicate neuronal plastic changes in pain-related cortical areas, can be used as endpoint measurements for chronic pain. Such cortical indexes are not only useful for those chronic pain conditions where a suitable animal model is lacking, but also serve as additional screening methods for potential drugs to treat chronic pain in humans. These cortical indexes are activity-dependent immediate early genes, electrophysiological identified plastic changes and biochemical assays of signaling proteins. It can be used to evaluate novel analgesic compounds that may act at peripheral or spinal sites. I hope that these new cortical endpoint measurements will facilitate our search for new, and more effective, pain medicines, and help to reduce false lead drug targets.

  7. A yeast screening system for simultaneously monitoring multiple genetic endpoints

    International Nuclear Information System (INIS)

    Dixon, M.L.; Mortimer, R.K.

    1986-01-01

    Mutation, recombination, and mitochondrial deficiencies have been proposed to have roles in the carcinogenic process. The authors describe a diploid strain of the yeast Saccharomyces cerevisiae capable of detecting this wide spectrum of genetic changes. The markers used for monitoring these events have been especially well characterized genetically. Ultraviolet light was chosen as a model carcinogenic agent to test this system. In addition to highly significant increases in the frequencies of each genetic change, increases in the absolute numbers of each change indicated induction and not selective survival. The relative amounts of each type of genetic change varied with dose. The wide spectrum of endpoints monitored in the XD83 yeast system may allow the detection of certain carcinogens and other genetically toxic agents which have escaped detection in more limited systems. Since only one strain is required to simultaneously monitor these genetic changes, this assay system should facilitate comparisons of the induced changes and be more efficient than using multiple strains to monitor the same endpoints. (Auth.)

  8. Parametric Study of Beta-Endpoint Energy in Direct Energy Converters

    Science.gov (United States)

    2007-01-01

    value to the endpoint energy of nickel-63 ( Ni63 ), whose endpoint energy is 66 keV. Only an approximation is sought. Nickel-63 is an easily...is known to vary from Sr90’s spectrum, where instead of peaking at approximately one third of the endpoint energy, the peak of Ni63 ’s output spectrum

  9. The Oral HIV/AIDS Research Alliance: updated case definitions of oral disease endpoints.

    Science.gov (United States)

    Shiboski, C H; Patton, L L; Webster-Cyriaque, J Y; Greenspan, D; Traboulsi, R S; Ghannoum, M; Jurevic, R; Phelan, J A; Reznik, D; Greenspan, J S

    2009-07-01

    The Oral HIV/AIDS Research Alliance (OHARA) is part of the AIDS Clinical Trials Group (ACTG), the largest HIV clinical trials organization in the world. Its main objective is to investigate oral complications associated with HIV/AIDS as the epidemic is evolving, in particular, the effects of antiretrovirals on oral mucosal lesion development and associated fungal and viral pathogens. The OHARA infrastructure comprises: the Epidemiologic Research Unit (at the University of California San Francisco), the Medical Mycology Unit (at Case Western Reserve University) and the Virology/Specimen Banking Unit (at the University of North Carolina). The team includes dentists, physicians, virologists, mycologists, immunologists, epidemiologists and statisticians. Observational studies and clinical trials are being implemented at ACTG-affiliated sites in the US and resource-poor countries. Many studies have shared end-points, which include oral diseases known to be associated with HIV/AIDS measured by trained and calibrated ACTG study nurses. In preparation for future protocols, we have updated existing diagnostic criteria of the oral manifestations of HIV published in 1992 and 1993. The proposed case definitions are designed to be used in large-scale epidemiologic studies and clinical trials, in both US and resource-poor settings, where diagnoses may be made by non-dental healthcare providers. The objective of this article is to present updated case definitions for HIV-related oral diseases that will be used to measure standardized clinical end-points in OHARA studies, and that can be used by any investigator outside of OHARA/ACTG conducting clinical research that pertains to these end-points.

  10. Use of endpoint adjudication to improve the quality and validity of endpoint assessment for medical device development and post marketing evaluation: Rationale and best practices. A report from the cardiac safety research consortium.

    Science.gov (United States)

    Seltzer, Jonathan H; Heise, Ted; Carson, Peter; Canos, Daniel; Hiatt, Jo Carol; Vranckx, Pascal; Christen, Thomas; Cutlip, Donald E

    2017-08-01

    This white paper provides a summary of presentations, discussions and conclusions of a Thinktank entitled "The Role of Endpoint Adjudication in Medical Device Clinical Trials". The think tank was cosponsored by the Cardiac Safety Research Committee, MDEpiNet and the US Food and Drug Administration (FDA) and was convened at the FDA's White Oak headquarters on March 11, 2016. Attention was focused on tailoring best practices for evaluation of endpoints in medical device clinical trials, practical issues in endpoint adjudication of therapeutic, diagnostic, biomarker and drug-device combinations, and the role of adjudication in regulatory and reimbursement issues throughout the device lifecycle. Attendees included representatives from medical device companies, the FDA, Centers for Medicare and Medicaid Services (CMS), end point adjudication specialist groups, clinical research organizations, and active, academically based adjudicators. The manuscript presents recommendations from the think tank regarding (1) rationale for when adjudication is appropriate, (2) best practices establishment and operation of a medical device adjudication committee and (3) the role of endpoint adjudication for post market evaluation in the emerging era of real world evidence. Copyright © 2017. Published by Elsevier Inc.

  11. An European inter-laboratory validation of alternative endpoints of the murine local lymph node assay

    International Nuclear Information System (INIS)

    Ehling, G.; Hecht, M.; Heusener, A.; Huesler, J.; Gamer, A.O.; Loveren, H. van; Maurer, Th.; Riecke, K.; Ullmann, L.; Ulrich, P.; Vandebriel, R.; Vohr, H.-W.

    2005-01-01

    The original local lymph node assay (LLNA) is based on the use of radioactive labelling to measure cell proliferation. Other endpoints for the assessment of proliferation are also authorized by the OECD Guideline 429 provided there is appropriate scientific support, including full citations and description of the methodology (OECD, 2002. OECD Guideline for the Testing of Chemicals; Skin Sensitization: Local Lymph Node Assay, Guideline 429. Paris, adopted 24th April 2002.). Here, we describe the outcome of the second round of an inter-laboratory validation of alternative endpoints in the LLNA conducted in nine laboratories in Europe. The validation study was managed and supervised by the Swiss Agency for Therapeutic Products (Swissmedic) in Bern. Ear-draining lymph node (LN) weight and cell counts were used to assess LN cell proliferation instead of [3H]TdR incorporation. In addition, the acute inflammatory skin reaction was measured by ear weight determination of circular biopsies of the ears to identify skin irritation properties of the test items. The statistical analysis was performed in the department of statistics at the university of Bern. Similar to the EC 3 values defined for the radioactive method, threshold values were calculated for the endpoints measured in this modification of the LLNA. It was concluded that all parameters measured have to be taken into consideration for the categorisation of compounds due to their sensitising potencies. Therefore, an assessment scheme has been developed which turned out to be of great importance to consistently assess sensitisation versus irritancy based on the data of the different parameters. In contrast to the radioactive method, irritants have been picked up by all the laboratories applying this assessment scheme

  12. Is automated kinetic measurement superior to end-point for advanced oxidation protein product?

    Science.gov (United States)

    Oguz, Osman; Inal, Berrin Bercik; Emre, Turker; Ozcan, Oguzhan; Altunoglu, Esma; Oguz, Gokce; Topkaya, Cigdem; Guvenen, Guvenc

    2014-01-01

    Advanced oxidation protein product (AOPP) was first described as an oxidative protein marker in chronic uremic patients and measured with a semi-automatic end-point method. Subsequently, the kinetic method was introduced for AOPP assay. We aimed to compare these two methods by adapting them to a chemistry analyzer and to investigate the correlation between AOPP and fibrinogen, the key molecule responsible for human plasma AOPP reactivity, microalbumin, and HbA1c in patients with type II diabetes mellitus (DM II). The effects of EDTA and citrate-anticogulated tubes on these two methods were incorporated into the study. This study included 93 DM II patients (36 women, 57 men) with HbA1c levels > or = 7%, who were admitted to the diabetes and nephrology clinics. The samples were collected in EDTA and in citrate-anticoagulated tubes. Both methods were adapted to a chemistry analyzer and the samples were studied in parallel. In both types of samples, we found a moderate correlation between the kinetic and the endpoint methods (r = 0.611 for citrate-anticoagulated, r = 0.636 for EDTA-anticoagulated, p = 0.0001 for both). We found a moderate correlation between fibrinogen-AOPP and microalbumin-AOPP levels only in the kinetic method (r = 0.644 and 0.520 for citrate-anticoagulated; r = 0.581 and 0.490 for EDTA-anticoagulated, p = 0.0001). We conclude that adaptation of the end-point method to automation is more difficult and it has higher between-run CV% while application of the kinetic method is easier and it may be used in oxidative stress studies.

  13. Low dose response analysis through a cytogenetic end-point

    International Nuclear Information System (INIS)

    Bojtor, I.; Koeteles, G.J.

    1998-01-01

    The effects of low doses were studied on human lymphocytes of various individuals. The frequency of micronuclei in cytokinesis-blocked cultured lymphocytes was taken as end-point. The probability distribution of radiation-induced increment was statistically proved and identified as to be asymmetric when the blood samples had been irradiated with doses of 0.01-0.05 Gy of X-rays, similarly to that in unirradiated control population. On the contrary, at or above 1 Gy the corresponding normal curve could be accepted only reflecting an approximately symmetrical scatter of the increments about their mean value. It was found that the slope as well as the closeness of correlation of the variables considerably changed when lower and lower dose ranges had been selected. Below approximately 0.2 Gy even an unrelatedness was found betwen the absorbed dose and the increment

  14. Hausdorff dimension of exponential parameter rays and their endpoints

    International Nuclear Information System (INIS)

    Bailesteanu, Mihai; Balan, Horia Vlad; Schleicher, Dierk

    2008-01-01

    We investigate the set I of parameters κ for which the singular value of z map e z + κ converges to ∞. The set I consists of uncountably many parameter rays, plus landing points of some of these rays (Förster et al 2008 Proc Am. Math. Soc. 136 at press (Preprint math.DS/0311427)). We show that the parameter rays have Hausdorff dimension 1, which implies (Qiu 1994 Acta Math. Sin. (N.S.) 10 362–8) that the ray endpoints in I alone have dimension 2. Analogous results were known for dynamical planes of exponential maps (Karpińska 1999 C. R. Acad. Sci. Paris Sér. I: Math. 328 1039–44; Schleicher and Zimmer 2003 J. Lond. Math. Soc. 67 380–400); our result shows that this also holds in parameter space

  15. Biomarkers of intermediate endpoints in environmental and occupational health

    DEFF Research Database (Denmark)

    Knudsen, Lisbeth E; Hansen, Ase M

    2007-01-01

    The use of biomarkers in environmental and occupational health is increasing due to increasing demands on information about health risks from unfavourable exposures. Biomarkers provide information about individual loads. Biomarkers of intermediate endpoints benefit in comparison with biomarkers...... of exposure from the fact that they are closer to the adverse outcome in the pathway from exposure to health effects and may provide powerful information for intervention. Some biomarkers are specific, e.g., DNA and protein adducts, while others are unspecific like the cytogenetic biomarkers of chromosomal...... health effect from the result of the measurement has been performed for the cytogenetic biomarkers showing a predictive value of high levels of CA and increased risk of cancer. The use of CA in future studies is, however, limited by the laborious and sensitive procedure of the test and lack of trained...

  16. Designing quantitative structure activity relationships to predict specific toxic endpoints for polybrominated diphenyl ethers in mammalian cells.

    Science.gov (United States)

    Rawat, S; Bruce, E D

    2014-01-01

    Polybrominated diphenyl ethers (PBDEs) are known as effective flame retardants and have vast industrial application in products like plastics, building materials and textiles. They are found to be structurally similar to thyroid hormones that are responsible for regulating metabolism in the body. Structural similarity with the hormones poses a threat to human health because, once in the system, PBDEs have the potential to affect thyroid hormone transport and metabolism. This study was aimed at designing quantitative structure-activity relationship (QSAR) models for predicting toxic endpoints, namely cell viability and apoptosis, elicited by PBDEs in mammalian cells. Cell viability was evaluated quantitatively using a general cytotoxicity bioassay using Janus Green dye and apoptosis was evaluated using a caspase assay. This study has thus modelled the overall cytotoxic influence of PBDEs at an early and a late endpoint by the Genetic Function Approximation method. This research was a twofold process including running in vitro bioassays to collect data on the toxic endpoints and modeling the evaluated endpoints using QSARs. Cell viability and apoptosis responses for Hep G2 cells exposed to PBDEs were successfully modelled with an r(2) of 0.97 and 0.94, respectively.

  17. Endpoint design for future renal denervation trials - Novel implications for a new definition of treatment response to renal denervation.

    Science.gov (United States)

    Lambert, Thomas; Nahler, Alexander; Rohla, Miklos; Reiter, Christian; Grund, Michael; Kammler, Jürgen; Blessberger, Hermann; Kypta, Alexander; Kellermair, Jörg; Schwarz, Stefan; Starnawski, Jennifer A; Lichtenauer, Michael; Weiss, Thomas W; Huber, Kurt; Steinwender, Clemens

    2016-10-01

    Defining an adequate endpoint for renal denervation trials represents a major challenge. A high inter-individual and intra-individual variability of blood pressure levels as well as a partial or total non-adherence on antihypertensive drugs hamper treatment evaluations after renal denervation. Blood pressure measurements at a single point in time as used as primary endpoint in most clinical trials on renal denervation, might not be sufficient to discriminate between patients who do or do not respond to renal denervation. We compared the traditional responder classification (defined as systolic 24-hour blood pressure reduction of -5mmHg six months after renal denervation) with a novel definition of an ideal respondership (based on a 24h blood pressure reduction at no point in time, one, or all follow-up timepoints). We were able to re-classify almost a quarter of patients. Blood pressure variability was substantial in patients traditionally defined as responders. On the other hand, our novel classification of an ideal respondership seems to be clinically superior in discriminating sustained from pseudo-response to renal denervation. Based on our observations, we recommend that the traditional response classification should be reconsidered and possibly strengthened by using a composite endpoint of 24h-BP reductions at different follow-up-visits. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  18. Comparison of earthworm responses to petroleum hydrocarbon exposure in aged field contaminated soil using traditional ecotoxicity endpoints and 1H NMR-based metabolomics

    International Nuclear Information System (INIS)

    Whitfield Åslund, Melissa; Stephenson, Gladys L.; Simpson, André J.; Simpson, Myrna J.

    2013-01-01

    1 H NMR metabolomics and conventional ecotoxicity endpoints were used to examine the response of earthworms exposed to petroleum hydrocarbons (PHCs) in soil samples collected from a site that was contaminated with crude oil from a pipeline failure in the mid-1990s. The conventional ecotoxicity tests showed that the soils were not acutely toxic to earthworms (average survival ≥90%), but some soil samples impaired reproduction endpoints by >50% compared to the field control soil. Additionally, metabolomics revealed significant relationships between earthworm metabolic profiles (collected after 2 or 14 days of exposure) and soil properties including soil PHC concentration. Further comparisons by partial least squares regression revealed a significant relationship between the earthworm metabolomic data (collected after only 2 or 14 days) and the reproduction endpoints (measured after 63 days). Therefore, metabolomic responses measured after short exposure periods may be predictive of chronic, ecologically relevant toxicity endpoints for earthworms exposed to soil contaminants. -- Highlights: •Earthworm response to petroleum hydrocarbon exposure in soil is examined. •Metabolomics shows significant changes to metabolic profile after 2 days. •Significant relationships observed between metabolomic and reproduction endpoints. •Metabolomics may have value as a rapid screening tool for chronic toxicity. -- Earthworm metabolomic responses measured after 2 and 14 days are compared to traditional earthworm ecotoxicity endpoints (survival and reproduction) in petroleum hydrocarbon contaminated soil

  19. Comparing and combining biomarkers as principle surrogates for time-to-event clinical endpoints.

    Science.gov (United States)

    Gabriel, Erin E; Sachs, Michael C; Gilbert, Peter B

    2015-02-10

    Principal surrogate endpoints are useful as targets for phase I and II trials. In many recent trials, multiple post-randomization biomarkers are measured. However, few statistical methods exist for comparison of or combination of biomarkers as principal surrogates, and none of these methods to our knowledge utilize time-to-event clinical endpoint information. We propose a Weibull model extension of the semi-parametric estimated maximum likelihood method that allows for the inclusion of multiple biomarkers in the same risk model as multivariate candidate principal surrogates. We propose several methods for comparing candidate principal surrogates and evaluating multivariate principal surrogates. These include the time-dependent and surrogate-dependent true and false positive fraction, the time-dependent and the integrated standardized total gain, and the cumulative distribution function of the risk difference. We illustrate the operating characteristics of our proposed methods in simulations and outline how these statistics can be used to evaluate and compare candidate principal surrogates. We use these methods to investigate candidate surrogates in the Diabetes Control and Complications Trial. Copyright © 2014 John Wiley & Sons, Ltd.

  20. Mesoscale simulation of semiflexible chains. I. Endpoint distribution and chain dynamics

    Science.gov (United States)

    Groot, Robert D.

    2013-06-01

    The endpoint distribution and dynamics of semiflexible fibers are studied by numerical simulation. A brief overview is given over the analytical theory of flexible and semiflexible polymers. In particular, a closed expression is given for the relaxation spectrum of wormlike chains, which determines polymer diffusion and rheology. Next a simulation model for wormlike chains with full hydrodynamic interaction is described, and relations for the bending and torsion modulus are given. Two methods are introduced to include torsion stiffness into the model. The model is validated by simulating single chains in a heat bath, and comparing the endpoint distribution of the chains with established Monte Carlo results. It is concluded that torsion stiffness leads to a slightly shorter effective persistence length for a given bending stiffness. To further validate the simulation model, polymer diffusion is studied for fixed persistence length and varying polymer length N. The diffusion constant shows crossover from Rouse (D ∝ N-1) to reptation behaviour (D ∝ N-2). The terminal relaxation time obtained from the monomer displacement is consistent with the theory of wormlike chains. The probability for chain crossing has also been studied. This probability is so low that it does not influence the present results.

  1. SpEnD: Linked Data SPARQL Endpoints Discovery Using Search Engines

    Science.gov (United States)

    Yumusak, Semih; Dogdu, Erdogan; Kodaz, Halife; Kamilaris, Andreas; Vandenbussche, Pierre-Yves

    In this study, a novel metacrawling method is proposed for discovering and monitoring linked data sources on the Web. We implemented the method in a prototype system, named SPARQL Endpoints Discovery (SpEnD). SpEnD starts with a "search keyword" discovery process for finding relevant keywords for the linked data domain and specifically SPARQL endpoints. Then, these search keywords are utilized to find linked data sources via popular search engines (Google, Bing, Yahoo, Yandex). By using this method, most of the currently listed SPARQL endpoints in existing endpoint repositories, as well as a significant number of new SPARQL endpoints, have been discovered. Finally, we have developed a new SPARQL endpoint crawler (SpEC) for crawling and link analysis.

  2. Relative Biological Effectiveness of HZE Particles for Chromosomal Exchanges and Other Surrogate Cancer Risk Endpoints.

    Directory of Open Access Journals (Sweden)

    Eliedonna Cacao

    Full Text Available The biological effects of high charge and energy (HZE particle exposures are of interest in space radiation protection of astronauts and cosmonauts, and estimating secondary cancer risks for patients undergoing Hadron therapy for primary cancers. The large number of particles types and energies that makeup primary or secondary radiation in HZE particle exposures precludes tumor induction studies in animal models for all but a few particle types and energies, thus leading to the use of surrogate endpoints to investigate the details of the radiation quality dependence of relative biological effectiveness (RBE factors. In this report we make detailed RBE predictions of the charge number and energy dependence of RBE's using a parametric track structure model to represent experimental results for the low dose response for chromosomal exchanges in normal human lymphocyte and fibroblast cells with comparison to published data for neoplastic transformation and gene mutation. RBE's are evaluated against acute doses of γ-rays for doses near 1 Gy. Models that assume linear or non-targeted effects at low dose are considered. Modest values of RBE (10 are predicted at low doses <0.1 Gy. The radiation quality dependence of RBE's against the effects of acute doses γ-rays found for neoplastic transformation and gene mutation studies are similar to those found for simple exchanges if a linear response is assumed at low HZE particle doses. Comparisons of the resulting model parameters to those used in the NASA radiation quality factor function are discussed.

  3. 21 CFR 314.510 - Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival...

    Science.gov (United States)

    2010-04-01

    ... Serious or Life-Threatening Illnesses § 314.510 Approval based on a surrogate endpoint or on an effect on... well-controlled. The applicant shall carry out any such studies with due diligence. ...

  4. Prediction of Tungsten CMP Pad Life Using Blanket Removal Rate Data and Endpoint Data Obtained from Process Temperature and Carrier Motor Current Measurments

    International Nuclear Information System (INIS)

    Hetherington, Dale L.; Stein, David J.

    1999-01-01

    Several techniques to predict pad failure during tungsten CMP were investigated for a specific consumable set. These techniques include blanket polish rate measurements and metrics derived from two endpoint detection schemes. Blanket polish rate decreased significantly near pad failure. Metrics from the thermal endpoint technique included change in peak temperature, change in the time to reach peak temperature, and the change in the slope of the temperature trace just prior to peak temperature all as a function of pad life. Average carrier motor current before endpoint was also investigated. Changes in these metrics were observed however these changes, excluding time to peak process temperature, were either not consistent between pads or too noisy to be reliable predictors of pad failure

  5. Primary explosives

    Energy Technology Data Exchange (ETDEWEB)

    Matyas, Robert; Pachman, Jiri [Pardubice Univ. (Czech Republic). Faculty of Chemical Technology

    2013-06-01

    The first chapter provides background such as the basics of initiation and differences between requirements on primary explosives used in detonators and igniters. The authors then clarify the influence of physical characteristics on explosive properties, focusing on those properties required for primary explosives. Furthermore, the issue of sensitivity is discussed. All the chapters on particular groups of primary explosives are structured in the same way, including introduction, physical and chemical properties, explosive properties, preparation and documented use.

  6. Is Doubling of Serum Creatinine a Valid Clinical 'Hard' Endpoint in Clinical Nephrology Trials?

    NARCIS (Netherlands)

    Lambers Heerspink, H. J.; Perkovic, V.; de Zeeuw, D.

    2011-01-01

    The composite of end stage renal disease (ESRD), doubling of serum creatinine and (renal) death, is a frequently used endpoint in randomized clinical trials in nephrology. Doubling of serum creatinine is a well-accepted part of this endpoint because a doubling of serum creatinine reflects a large

  7. Right-handed currents at B→ K l+l− kinematic endpoint

    Indian Academy of Sciences (India)

    2017-10-09

    Oct 9, 2017 ... The recent LHCb measured values of these observables are used to conclude an evidence of right-handed currents at the kinematic endpoint of this decay mode. As the conclusion is drawn at the maximum dilepton invariant mass square ( q 2 ) kinematic endpoint, it relies only on heavy quark symmetries ...

  8. Restoration for the future: Setting endpoints and targets and selecting indicators of progress and success

    Science.gov (United States)

    Daniel C. Dey; Callie Jo Schweitzer; John M. Kabrick

    2014-01-01

    Setting endpoints and targets in forest restoration is a complicated task that is best accomplished in cooperative partnerships that account for the ecology of the system, production of desired ecosystem goods and services, economics and well-being of society, and future environments. Clearly written and quantitative endpoints and intermediary targets need to be...

  9. Restoration for the future: endpoints, targets, and indicators of progress and success

    Science.gov (United States)

    Daniel C. Dey; Callie Jo. Schweitzer

    2014-01-01

    Setting endpoints and targets in forest restoration is a complicated task that is best accomplished in cooperative partnerships that account for the ecology of the system, production of desired ecosystem goods and services, economics and well-being of society, and future environments. Clearly described and quantitative endpoints and intermediary targets are needed to...

  10. OPERA models for predicting physicochemical properties and environmental fate endpoints.

    Science.gov (United States)

    Mansouri, Kamel; Grulke, Chris M; Judson, Richard S; Williams, Antony J

    2018-03-08

    The collection of chemical structure information and associated experimental data for quantitative structure-activity/property relationship (QSAR/QSPR) modeling is facilitated by an increasing number of public databases containing large amounts of useful data. However, the performance of QSAR models highly depends on the quality of the data and modeling methodology used. This study aims to develop robust QSAR/QSPR models for chemical properties of environmental interest that can be used for regulatory purposes. This study primarily uses data from the publicly available PHYSPROP database consisting of a set of 13 common physicochemical and environmental fate properties. These datasets have undergone extensive curation using an automated workflow to select only high-quality data, and the chemical structures were standardized prior to calculation of the molecular descriptors. The modeling procedure was developed based on the five Organization for Economic Cooperation and Development (OECD) principles for QSAR models. A weighted k-nearest neighbor approach was adopted using a minimum number of required descriptors calculated using PaDEL, an open-source software. The genetic algorithms selected only the most pertinent and mechanistically interpretable descriptors (2-15, with an average of 11 descriptors). The sizes of the modeled datasets varied from 150 chemicals for biodegradability half-life to 14,050 chemicals for logP, with an average of 3222 chemicals across all endpoints. The optimal models were built on randomly selected training sets (75%) and validated using fivefold cross-validation (CV) and test sets (25%). The CV Q 2 of the models varied from 0.72 to 0.95, with an average of 0.86 and an R 2 test value from 0.71 to 0.96, with an average of 0.82. Modeling and performance details are described in QSAR model reporting format and were validated by the European Commission's Joint Research Center to be OECD compliant. All models are freely available as an open

  11. Defining the end-point of mastication: A conceptual model.

    Science.gov (United States)

    Gray-Stuart, Eli M; Jones, Jim R; Bronlund, John E

    2017-10-01

    properties define the end-point texture and enduring sensory perception of the food. © 2017 Wiley Periodicals, Inc.

  12. Endpoints and cutpoints in head and neck oncology trials: methodical background, challenges, current practice and perspectives.

    Science.gov (United States)

    Hezel, Marcus; von Usslar, Kathrin; Kurzweg, Thiemo; Lörincz, Balazs B; Knecht, Rainald

    2016-04-01

    This article reviews the methodical and statistical basics of designing a trial, with a special focus on the process of defining and choosing endpoints and cutpoints as the foundations of clinical research, and ultimately that of evidence-based medicine. There has been a significant progress in the treatment of head and neck cancer in the past few decades. Currently available treatment options can have a variety of different goals, depending e.g. on tumor stage, among other factors. The outcome of a specific treatment in clinical trials is measured using endpoints. Besides classical endpoints, such as overall survival or organ preservation, other endpoints like quality of life are becoming increasingly important in designing and conducting a trial. The present work is based on electronic research and focuses on the solid methodical and statistical basics of a clinical trial, on the structure of study designs and on the presentation of various endpoints.

  13. Assessment of sublethal endpoints after chronic exposure of the nematode Caenorhabditis elegans to palladium, platinum and rhodium.

    Science.gov (United States)

    Schertzinger, Gerhard; Zimmermann, Sonja; Grabner, Daniel; Sures, Bernd

    2017-11-01

    The aim of this study was to investigate chronic effects of the platinum-group elements (PGE) palladium (Pd), platinum (Pt) and rhodium (Rh) on the nematode Caenorhabditis elegans. Aquatic toxicity testing was carried out according to ISO 10872 by determining 96 h EC 50 values for sublethal endpoints, including growth, fertility and reproduction. Single PGE standard solutions were used as metal source. Based on the EC 50 values for Pt, reproduction (96 h EC 50  = 497 μg/L) was the most sensitive endpoint followed by fertility (96 h EC 50  = 726 μg/L) and growth (96 h EC 50  = 808 μg/L). For Pd, no precise EC 50 values could be calculated due to bell-shaped concentration response curves, but the 96 h EC 50 for reproduction ranged between 10 and 100 μg/L. Pd and Pt had effects on all endpoints. With raising element concentrations reproduction was inhibited first. At a certain concentration, fertility was also affected, which in turn had an additional effect on reproduction. Growth inhibition can also lead to a loss of fertility if the worms do not reach an appropriate body size to become fertile. Rhodium showed no inhibition of any endpoint between concentrations of 100 to 10,000 μg Rh/L. The results of this study allow the following order of PGE with respect to decreasing toxicity to C. elegans: Pd > Pt » Rh. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. Studies on potassium chlorate as a primary oxidimetric reagent.

    Science.gov (United States)

    Murty, C R; Rao, G G

    1972-01-01

    Conditions have been established for the use of potassium chlorate as a primary oxidizing agent in the direct titration of vanadium(III), tin(II) and titanium(III) with visual or potentiometric end-points.

  15. Biological and chemical tests of contaminated soils to determine bioavailability and environmentally acceptable endpoints (EAE)

    International Nuclear Information System (INIS)

    Montgomery, C.R.; Menzie, C.A.; Pauwells, S.J.

    1995-01-01

    The understanding of the concept of bioavailability of soil contaminants to receptors and its use in supporting the development of EAE is growing but still incomplete. Nonetheless, there is increased awareness of the importance of such data to determine acceptable cleanup levels and achieve timely site closures. This presentation discusses a framework for biological and chemical testing of contaminated soils developed as part of a Gas Research Institute (GRI) project entitled ''Environmentally Acceptable Endpoints in Soil Using a Risk Based Approach to Contaminated Site Management Based on Bioavailability of Chemicals in Soil.'' The presentation reviews the GRI program, and summarizes the findings of the biological and chemical testing section published in the GRI report. The three primary components of the presentation are: (1) defining the concept of bioavailability within the existing risk assessment paradigm, (2) assessing the usefulness of the existing tests to measure bioavailability and test frameworks used to interpret these measurements, and (3) suggesting how a small selection of relevant tests could be incorporated into a flexible testing scheme for soils to address this issue

  16. Comparison of different application systems and CT- assisted treatment planning procedures in primary endometrium cancer: Is it technically possible to include the whole uterus volume in the volume treated by brachytherapy

    International Nuclear Information System (INIS)

    Mock, U.; Knocke, Th.; Fellner, C.; Poetter, R.

    1996-01-01

    Purpose: Brachytherapy is regarded as the definitive component of treatment for inoperable patients with endometrium cancer. In published series the whole uterus has been claimed to represent the target volume independently of the individual tumor spread. The purpose of this work is to compare different planning and application procedures and to analyze the target volumes (whole uterus), treatment volumes and their respective relation for the given various conditions. Material and Methods: In ten patients with primary endometrium cancer the correlation between target- and treatment volume was analysed based on standard one-channel applicators or individual Heyman applicators. A comparative analysis of target volumes resulting from two different planning procedures of Heyman applications was performed. CT was carried out after insertion of the Heyman ovoids. Target volume was estimated by measuring the uterus size at different cross sections of the CT images. Dose calculation was performed with (PLATO-system) or without (NPS-system) transferring these data directly to the planning system. We report on the differences in treatment volumes resulting from the two application and planning systems. Results: The mean value of the uterus volume was 180 ccm (range 57 ccm to 316 ccm). Four out of 10 patients had an asymmetric uterus configuration with a side-difference (in longitudinal or transversal direction) of more than 1 cm. On average 70% (range 48-95%) of the uterus volume was included by the treatment volume when Heymann applicators were used compared to 45 % (range 25-89%) when standard one channel applicators were used. This represents an improvement of 25% (range from 11%-35%). By utilizing the more sophisticated way of treatment planning a more adequate coverage of the uterus volume was achieved in five out of ten patients. The treated volume increased on the average by 20 % (range 11 %-32%). In three cases changes in the irradiation volume were less than 5%. In

  17. Primary Myelofibrosis

    Science.gov (United States)

    ... attack is higher. Patients also have an increased risk of acute myeloid leukemia or primary myelofibrosis . Symptoms of polycythemia vera include headaches and a feeling of fullness below the ribs on the left ...

  18. Pollutant threshold concentration determination in marine ecosystems using an ecological interaction endpoint

    International Nuclear Information System (INIS)

    Wang, Changyou; Liang, Shengkang; Guo, Wenting; Yu, Hua; Xing, Wenhui

    2015-01-01

    The threshold concentrations of pollutants are determined by extrapolating single-species effect data to community-level effects. This assumes the most sensitive endpoint of the life cycle of individuals and the species sensitivity distribution from single-species toxic effect tests, thus, ignoring the ecological interactions. The uncertainties due to this extrapolation can be partially overcome using the equilibrium point of a customized ecosystem. This method incorporates ecological interactions and integrates the effects on growth, survival, and ingestion into a single effect measure, the equilibrium point excursion in the customized ecosystem, in order to describe the toxic effects on plankton. A case study showed that the threshold concentration of copper calculated with the endpoint of the equilibrium point was 10 μg L −1 , which is significantly different from the threshold calculated with a single-species endpoint. The endpoint calculated using this method provides a more relevant measure of the ecological impact than any single individual-level endpoint. - Highlights: • Ecotoxicological effect of exposure to copper was tested on a customized ecosystem. • Equilibrium point of biomasses in the customized ecosystem was used as an endpoint. • Exposure–response relationship in a community level was built on equilibrium point. • A threshold concentration incorporating ecological interactions was derived. - The equilibrium biomass incorporating ecological interactions in a customized ecosystem was used as an endpoint to calculate the threshold concentration at a community level

  19. A step towards standardization: A method for end-point titer determination by fluorescence index of an automated microscope. End-point titer determination by fluorescence index.

    Science.gov (United States)

    Carbone, Teresa; Gilio, Michele; Padula, Maria Carmela; Tramontano, Giuseppina; D'Angelo, Salvatore; Pafundi, Vito

    2018-05-01

    Indirect Immunofluorescence (IIF) is widely considered the Gold Standard for Antinuclear Antibody (ANA) screening. However, the high inter-reader variability remains the major disadvantage associated with ANA testing and the main reason for the increasing demand of the computer-aided immunofluorescence microscope. Previous studies proposed the quantification of the fluorescence intensity as an alternative for the classical end-point titer evaluation. However, the different distribution of bright/dark light linked to the nature of the self-antigen and its location in the cells result in different mean fluorescence intensities. The aim of the present study was to correlate Fluorescence Index (F.I.) with end-point titers for each well-defined ANA pattern. Routine serum samples were screened for ANA testing on HEp-2000 cells using Immuno Concepts Image Navigator System, and positive samples were serially diluted to assign the end-point titer. A comparison between F.I. and end-point titers related to 10 different staining patterns was made. According to our analysis, good technical performance of F.I. (97% sensitivity and 94% specificity) was found. A significant correlation between quantitative reading of F.I. and end-point titer groups was observed using Spearman's test and regression analysis. A conversion scale of F.I. in end-point titers for each recognized ANA-pattern was obtained. The Image Navigator offers the opportunity to improve worldwide harmonization of ANA test results. In particular, digital F.I. allows quantifying ANA titers by using just one sample dilution. It could represent a valuable support for the routine laboratory and an effective tool to reduce inter- and intra-laboratory variability. Copyright © 2018. Published by Elsevier B.V.

  20. Ovarian cancer clinical trial endpoints: Society of Gynecologic Oncology white paper

    Science.gov (United States)

    Herzog, Thomas J.; Armstrong, Deborah K.; Brady, Mark F.; Coleman, Robert L.; Einstein, Mark H.; Monk, Bradley J.; Mannel, Robert S.; Thigpen, J. Tate; Umpierre, Sharee A.; Villella, Jeannine A.; Alvarez, Ronald D.

    2015-01-01

    Objective To explore the value of multiple clinical endpoints in the unique setting of ovarian cancer. Methods A clinical trial workgroup was established by the Society of Gynecologic Oncology to develop a consensus statement via multiple conference calls, meetings and white paper drafts. Results Clinical trial endpoints have profound effects on late phase clinical trial design, result interpretation, drug development, and regulatory approval of therapeutics. Selection of the optimal clinical trial endpoint is particularly provocative in ovarian cancer where long overall survival (OS) is observed. The lack of new regulatory approvals and the lack of harmony between regulatory bodies globally for ovarian cancer therapeutics are of concern. The advantages and disadvantages of the numerous endpoints available are herein discussed within the unique context of ovarian cancer where both crossover and post-progression therapies potentially uncouple surrogacy between progression-free survival (PFS) and OS, the two most widely supported and utilized endpoints. The roles of patient reported outcomes (PRO) and health related quality of life (HRQoL) are discussed, but even these widely supported parameters are affected by the unique characteristics of ovarian cancer where a significant percentage of patients may be asymptomatic. Original data regarding the endpoint preferences of ovarian cancer advocates is presented. Conclusions Endpoint selection in ovarian cancer clinical trials should reflect the impact on disease burden and unique characteristics of the treatment cohort while reflecting true patient benefit. Both OS and PFS have led to regulatory approvals and are clinically important. OS remains the most objective and accepted endpoint because it is least vulnerable to bias; however, the feasibility of OS in ovarian cancer is compromised by the requirement for large trial size, prolonged time-line for final analysis, and potential for unintended loss of treatment effect

  1. Ovarian cancer clinical trial endpoints: Society of Gynecologic Oncology white paper.

    Science.gov (United States)

    Herzog, Thomas J; Armstrong, Deborah K; Brady, Mark F; Coleman, Robert L; Einstein, Mark H; Monk, Bradley J; Mannel, Robert S; Thigpen, J Tate; Umpierre, Sharee A; Villella, Jeannine A; Alvarez, Ronald D

    2014-01-01

    To explore the value of multiple clinical endpoints in the unique setting of ovarian cancer. A clinical trial workgroup was established by the Society of Gynecologic Oncology to develop a consensus statement via multiple conference calls, meetings and white paper drafts. Clinical trial endpoints have profound effects on late phase clinical trial design, result interpretation, drug development, and regulatory approval of therapeutics. Selection of the optimal clinical trial endpoint is particularly provocative in ovarian cancer where long overall survival (OS) is observed. The lack of new regulatory approvals and the lack of harmony between regulatory bodies globally for ovarian cancer therapeutics are of concern. The advantages and disadvantages of the numerous endpoints available are herein discussed within the unique context of ovarian cancer where both crossover and post-progression therapies potentially uncouple surrogacy between progression-free survival (PFS) and OS, the two most widely supported and utilized endpoints. The roles of patient reported outcomes (PRO) and health related quality of life (HRQoL) are discussed, but even these widely supported parameters are affected by the unique characteristics of ovarian cancer where a significant percentage of patients may be asymptomatic. Original data regarding the endpoint preferences of ovarian cancer advocates is presented. Endpoint selection in ovarian cancer clinical trials should reflect the impact on disease burden and unique characteristics of the treatment cohort while reflecting true patient benefit. Both OS and PFS have led to regulatory approvals and are clinically important. OS remains the most objective and accepted endpoint because it is least vulnerable to bias; however, the feasibility of OS in ovarian cancer is compromised by the requirement for large trial size, prolonged time-line for final analysis, and potential for unintended loss of treatment effect from active post-progression therapies

  2. Schools K-12, School locations within Sedgwick County. This layer is maintained interactively by GIS staff. Primary attributes include school name, class, funding source, address, and parachial status. Published to scschoop.shp., Published in 2008, 1:1200 (1in=100ft) scale, Sedgwick County Government.

    Data.gov (United States)

    NSGIC Local Govt | GIS Inventory — Schools K-12 dataset current as of 2008. School locations within Sedgwick County. This layer is maintained interactively by GIS staff. Primary attributes include...

  3. Parcels and Land Ownership, Derived from countywide parcel cover (scparcel) and CAMA.dat info table. Primary attributes include Parcel IDS (Control, Key, and PIN), calculated acreage, Appraiser's most recent landcover assessment year, and Appraiser's property ownership and value., Published in 2008, 1:1200 (1in=100ft) scale, Sedgwick County Government.

    Data.gov (United States)

    NSGIC Local Govt | GIS Inventory — Parcels and Land Ownership dataset current as of 2008. Derived from countywide parcel cover (scparcel) and CAMA.dat info table. Primary attributes include Parcel IDS...

  4. Soils, County-wide soils cover - an aggregation of section-wide soil coverages with additional attributes. Primary attributes include mu symbol and ID, state symbol, name, category, percolation rate and passing percentage., Published in 2008, 1:1200 (1in=100ft) scale, Sedgwick County Government.

    Data.gov (United States)

    NSGIC Local Govt | GIS Inventory — Soils dataset current as of 2008. County-wide soils cover - an aggregation of section-wide soil coverages with additional attributes. Primary attributes include mu...

  5. Endpoint behavior of the pion distribution amplitude in QCD sum rules with nonlocal condensates

    International Nuclear Information System (INIS)

    Mikhailov, S. V.; Pimikov, A. V.; Stefanis, N. G.

    2010-01-01

    Starting from the QCD sum rules with nonlocal condensates for the pion distribution amplitude, we derive another sum rule for its derivative and its ''integral derivatives''--defined in this work. We use this new sum rule to analyze the fine details of the pion distribution amplitude in the endpoint region x∼0. The results for endpoint-suppressed and flattop (or flatlike) pion distribution amplitudes are compared with those we obtained with differential sum rules by employing two different models for the distribution of vacuum-quark virtualities. We determine the range of values of the derivatives of the pion distribution amplitude and show that endpoint-suppressed distribution amplitudes lie within this range, while those with endpoint enhancement--flat-type or Chernyak-Zhitnitsky like--yield values outside this range.

  6. 78 FR 49530 - Gastroenterology Regulatory Endpoints and the Advancement of Therapeutics; Public Workshop

    Science.gov (United States)

    2013-08-14

    ...] Gastroenterology Regulatory Endpoints and the Advancement of Therapeutics; Public Workshop AGENCY: Food and Drug... for Drug Evaluation and Research, in cosponsorship with the American College of Gastroenterology, the... American Society for Pediatric Gastroenterology, Hepatology, and Nutrition, and the Pediatric IBD...

  7. On weighted hardy inequalities on semiaxis for functions vanishing at the endpoints

    Directory of Open Access Journals (Sweden)

    Stepanov Vladimir

    1997-01-01

    Full Text Available We study the weighted Hardy inequalities on the semiaxis of the form for functions vanishing at the endpoints together with derivatives up to the order . The case is completely characterized.

  8. 76 FR 51993 - Draft Guidance for Industry on Standards for Clinical Trial Imaging Endpoints; Availability

    Science.gov (United States)

    2011-08-19

    ... clinical trials of therapeutic drugs and biological products. The draft guidance describes standards... important imaging endpoint is used in a clinical trial of a therapeutic drug or biological product... Services to the Chairman of [[Page 51994

  9. SpEnD: Linked Data SPARQL Endpoints Discovery Using Search Engines

    OpenAIRE

    Yumusak, Semih; Dogdu, Erdogan; Kodaz, Halife; Kamilaris, Andreas

    2016-01-01

    In this study, a novel metacrawling method is proposed for discovering and monitoring linked data sources on the Web. We implemented the method in a prototype system, named SPARQL Endpoints Discovery (SpEnD). SpEnD starts with a "search keyword" discovery process for finding relevant keywords for the linked data domain and specifically SPARQL endpoints. Then, these search keywords are utilized to find linked data sources via popular search engines (Google, Bing, Yahoo, Yandex). By using this ...

  10. The use of intermediate endpoints in the design of type 1 diabetes prevention trials.

    Science.gov (United States)

    Krischer, Jeffrey P

    2013-09-01

    This paper presents a rationale for the selection of intermediate endpoints to be used in the design of type 1 diabetes prevention clinical trials. Relatives of individuals diagnosed with type 1 diabetes were enrolled on the TrialNet Natural History Study and screened for diabetes-related autoantibodies. Those with two or more such autoantibodies were analysed with respect to increased HbA1c, decreased C-peptide following an OGTT, or abnormal OGTT values as intermediate markers of disease progression. Over 2 years, a 10% increase in HbA1c, and a 20% or 30% decrease in C-peptide from baseline, or progression to abnormal OGTT, occurred with a frequency between 20% and 41%. The 3- to 5-year risk of type 1 diabetes following each intermediate endpoint was high, namely 47% to 84%. The lower the incidence of the endpoint being reached, the higher the risk of diabetes. A diabetes prevention trial using these intermediate endpoints would require a 30% to 50% smaller sample size than one using type 1 diabetes as the endpoint. The use of an intermediate endpoint in diabetes prevention is based on the generally held view of disease progression from initial occurrence of autoantibodies through successive immunological and metabolic changes to manifest type 1 diabetes. Thus, these markers are suitable for randomised phase 2 trials, which can more rapidly screen promising new therapies, allowing them to be subsequently confirmed in definitive phase 3 trials.

  11. Five criteria for using a surrogate endpoint to predict treatment effect based on data from multiple previous trials.

    Science.gov (United States)

    Baker, Stuart G

    2018-02-20

    A surrogate endpoint in a randomized clinical trial is an endpoint that occurs after randomization and before the true, clinically meaningful, endpoint that yields conclusions about the effect of treatment on true endpoint. A surrogate endpoint can accelerate the evaluation of new treatments but at the risk of misleading conclusions. Therefore, criteria are needed for deciding whether to use a surrogate endpoint in a new trial. For the meta-analytic setting of multiple previous trials, each with the same pair of surrogate and true endpoints, this article formulates 5 criteria for using a surrogate endpoint in a new trial to predict the effect of treatment on the true endpoint in the new trial. The first 2 criteria, which are easily computed from a zero-intercept linear random effects model, involve statistical considerations: an acceptable sample size multiplier and an acceptable prediction separation score. The remaining 3 criteria involve clinical and biological considerations: similarity of biological mechanisms of treatments between the new trial and previous trials, similarity of secondary treatments following the surrogate endpoint between the new trial and previous trials, and a negligible risk of harmful side effects arising after the observation of the surrogate endpoint in the new trial. These 5 criteria constitute an appropriately high bar for using a surrogate endpoint to make a definitive treatment recommendation. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

  12. Effect of eplerenone on parathyroid hormone levels in patients with primary hyperparathyroidism: a randomized, double-blind, placebo-controlled trial

    Directory of Open Access Journals (Sweden)

    Tomaschitz Andreas

    2012-09-01

    Full Text Available Abstract Background Increasing evidence suggests the bidirectional interplay between parathyroid hormone and aldosterone as an important mechanism behind the increased risk of cardiovascular damage and bone disease observed in primary hyperparathyroidism. Our primary object is to assess the efficacy of the mineralocorticoid receptor-blocker eplerenone to reduce parathyroid hormone secretion in patients with parathyroid hormone excess. Methods/design Overall, 110 adult male and female patients with primary hyperparathyroidism will be randomly assigned to eplerenone (25 mg once daily for 4 weeks and 4 weeks with 50 mg once daily after dose titration] or placebo, over eight weeks. Each participant will undergo detailed clinical assessment, including anthropometric evaluation, 24-h ambulatory arterial blood pressure monitoring, echocardiography, kidney function and detailed laboratory determination of biomarkers of bone metabolism and cardiovascular disease. The study comprises the following exploratory endpoints: mean change from baseline to week eight in (1 parathyroid hormone(1–84 as the primary endpoint and (2 24-h systolic and diastolic ambulatory blood pressure levels, NT-pro-BNP, biomarkers of bone metabolism, 24-h urinary protein/albumin excretion and echocardiographic parameters reflecting systolic and diastolic function as well as cardiac dimensions, as secondary endpoints. Discussion In view of the reciprocal interaction between aldosterone and parathyroid hormone and the potentially ensuing target organ damage, the EPATH trial is designed to determine whether eplerenone, compared to placebo, will effectively impact on parathyroid hormone secretion and improve cardiovascular, renal and bone health in patients with primary hyperparathyroidism. Trial registration ISRCTN33941607

  13. Transmission assessment surveys (TAS to define endpoints for lymphatic filariasis mass drug administration: a multicenter evaluation.

    Directory of Open Access Journals (Sweden)

    Brian K Chu

    Full Text Available BACKGROUND: Lymphatic filariasis (LF is targeted for global elimination through treatment of entire at-risk populations with repeated annual mass drug administration (MDA. Essential for program success is defining and confirming the appropriate endpoint for MDA when transmission is presumed to have reached a level low enough that it cannot be sustained even in the absence of drug intervention. Guidelines advanced by WHO call for a transmission assessment survey (TAS to determine if MDA can be stopped within an LF evaluation unit (EU after at least five effective rounds of annual treatment. To test the value and practicality of these guidelines, a multicenter operational research trial was undertaken in 11 countries covering various geographic and epidemiological settings. METHODOLOGY: The TAS was conducted twice in each EU with TAS-1 and TAS-2 approximately 24 months apart. Lot quality assurance sampling (LQAS formed the basis of the TAS survey design but specific EU characteristics defined the survey site (school or community, eligible population (6-7 year olds or 1(st-2(nd graders, survey type (systematic or cluster-sampling, target sample size, and critical cutoff (a statistically powered threshold below which transmission is expected to be no longer sustainable. The primary diagnostic tools were the immunochromatographic (ICT test for W. bancrofti EUs and the BmR1 test (Brugia Rapid or PanLF for Brugia spp. EUs. PRINCIPAL FINDINGS/CONCLUSIONS: In 10 of 11 EUs, the number of TAS-1 positive cases was below the critical cutoff, indicating that MDA could be stopped. The same results were found in the follow-up TAS-2, therefore, confirming the previous decision outcome. Sample sizes were highly sex and age-representative and closely matched the target value after factoring in estimates of non-participation. The TAS was determined to be a practical and effective evaluation tool for stopping MDA although its validity for longer-term post

  14. Transmission assessment surveys (TAS) to define endpoints for lymphatic filariasis mass drug administration: a multicenter evaluation.

    Science.gov (United States)

    Chu, Brian K; Deming, Michael; Biritwum, Nana-Kwadwo; Bougma, Windtaré R; Dorkenoo, Améyo M; El-Setouhy, Maged; Fischer, Peter U; Gass, Katherine; Gonzalez de Peña, Manuel; Mercado-Hernandez, Leda; Kyelem, Dominique; Lammie, Patrick J; Flueckiger, Rebecca M; Mwingira, Upendo J; Noordin, Rahmah; Offei Owusu, Irene; Ottesen, Eric A; Pavluck, Alexandre; Pilotte, Nils; Rao, Ramakrishna U; Samarasekera, Dilhani; Schmaedick, Mark A; Settinayake, Sunil; Simonsen, Paul E; Supali, Taniawati; Taleo, Fasihah; Torres, Melissa; Weil, Gary J; Won, Kimberly Y

    2013-01-01

    Lymphatic filariasis (LF) is targeted for global elimination through treatment of entire at-risk populations with repeated annual mass drug administration (MDA). Essential for program success is defining and confirming the appropriate endpoint for MDA when transmission is presumed to have reached a level low enough that it cannot be sustained even in the absence of drug intervention. Guidelines advanced by WHO call for a transmission assessment survey (TAS) to determine if MDA can be stopped within an LF evaluation unit (EU) after at least five effective rounds of annual treatment. To test the value and practicality of these guidelines, a multicenter operational research trial was undertaken in 11 countries covering various geographic and epidemiological settings. The TAS was conducted twice in each EU with TAS-1 and TAS-2 approximately 24 months apart. Lot quality assurance sampling (LQAS) formed the basis of the TAS survey design but specific EU characteristics defined the survey site (school or community), eligible population (6-7 year olds or 1(st)-2(nd) graders), survey type (systematic or cluster-sampling), target sample size, and critical cutoff (a statistically powered threshold below which transmission is expected to be no longer sustainable). The primary diagnostic tools were the immunochromatographic (ICT) test for W. bancrofti EUs and the BmR1 test (Brugia Rapid or PanLF) for Brugia spp. EUs. In 10 of 11 EUs, the number of TAS-1 positive cases was below the critical cutoff, indicating that MDA could be stopped. The same results were found in the follow-up TAS-2, therefore, confirming the previous decision outcome. Sample sizes were highly sex and age-representative and closely matched the target value after factoring in estimates of non-participation. The TAS was determined to be a practical and effective evaluation tool for stopping MDA although its validity for longer-term post-MDA surveillance requires further investigation.

  15. Electrode assemblies, plasma apparatuses and systems including electrode assemblies, and methods for generating plasma

    Science.gov (United States)

    Kong, Peter C; Grandy, Jon D; Detering, Brent A; Zuck, Larry D

    2013-09-17

    Electrode assemblies for plasma reactors include a structure or device for constraining an arc endpoint to a selected area or region on an electrode. In some embodiments, the structure or device may comprise one or more insulating members covering a portion of an electrode. In additional embodiments, the structure or device may provide a magnetic field configured to control a location of an arc endpoint on the electrode. Plasma generating modules, apparatus, and systems include such electrode assemblies. Methods for generating a plasma include covering at least a portion of a surface of an electrode with an electrically insulating member to constrain a location of an arc endpoint on the electrode. Additional methods for generating a plasma include generating a magnetic field to constrain a location of an arc endpoint on an electrode.

  16. Ecosystem services as assessment endpoints for ecological risk assessment

    Science.gov (United States)

    Ecosystem services (ES) are defined as the outputs of ecological processes that contribute to human welfare or have the potential to do so in the future, and include the production of food and drinking water, purification of air and water, pollination, and nutrient cycling. The n...

  17. Therapeutic Targets and Translational Endpoints in Fragile X Syndrome

    NARCIS (Netherlands)

    C.E.F. de Esch (Celine)

    2014-01-01

    markdownabstract__Abstract__ Fragile X syndrome is the most common inherited cause of intellectual disability. It is more common in boys (1 in 4000) than girls (1 in 6000). In addition to the intellectual disability patients often exhibit behavioral abnormalities including hyperactivity and

  18. Environmentally acceptable endpoints for PAHs at a manufactured gas plant site

    Energy Technology Data Exchange (ETDEWEB)

    Stroo, H.F.; Jensen, R.; Loehr, R.C.; Nakles, D.V.; Fairbrother, A.; Liban, C.B. [ThermoRetec Corp., Carson, CA (USA)

    2000-09-01

    Samples from a former manufactured gas plant (MGP) site in Santa Barbara, CA were tested to evaluate the environmentally acceptable endpoints (EAE) process for setting risk-based cleanup criteria. The research was part of an ongoing effort to develop and demonstrate a protocol for assessing risk-based criteria for MGP sites that incorporates the availability of polycyclic aromatic hydrocarbons (PAHs). Six soil samples were subjected to a battery of physical and biological tests that focused on determining the 'availability' of the soil-bound contaminants to groundwater, ecological receptors, and human receptors. Results demonstrated that sorption to soil, matrix effects, aging, and treatment can significantly reduce chemical availability. Including these reduced availability results in risk assessment calculations yielded environmentally protective cleanup levels almost 3-10 times greater than levels derived using California default risk assessment assumptions. Using an EAE-based approach for MGP soils, especially those containing lampblack, could provide more realistic risk assessment. 23 refs., 6 tabs.

  19. Free-time and fixed end-point multi-target optimal control theory: Application to quantum computing

    International Nuclear Information System (INIS)

    Mishima, K.; Yamashita, K.

    2011-01-01

    Graphical abstract: The two-state Deutsch-Jozsa algortihm used to demonstrate the utility of free-time and fixed-end point multi-target optimal control theory. Research highlights: → Free-time and fixed-end point multi-target optimal control theory (FRFP-MTOCT) was constructed. → The features of our theory include optimization of the external time-dependent perturbations with high transition probabilities, that of the temporal duration, the monotonic convergence, and the ability to optimize multiple-laser pulses simultaneously. → The advantage of the theory and a comparison with conventional fixed-time and fixed end-point multi-target optimal control theory (FIFP-MTOCT) are presented by comparing data calculated using the present theory with those published previously [K. Mishima, K. Yamashita, Chem. Phys. 361 (2009) 106]. → The qubit system of our interest consists of two polar NaCl molecules coupled by dipole-dipole interaction. → The calculation examples show that our theory is useful for minor adjustment of the external fields. - Abstract: An extension of free-time and fixed end-point optimal control theory (FRFP-OCT) to monotonically convergent free-time and fixed end-point multi-target optimal control theory (FRFP-MTOCT) is presented. The features of our theory include optimization of the external time-dependent perturbations with high transition probabilities, that of the temporal duration, the monotonic convergence, and the ability to optimize multiple-laser pulses simultaneously. The advantage of the theory and a comparison with conventional fixed-time and fixed end-point multi-target optimal control theory (FIFP-MTOCT) are presented by comparing data calculated using the present theory with those published previously [K. Mishima, K. Yamashita, Chem. Phys. 361, (2009), 106]. The qubit system of our interest consists of two polar NaCl molecules coupled by dipole-dipole interaction. The calculation examples show that our theory is useful for minor

  20. Comparing three novel endpoints for developmental osteotoxicity in the embryonic stem cell test

    International Nuclear Information System (INIS)

    Nieden, Nicole I. zur; Davis, Lesley A.; Rancourt, Derrick E.

    2010-01-01

    Birth defects belong to the most serious side effects of pharmaceutical compounds or environmental chemicals. In vivo, teratogens most often affect the normal development of bones, causing growth retardation, limb defects or craniofacial malformations. The embryonic stem cell test (EST) is one of the most promising models that allow the in vitro prediction of embryotoxicity, with one of its endpoints being bone tissue development. The present study was designed to describe three novel inexpensive endpoints to assess developmental osteotoxicity using the model compounds penicillin G (non-teratogenic), 5-fluorouracil (strong teratogen) and all-trans retinoic acid (bone teratogen). These three endpoints were: quantification of matrix incorporated calcium by (1) morphometric analysis and (2) measurement of calcium levels as well as (3) activity of alkaline phosphatase, an enzyme involved in matrix calcification. To evaluate our data, we have compared the concentration curves and resulting ID 50 s of the new endpoints with mRNA expression for osteocalcin. Osteocalcin is an exclusive marker found only in mineralized tissues, is regulated upon compound treatment and reliably predicts the potential of a chemical entity acting as a bone teratogen. By comparing the new endpoints to quantitative expression of osteocalcin, which we previously identified as suitable to detect developmental osteotoxicity, we were ultimately able to illustrate IMAGE analysis and Ca 2+ deposition assays as two reliable novel endpoints for the EST. This is of particular importance for routine industrial assessment of novel compounds as these two new endpoints may substitute previously used molecular read-out methods, which are often costly and time-consuming.

  1. Plasma TIMP-1 and CEA in detection of primary colorectal cancer: a prospective, population based study of 4509 high-risk individuals

    DEFF Research Database (Denmark)

    Nielsen, Hans J; Brünner, Nils; Jørgensen, Lars Nannestad

    2011-01-01

    . Individuals (n = 4509) referred for large bowel endoscopy due to symptoms of CRC were prospectively included. Baseline data and concurrent diseases were recorded. The primary endpoint was detection of CRC and findings at examinations were recorded using International Classification of Diseases-10 codes....... This prospective validation study supports the use of the combination of plasma TIMP-1 and CEA protein measurements as a potential aid in early detection of CRC and specifically of CC....

  2. Food Safety: Recommendations for Determining Doneness in Consumer Egg Dish Recipes and Measurement of Endpoint Temperatures When Recipes Are Followed

    Directory of Open Access Journals (Sweden)

    Sandria Godwin

    2016-06-01

    Full Text Available Many consumers do not follow recommended food safety practices for cooking egg dishes, such as pies, quiches, and casseroles, potentially leading to foodborne illnesses such as Salmonellosis. The United States Department of Agriculture (USDA recommends cooking egg mixtures until the center reaches 71 °C (160 °F. The objectives of this study were to determine what endpoint temperature information consumers receive from egg dish recipes, and if recipes would lead to safe temperatures when followed. Egg dish recipes (n = 226 from 65 websites, 50 cookbooks, and nine magazine titles (multiple issues of each were analyzed. Time was the most frequently used indicator, given in 92% of the recipes, with 15% using only time. Other indicators included: set (89, browned (76, clean toothpick/knife (60, puffed (27, and jiggled (13. Only two recipes indicated final endpoint temperatures. Three recipes (a pie, a quiche, and an egg casserole were chosen and prepared in triplicate to see if they would reach recommended temperatures. The pie and quiche were still liquid at 71 °C, and were well over the recommended temperature when cooked according to instructions, but the egg casserole was not consistently above 71 °C, when the recipe instructions indicated it was done and the center was light brown and “jiggled” This research indicates that consumers are not receiving information on endpoint temperatures in egg recipes, but the likelihood of foodborne illness is low since most dishes probably be cooked past the recommended temperature before the consumer considers them done unless there are many inclusions that may absorb liquid and reduce the appearance of liquid in the dish.

  3. Food Safety: Recommendations for Determining Doneness in Consumer Egg Dish Recipes and Measurement of Endpoint Temperatures When Recipes Are Followed

    Science.gov (United States)

    Godwin, Sandria; Maughan, Curtis; Chambers, Edgar

    2016-01-01

    Many consumers do not follow recommended food safety practices for cooking egg dishes, such as pies, quiches, and casseroles, potentially leading to foodborne illnesses such as Salmonellosis. The United States Department of Agriculture (USDA) recommends cooking egg mixtures until the center reaches 71 °C (160 °F). The objectives of this study were to determine what endpoint temperature information consumers receive from egg dish recipes, and if recipes would lead to safe temperatures when followed. Egg dish recipes (n = 226) from 65 websites, 50 cookbooks, and nine magazine titles (multiple issues of each) were analyzed. Time was the most frequently used indicator, given in 92% of the recipes, with 15% using only time. Other indicators included: set (89), browned (76), clean toothpick/knife (60), puffed (27), and jiggled (13). Only two recipes indicated final endpoint temperatures. Three recipes (a pie, a quiche, and an egg casserole) were chosen and prepared in triplicate to see if they would reach recommended temperatures. The pie and quiche were still liquid at 71 °C, and were well over the recommended temperature when cooked according to instructions, but the egg casserole was not consistently above 71 °C, when the recipe instructions indicated it was done and the center was light brown and “jiggled” This research indicates that consumers are not receiving information on endpoint temperatures in egg recipes, but the likelihood of foodborne illness is low since most dishes probably be cooked past the recommended temperature before the consumer considers them done unless there are many inclusions that may absorb liquid and reduce the appearance of liquid in the dish. PMID:28231140

  4. An European inter-laboratory validation of alternative endpoints of the murine local lymph node assay: 2nd round.

    Science.gov (United States)

    Ehling, G; Hecht, M; Heusener, A; Huesler, J; Gamer, A O; van Loveren, H; Maurer, Th; Riecke, K; Ullmann, L; Ulrich, P; Vandebriel, R; Vohr, H-W

    2005-08-15

    The original local lymph node assay (LLNA) is based on the use of radioactive labelling to measure cell proliferation. Other endpoints for the assessment of proliferation are also authorized by the OECD Guideline 429 provided there is appropriate scientific support, including full citations and description of the methodology (OECD, 2002. OECD Guideline for the Testing of Chemicals; Skin Sensitization: Local Lymph Node Assay, Guideline 429. Paris, adopted 24th April 2002.). Here, we describe the outcome of the second round of an inter-laboratory validation of alternative endpoints in the LLNA conducted in nine laboratories in Europe. The validation study was managed and supervised by the Swiss Agency for Therapeutic Products (Swissmedic) in Bern. Ear-draining lymph node (LN) weight and cell counts were used to assess LN cell proliferation instead of [3H]TdR incorporation. In addition, the acute inflammatory skin reaction was measured by ear weight determination of circular biopsies of the ears to identify skin irritation properties of the test items. The statistical analysis was performed in the department of statistics at the university of Bern. Similar to the EC(3) values defined for the radioactive method, threshold values were calculated for the endpoints measured in this modification of the LLNA. It was concluded that all parameters measured have to be taken into consideration for the categorisation of compounds due to their sensitising potencies. Therefore, an assessment scheme has been developed which turned out to be of great importance to consistently assess sensitisation versus irritancy based on the data of the different parameters. In contrast to the radioactive method, irritants have been picked up by all the laboratories applying this assessment scheme.

  5. Food Safety: Recommendations for Determining Doneness in Consumer Egg Dish Recipes and Measurement of Endpoint Temperatures When Recipes Are Followed.

    Science.gov (United States)

    Godwin, Sandria; Maughan, Curtis; Chambers, Edgar

    2016-06-23

    Many consumers do not follow recommended food safety practices for cooking egg dishes, such as pies, quiches, and casseroles, potentially leading to foodborne illnesses such as Salmonellosis. The United States Department of Agriculture (USDA) recommends cooking egg mixtures until the center reaches 71 °C (160 °F). The objectives of this study were to determine what endpoint temperature information consumers receive from egg dish recipes, and if recipes would lead to safe temperatures when followed. Egg dish recipes ( n = 226) from 65 websites, 50 cookbooks, and nine magazine titles (multiple issues of each) were analyzed. Time was the most frequently used indicator, given in 92% of the recipes, with 15% using only time. Other indicators included: set (89), browned (76), clean toothpick/knife (60), puffed (27), and jiggled (13). Only two recipes indicated final endpoint temperatures. Three recipes (a pie, a quiche, and an egg casserole) were chosen and prepared in triplicate to see if they would reach recommended temperatures. The pie and quiche were still liquid at 71 °C, and were well over the recommended temperature when cooked according to instructions, but the egg casserole was not consistently above 71 °C, when the recipe instructions indicated it was done and the center was light brown and "jiggled" This research indicates that consumers are not receiving information on endpoint temperatures in egg recipes, but the likelihood of foodborne illness is low since most dishes probably be cooked past the recommended temperature before the consumer considers them done unless there are many inclusions that may absorb liquid and reduce the appearance of liquid in the dish.

  6. Parcels and Land Ownership, Square-mile, section-wide, property ownerhip parcel and lot-block boundaries. Includes original platted lot lines. These coverages are maintained interactively by GIS staff. Primary attributes include Parcel IDS (Control, Key, and PIN), platted lot and, Published in 2008, 1:1200 (1in=100ft) scale, Sedgwick County Government.

    Data.gov (United States)

    NSGIC Local Govt | GIS Inventory — Parcels and Land Ownership dataset current as of 2008. Square-mile, section-wide, property ownerhip parcel and lot-block boundaries. Includes original platted lot...

  7. Endpoint Security Using Biometric Authentication for Secure Remote Mission Operations

    Science.gov (United States)

    Donohue, John T.; Critchfield, Anna R.

    2000-01-01

    We propose a flexible security authentication solution for the spacecraft end-user, which will allow the user to interact over Internet with the spacecraft, its instruments, or with the ground segment from anywhere, anytime based on the user's pre-defined set of privileges. This package includes biometrics authentication products, such as face, voice or fingerprint recognition, authentication services and procedures, such as: user registration and verification over the Internet and user database maintenance, with a configurable schema of spacecraft users' privileges. This fast and reliable user authentication mechanism will become an integral part of end-to-end ground-to-space secure Internet communications and migration from current practice to the future. All modules and services of the proposed package are commercially available and built to the NIST BioAPI standard, which facilitates "pluggability" and interoperability.

  8. Endpoint in plasma etch process using new modified w-multivariate charts and windowed regression

    Science.gov (United States)

    Zakour, Sihem Ben; Taleb, Hassen

    2017-09-01

    Endpoint detection is very important undertaking on the side of getting a good understanding and figuring out if a plasma etching process is done in the right way, especially if the etched area is very small (0.1%). It truly is a crucial part of supplying repeatable effects in every single wafer. When the film being etched has been completely cleared, the endpoint is reached. To ensure the desired device performance on the produced integrated circuit, the high optical emission spectroscopy (OES) sensor is employed. The huge number of gathered wavelengths (profiles) is then analyzed and pre-processed using a new proposed simple algorithm named Spectra peak selection (SPS) to select the important wavelengths, then we employ wavelet analysis (WA) to enhance the performance of detection by suppressing noise and redundant information. The selected and treated OES wavelengths are then used in modified multivariate control charts (MEWMA and Hotelling) for three statistics (mean, SD and CV) and windowed polynomial regression for mean. The employ of three aforementioned statistics is motivated by controlling mean shift, variance shift and their ratio (CV) if both mean and SD are not stable. The control charts show their performance in detecting endpoint especially W-mean Hotelling chart and the worst result is given by CV statistic. As the best detection of endpoint is given by the W-Hotelling mean statistic, this statistic will be used to construct a windowed wavelet Hotelling polynomial regression. This latter can only identify the window containing endpoint phenomenon.

  9. Multi-Toxic Endpoints of the Foodborne Mycotoxins in Nematode Caenorhabditis elegans

    Directory of Open Access Journals (Sweden)

    Zhendong Yang

    2015-12-01

    Full Text Available Aflatoxins B1 (AFB1, deoxynivalenol (DON, fumonisin B1 (FB1, T-2 toxin (T-2, and zearalenone (ZEA are the major foodborne mycotoxins of public health concerns. In the present study, the multiple toxic endpoints of these naturally-occurring mycotoxins were evaluated in Caenorhabditis elegans model for their lethality, toxic effects on growth and reproduction, as well as influence on lifespan. We found that the lethality endpoint was more sensitive for T-2 toxicity with the EC50 at 1.38 mg/L, the growth endpoint was relatively sensitive for AFB1 toxic effects, and the reproduction endpoint was more sensitive for toxicities of AFB1, FB1, and ZEA. Moreover, the lifespan endpoint was sensitive to toxic effects of all five tested mycotoxins. Data obtained from this study may serve as an important contribution to knowledge on assessment of mycotoxin toxic effects, especially for assessing developmental and reproductive toxic effects, using the C. elegans model.

  10. Pollutant threshold concentration determination in marine ecosystems using an ecological interaction endpoint.

    Science.gov (United States)

    Wang, Changyou; Liang, Shengkang; Guo, Wenting; Yu, Hua; Xing, Wenhui

    2015-09-01

    The threshold concentrations of pollutants are determined by extrapolating single-species effect data to community-level effects. This assumes the most sensitive endpoint of the life cycle of individuals and the species sensitivity distribution from single-species toxic effect tests, thus, ignoring the ecological interactions. The uncertainties due to this extrapolation can be partially overcome using the equilibrium point of a customized ecosystem. This method incorporates ecological interactions and integrates the effects on growth, survival, and ingestion into a single effect measure, the equilibrium point excursion in the customized ecosystem, in order to describe the toxic effects on plankton. A case study showed that the threshold concentration of copper calculated with the endpoint of the equilibrium point was 10 μg L(-1), which is significantly different from the threshold calculated with a single-species endpoint. The endpoint calculated using this method provides a more relevant measure of the ecological impact than any single individual-level endpoint. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. Effects of un-ionized ammonia on histological, endocrine, and whole organism endpoints in slimy sculpin (Cottus cognatus)

    Energy Technology Data Exchange (ETDEWEB)

    Spencer, P. [Toxicology Centre, University of Saskatchewan, 44 Campus Drive, Saskatoon, SK, S7N 5B3 (Canada)], E-mail: paula.spencer@usask.ca; Pollock, R.; Dube, M. [Toxicology Centre, University of Saskatchewan, 44 Campus Drive, Saskatoon, SK, S7N 5B3 (Canada)

    2008-12-11

    reported in northern mine effluents hold potential to affect the health of slimy sculpin including acute, chronic, histological and endocrine endpoints.

  12. Transcervical, intrauterine ultrasound-guided radiofrequency ablation of uterine fibroids with the VizAblate® System: three- and six-month endpoint results from the FAST-EU study.

    Science.gov (United States)

    Bongers, Marlies; Brölmann, Hans; Gupta, Janesh; Garza-Leal, José Gerardo; Toub, David

    This was a prospective, longitudinal, multicenter, single-arm controlled trial, using independent core laboratory validation of MRI results, to establish the effectiveness and confirm the safety of the VizAblate® System in the treatment of symptomatic uterine fibroids. The VizAblate System is a transcervical device that ablates fibroids with radiofrequency energy, guided by a built-in intrauterine ultrasound probe. Fifty consecutive women with symptomatic uterine fibroids received treatment with the VizAblate System. Patients had a minimum Menstrual Pictogram score of 120, no desire for fertility, and met additional inclusion and exclusion criteria. The VizAblate System was inserted transcervically and individual fibroids were ablated with radiofrequency energy. An integrated intrauterine ultrasound probe was used for fibroid imaging and targeting. Anesthesia was at the discretion of each investigator. The primary study endpoint was the percentage change in perfused fibroid volume, as assessed by contrast-enhanced MRI at 3 months. Secondary endpoints, reached at 6 months, included safety, percentage reductions in the Menstrual Pictogram (MP) score and the Symptom Severity Score (SSS) subscale of the Uterine Fibroid Symptom-Quality of Life questionnaire (UFS-QOL), along with the rate of surgical reintervention for abnormal uterine bleeding and the mean number of days to return to normal activity. Additional assessments included the Health-Related Quality of Life (HRQOL) subscale of the UFS-QOL, medical reintervention for abnormal uterine bleeding, and procedure times. Fifty patients were treated, representing 92 fibroids. Perfused fibroid volumes were reduced at 3 months by an average of 68.8 ± 27.8 % ( P  abnormal uterine bleeding associated with fibroids, with appropriate safety and a low reintervention rate.

  13. Health Endpoint Attributed to Sulfur Dioxide Air Pollutants

    Directory of Open Access Journals (Sweden)

    Geravandi

    2015-07-01

    Full Text Available Background Sulfur dioxide is a colorless gas, released from burning of coal, high-sulfur coal,s and diesel fuel. Sulfur dioxide harms human health by reacting with the moisture in the nose, nasal cavity and throat and this is the way by which it destroys the nerves in the respiratory system. Objectives The aim of this study was to focus on identifying the effects associated with sulfur dioxide on health in Ahvaz, Iran. Materials and Methods Data collections were performed by Ahvaz meteorological organization and the department of environment. Sampling was performed for 24 hours in four stations. Methods of sampling and analysis were according to US environmental protection agency (EPA guideline. Afterwards, we processed the raw data including instruction set correction of averaging, coding and filtering by Excel software and then, the impact of meteorological parameters were converted as the input file to the AirQ model. Finally, we calculated the health effects of exposure to sulfur dioxide. Results According to the findings, the concentration of sulfur dioxide in Ahvaz had an annual average of 51 μg/m3. Sum of the numbers of hospital admissions for respiratory diseases attributed to sulfur dioxide was 25 cases in 2012. Approximately, 5% of the total hospital admissions for respiratory disease and respiratory mortality happened when sulfur dioxide concentration was more than 10 mg/m3. Conclusions According to the results of this study, this increase could be due to higher fuel consumption, usage of gasoline in vehicles, oil industry, and steel and heavy industries in Ahwaz. The risk of mortality and morbidity were detected at the current concentrations of air pollutants.

  14. Meeting report: Measuring endocrine-sensitive endpoints within the first years of life

    DEFF Research Database (Denmark)

    Arbuckle, T.E.; Hauser, R.; Swan, S.H.

    2008-01-01

    An international workshop tided "Assessing Endocrine-Related Endpoints within the First Years of Life" was held 30 April-1 May 2007, in Ottawa, Ontario, Canada. Representatives from a number of pregnancy cohort studies in North America and Europe presented options for measuring various endocrine......-sensitive endpoints in early life and discussed issues related to performing and using those measures. The workshop focused on measuring reproductive tract developmental endpoints [e.g., anogenital distance (AGD)], endocrine status, and infant anthropometry. To the extent possible, workshop participants strove...... on the genital exam. Although a number of outcome measures recommended during the genital exam have been associated with exposure to endocrine-disrupting chemicals, little is known about how predictive these effects are of later reproductive health or other chronic health conditions....

  15. Implementation of minimally invasive and objective humane endpoints in the study of murine Plasmodium infections

    DEFF Research Database (Denmark)

    Dellavalle, B; Kirchhoff, J; Maretty, L

    2014-01-01

    SUMMARY Defining appropriate and objective endpoints for animal research can be difficult. Previously we evaluated and implemented a body temperature (BT) of ECM) and were interested in a similar endpoint for a model of severe malarial...... anaemia (SMA). Furthermore, we investigate the potential of a minimally invasive, non-contact infrared thermometer for repeated BT measurement. ECM was induced with Plasmodium berghei ANKA infection in C57Bl/6 mice. SMA was induced with Plasmodium chabaudi AS infection in A/J mice. Our previous published...... endpoint was applied in ECM and 30 °C was pre-determined as the lowest permitted limit for termination in SMA according to consultation with the Danish Animal Inspectorate. Infrared thermometer was compared with the rectal probe after cervical dislocation, ECM and SMA. Linear regression analysis of rectal...

  16. SU-D-204-01: A Methodology Based On Machine Learning and Quantum Clustering to Predict Lung SBRT Dosimetric Endpoints From Patient Specific Anatomic Features

    Energy Technology Data Exchange (ETDEWEB)

    Lafata, K; Ren, L; Wu, Q; Kelsey, C; Hong, J; Cai, J; Yin, F [Duke University Medical Center, Durham, NC (United States)

    2016-06-15

    Purpose: To develop a data-mining methodology based on quantum clustering and machine learning to predict expected dosimetric endpoints for lung SBRT applications based on patient-specific anatomic features. Methods: Ninety-three patients who received lung SBRT at our clinic from 2011–2013 were retrospectively identified. Planning information was acquired for each patient, from which various features were extracted using in-house semi-automatic software. Anatomic features included tumor-to-OAR distances, tumor location, total-lung-volume, GTV and ITV. Dosimetric endpoints were adopted from RTOG-0195 recommendations, and consisted of various OAR-specific partial-volume doses and maximum point-doses. First, PCA analysis and unsupervised quantum-clustering was used to explore the feature-space to identify potentially strong classifiers. Secondly, a multi-class logistic regression algorithm was developed and trained to predict dose-volume endpoints based on patient-specific anatomic features. Classes were defined by discretizing the dose-volume data, and the feature-space was zero-mean normalized. Fitting parameters were determined by minimizing a regularized cost function, and optimization was performed via gradient descent. As a pilot study, the model was tested on two esophageal dosimetric planning endpoints (maximum point-dose, dose-to-5cc), and its generalizability was evaluated with leave-one-out cross-validation. Results: Quantum-Clustering demonstrated a strong separation of feature-space at 15Gy across the first-and-second Principle Components of the data when the dosimetric endpoints were retrospectively identified. Maximum point dose prediction to the esophagus demonstrated a cross-validation accuracy of 87%, and the maximum dose to 5cc demonstrated a respective value of 79%. The largest optimized weighting factor was placed on GTV-to-esophagus distance (a factor of 10 greater than the second largest weighting factor), indicating an intuitively strong

  17. Approving cancer treatments based on endpoints other than overall survival: an analysis of historical data using the PACE Continuous Innovation Indicators™ (CII).

    Science.gov (United States)

    Brooks, Neon; Campone, Mario; Paddock, Silvia; Shortenhaus, Scott; Grainger, David; Zummo, Jacqueline; Thomas, Samuel; Li, Rose

    2017-01-01

    There is an active debate about the role that endpoints other than overall survival (OS) should play in the drug approval process. Yet the term 'surrogate endpoint' implies that OS is the only critical metric for regulatory approval of cancer treatments. We systematically analyzed the relationship between U.S. Food and Drug Administration (FDA) approval and publication of OS evidence to understand better the risks and benefits of delaying approval until OS evidence is available. Using the PACE Continuous Innovation Indicators (CII) platform, we analyzed the effects of cancer type, treatment goal, and year of approval on the lag time between FDA approval and publication of first significant OS finding for 53 treatments approved between 1952 and 2016 for 10 cancer types (n = 71 approved indications). Greater than 59% of treatments were approved before significant OS data for the approved indication were published. Of the drugs in the sample, 31% had lags between approval and first published OS evidence of 4 years or longer. The average number of years between approval and first OS evidence varied by cancer type and did not reliably predict the eventual amount of OS evidence accumulated. Striking the right balance between early access and minimizing risk is a central challenge for regulators worldwide. We illustrate that endpoints other than OS have long helped to provide timely access to new medicines, including many current standards of care. We found that many critical drugs are approved many years before OS data are published, and that OS may not be the most appropriate endpoint in some treatment contexts. Our examination of approved treatments without significant OS data suggests contexts where OS may not be the most relevant endpoint and highlights the importance of using a wide variety of fit-for-purpose evidence types in the approval process.

  18. Primary Progressive Aphasia

    Science.gov (United States)

    ... which cause different symptoms. Semantic variant primary progressive aphasia Symptoms include these difficulties: Comprehending spoken or written ... word meanings Naming objects Logopenic variant primary progressive aphasia Symptoms include: Having difficulty retrieving words Frequently pausing ...

  19. Importance of soil-water relation in assessment endpoint in bioremediated soils: Plant growth and soil physical properties

    International Nuclear Information System (INIS)

    Li, X.; Sawatsky, N.

    1995-01-01

    Much effort has been focused on defining the end-point of bioremediated soils by chemical analysis (Alberta Tier 1 or CCME Guideline for Contaminated Soils) or toxicity tests. However, these tests do not completely assess the soil quality, or the capability of soil to support plant growth after bioremediation. This study compared barley (Hordeum vulgare) growth on: (i) non-contaminated, agricultural topsoil, (2) oil-contaminated soil (4% total extractable hydrocarbons, or TEH), and (3) oil-contaminated soil treated by bioremediation (< 2% TEH). Soil physical properties including water retention, water uptake, and water repellence were measured. The results indicated that the growth of barley was significantly reduced by oil-contamination of agricultural topsoil. Furthermore, bioremediation did not improve the barley yield. The lack of effects from bioremediation was attributed to development of water repellence in hydrocarbon contaminated soils. There seemed to be a critical water content around 18% to 20% in contaminated soils. Above this value the water uptake by contaminated soil was near that of the agricultural topsoil. For lower water contents, there was a strong divergence in sorptivity between contaminated and agricultural topsoil. For these soils, water availability was likely the single most important parameter controlling plant growth. This parameter should be considered in assessing endpoint of bioremediation for hydrocarbon contaminated soils

  20. Radiometric titration of officinal radiopharmaceuticals using radioactive kryptonates as end-point indicators. I

    International Nuclear Information System (INIS)

    Toelgyessy, J.; Dillinger, P.; Harangozo, M.; Jombik, J.

    1980-01-01

    A method for the determination of salicylic, acetylsalicylic and benzoic acids in officinal pharmaceutical based on radiometric titration with 0.1 mol.l -1 NaOH was developed. The end-point was detected with the aid of radioactive glass kryptonate. After the end-point, the excess titrant attacks the glass surface layers and this results in releasing 85 Kr, and consequently, in decreasing the radioactivity of the kryptonate employed. The radioactive kryptonate used as an indicator was prepared by the bombardment of glass with accelerated 85 Kr ions. The developed method is simple, accurate and correct. (author)

  1. A duplex endpoint PCR assay for rapid detection and differentiation of Leptospira strains.

    Science.gov (United States)

    Benacer, Douadi; Zain, Siti Nursheena Mohd; Lewis, John W; Khalid, Mohd Khairul Nizam Mohd; Thong, Kwai Lin

    2017-01-01

    This study aimed to develop a duplex endpoint PCR assay for rapid detection and differentiation of Leptospira strains. Primers were designed to target the rrs (LG1/LG2) and ligB (LP1/LP2) genes to confirm the presence of the Leptospira genus and the pathogenic species, respectively. The assay showed 100% specificity against 17 Leptospira strains with a limit of detection of 23.1pg/µl of leptospiral DNA and sensitivity of 103 leptospires/ml in both spiked urine and water. Our duplex endpoint PCR assay is suitable for rapid early detection of Leptospira with high sensitivity and specificity.

  2. Comparison of methods for accurate end-point detection of potentiometric titrations

    International Nuclear Information System (INIS)

    Villela, R L A; Borges, P P; Vyskočil, L

    2015-01-01

    Detection of the end point in potentiometric titrations has wide application on experiments that demand very low measurement uncertainties mainly for certifying reference materials. Simulations of experimental coulometric titration data and consequential error analysis of the end-point values were conducted using a programming code. These simulations revealed that the Levenberg-Marquardt method is in general more accurate than the traditional second derivative technique used currently as end-point detection for potentiometric titrations. Performance of the methods will be compared and presented in this paper

  3. Comparison of methods for accurate end-point detection of potentiometric titrations

    Science.gov (United States)

    Villela, R. L. A.; Borges, P. P.; Vyskočil, L.

    2015-01-01

    Detection of the end point in potentiometric titrations has wide application on experiments that demand very low measurement uncertainties mainly for certifying reference materials. Simulations of experimental coulometric titration data and consequential error analysis of the end-point values were conducted using a programming code. These simulations revealed that the Levenberg-Marquardt method is in general more accurate than the traditional second derivative technique used currently as end-point detection for potentiometric titrations. Performance of the methods will be compared and presented in this paper.

  4. Verifying Elimination Programs with a Special Emphasis on Cysticercosis Endpoints and Postelimination Surveillance

    Directory of Open Access Journals (Sweden)

    Sukwan Handali

    2012-01-01

    Full Text Available Methods are needed for determining program endpoints or postprogram surveillance for any elimination program. Cysticercosis has the necessary effective strategies and diagnostic tools for establishing an elimination program; however, tools to verify program endpoints have not been determined. Using a statistical approach, the present study proposed that taeniasis and porcine cysticercosis antibody assays could be used to determine with a high statistical confidence whether an area is free of disease. Confidence would be improved by using secondary tests such as the taeniasis coproantigen assay and necropsy of the sentinel pigs.

  5. Evaluation of biological endpoints in crop plants after exposure to non-steroidal anti-inflammatory drugs (NSAIDs): implications for phytotoxicological assessment of novel contaminants.

    Science.gov (United States)

    Schmidt, Wiebke; Redshaw, Clare H

    2015-02-01

    Human pharmaceuticals have been detected in the terrestrial environment at µg to mg kg(-1) concentrations. Repeated application of sewage sludge (biosolids) and increasing reclaimed wastewater use for irrigation could lead to accumulation of these novel contaminants in soil systems. Despite this, potential phytotoxicological effects on higher plants have rarely been evaluated. These studies aimed to test effects upon germination, development, growth and physiology of two crop plants, namely radish (Raphanus sativus Spakler 3) and lettuce (Lactuca sativa All Year Around), after exposure to different, but structurally related non-steroidal anti-inflammatory drugs (NSAIDs) at environmentally relevant concentrations. A range of biological endpoints comprising biomass, length, water content, specific root and shoot length, root to shoot ratio, daily progress of stages of cell elongation and organ emergence (primary root, hypocotyl elongation, cotyledon emergence, cotyledon opening, and no change), as well as photosynthetic measurements were evaluated. Compounds from the fenamic acid class were found to affect R. sativus root endpoints (root length and water content), while ibuprofen affected early root development of L. sativa. In general, phytotoxicological effects on root endpoints demonstrated that impacts upon higher plants are not only compound specific, but also differ between plant species. It was found that the usage of a wide range of biological endpoints (all simple, cost-effective and ecologically relevant) were beneficial in detecting differences in plant responses to NSAID exposure. Due to paucity and discrepancy within the few previously available phytotoxicological studies with pharmaceuticals, it is now essential to allocate time and resources to consider development of suitable chronic toxicity tests, and some suggestions regarding this are presented. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. Risk of second non-breast cancer among patients treated with and without postoperative radiotherapy for primary breast cancer: A systematic review and meta-analysis of population-based studies including 522,739 patients

    DEFF Research Database (Denmark)

    Grantzau, Trine; Overgaard, Jens

    2016-01-01

    -irradiated women. Irradiated patients had an overall increased risk of second non-breast cancer, with a SIR of 1.23 (95% confidence interval [CI] 1.12-1.36). For non-irradiated patients the SIR was 1.08 (95% CI, 1.03-1.13). For irradiated patients the incidence of second cancers including the lung, esophagus......, thyroid and connective tissues progressively increased over time, peaking at 10-15years following breast cancer diagnosis. Summary estimates at ⩾15years after breast cancer irradiation were 1.91 for lung, 2.71 for esophagus, 3.15 for thyroid and 6.54 at ⩾10years for second sarcomas. Non......-irradiated patients had no increased risk of second lung or esophagus cancer, neither overall nor over time. For non-irradiated patients' risk of second thyroid cancer (SIR 1.21) and sarcomas (SIR 1.42) were increased overall, but with no remaining risk ⩾10 after breast cancer. CONCLUSION: Radiotherapy for breast...

  7. Effect of dietary oils on peripheral neuropathy-related endpoints in dietary obese rats

    Directory of Open Access Journals (Sweden)

    Coppey L

    2018-04-01

    Full Text Available Lawrence Coppey,1 Eric Davidson,1 Hanna Shevalye,1 Michael E Torres,1 Mark A Yorek1–4 1Department of Internal Medicine, University of Iowa, Iowa City, IA, USA; 2Department of Veterans Affairs Iowa City Health Care System, Iowa City, IA, USA; 3Department of Veterans Affairs, Veterans Affairs Center for the Prevention and Treatment of Visual Loss, Iowa City, IA, USA; 4Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA, USA Purpose: This study aimed to determine the effect of dietary oils (olive, safflower, evening primrose, flaxseed, or menhaden enriched in different mono unsaturated fatty acids or polyunsaturated fatty acids on peripheral neuropathies in diet-induced obese Sprague-Dawley rats.Materials and methods: Rats at 12 weeks of age were fed a high-fat diet (45% kcal for 16 weeks. Afterward, the rats were fed diets with 50% of the kilocalories of fat derived from lard replaced by the different dietary oils. In addition, a control group fed a standard diet (4% kcal fat and a high fat fed group (45% kcal were maintained. The treatment period was 32 weeks. The endpoints evaluated included motor and sensory nerve conduction velocity, thermal sensitivity, innervation of sensory nerves in the cornea and skin, and vascular relaxation by epineurial arterioles.Results: Menhaden oil provided the greatest benefit for improving peripheral nerve damage caused by dietary obesity. Similar results were obtained when we examined acetylcholine-mediated vascular relaxation of epineurial arterioles of the sciatic nerve. Enriching the diets with fatty acids derived from the other oils provided minimal to partial improvements.Conclusion: These studies suggest that omega-3 polyunsaturated fatty acids derived from fish oil could be an effective treatment for neural and vascular complications associated with obesity. Keywords: peripheral neuropathy, fish oil, omega-3 polyunsaturated fatty acids, omega-6 polyunsaturated fatty

  8. Is Overall Mortality the Right Composite Endpoint in Clinical Trials of Acute Respiratory Distress Syndrome?

    Science.gov (United States)

    Villar, Jesús; Martínez, Domingo; Mosteiro, Fernando; Ambrós, Alfonso; Añón, José M; Ferrando, Carlos; Soler, Juan A; Montiel, Raquel; Vidal, Anxela; Conesa-Cayuela, Luís A; Blanco, Jesús; Arrojo, Regina; Solano, Rosario; Capilla, Lucía; Del Campo, Rafael; Civantos, Belén; Fernández, María Mar; Aldecoa, César; Parra, Laura; Gutiérrez, Andrea; Martínez-Jiménez, Chanel; González-Martín, Jesús M; Fernández, Rosa L; Kacmarek, Robert M

    2018-06-01

    Overall mortality in patients with acute respiratory distress syndrome is a composite endpoint because it includes death from multiple causes. In most acute respiratory distress syndrome trials, it is unknown whether reported deaths are due to acute respiratory distress syndrome or the underlying disease, unrelated to the specific intervention tested. We investigated the causes of death after contracting acute respiratory distress syndrome in a large cohort. A secondary analysis from three prospective, multicenter, observational studies. A network of multidisciplinary ICUs. We studied 778 patients with moderate-to-severe acute respiratory distress syndrome treated with lung-protective ventilation. None. We examined death in the ICU from individual causes. Overall ICU mortality was 38.8% (95% CI, 35.4-42.3). Causes of acute respiratory distress syndrome modified the risk of death. Twenty-three percent of deaths occurred from refractory hypoxemia due to nonresolving acute respiratory distress syndrome. Most patients died from causes unrelated to acute respiratory distress syndrome: 48.7% of nonsurvivors died from multisystem organ failure, and cancer or brain injury was involved in 37.1% of deaths. When quantifying the true burden of acute respiratory distress syndrome outcome, we identified 506 patients (65.0%) with one or more exclusion criteria for enrollment into current interventional trials. Overall ICU mortality of the "trial cohort" (21.3%) was markedly lower than the parent cohort (relative risk, 0.55; 95% CI, 0.43-0.70; p respiratory distress syndrome patients are not directly related to lung damage but to extrapulmonary multisystem organ failure. It would be challenging to prove that specific lung-directed therapies have an effect on overall survival.

  9. Clinical Trial Design Principles and Endpoint Definitions for Transcatheter Mitral Valve Repair and Replacement: Part 1: Clinical Trial Design Principles: A Consensus Document From the Mitral Valve Academic Research Consortium.

    Science.gov (United States)

    Stone, Gregg W; Vahanian, Alec S; Adams, David H; Abraham, William T; Borer, Jeffrey S; Bax, Jeroen J; Schofer, Joachim; Cutlip, Donald E; Krucoff, Mitchell W; Blackstone, Eugene H; Généreux, Philippe; Mack, Michael J; Siegel, Robert J; Grayburn, Paul A; Enriquez-Sarano, Maurice; Lancellotti, Patrizio; Filippatos, Gerasimos; Kappetein, Arie Pieter

    2015-07-21

    Mitral regurgitation (MR) is one of the most prevalent valve disorders and has numerous etiologies, including primary (organic) MR, due to underlying degenerative/structural mitral valve (MV) pathology, and secondary (functional) MR, which is principally caused by global or regional left ventricular remodeling and/or severe left atrial dilation. Diagnosis and optimal management of MR requires integration of valve disease and heart failure specialists, MV cardiac surgeons, interventional cardiologists with expertise in structural heart disease, and imaging experts. The introduction of transcatheter MV therapies has highlighted the need for a consensus approach to pragmatic clinical trial design and uniform endpoint definitions to evaluate outcomes in patients with MR. The Mitral Valve Academic Research Consortium is a collaboration between leading academic research organizations and physician-scientists specializing in MV disease from the United States and Europe. Three in-person meetings were held in Virginia and New York during which 44 heart failure, valve, and imaging experts, MV surgeons and interventional cardiologists, clinical trial specialists and statisticians, and representatives from the U.S. Food and Drug Administration considered all aspects of MV pathophysiology, prognosis, and therapies, culminating in a 2-part document describing consensus recommendations for clinical trial design (Part 1) and endpoint definitions (Part 2) to guide evaluation of transcatheter and surgical therapies for MR. The adoption of these recommendations will afford robustness and consistency in the comparative effectiveness evaluation of new devices and approaches to treat MR. These principles may be useful for regulatory assessment of new transcatheter MV devices, as well as for monitoring local and regional outcomes to guide quality improvement initiatives. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  10. Surrogate endpoints for overall survival in digestive oncology trials: which candidates? A questionnaires survey among clinicians and methodologists

    OpenAIRE

    Bonnetain Franck; Bedenne Laurent; Methy Nicolas

    2010-01-01

    Abstract Background Overall survival (OS) is the gold standard for the demonstration of a clinical benefit in cancer trials. Replacement of OS by a surrogate endpoint allows to reduce trial duration. To date, few surrogate endpoints have been validated in digestive oncology. The aim of this study was to draw up an ordered list of potential surrogate endpoints for OS in digestive cancer trials, by way of a survey among clinicians and methodologists. Secondary objective was to obtain their opin...

  11. 78 FR 73199 - Draft Guidance for Industry on Bioequivalence Studies With Pharmacokinetic Endpoints for Drugs...

    Science.gov (United States)

    2013-12-05

    ... exposure measures is suitable for documenting BE (e.g., transdermal delivery systems and certain rectal and... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2013-D-1464] Draft Guidance for Industry on Bioequivalence Studies With Pharmacokinetic Endpoints for Drugs Submitted...

  12. Baseline characteristics in the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE)

    DEFF Research Database (Denmark)

    Parving, Hans-Henrik; Brenner, Barry M; McMurray, John J V

    2012-01-01

    Patients with type 2 diabetes are at enhanced risk for macro- and microvascular complications. Albuminuria and/or reduced kidney function further enhances the vascular risk. We initiated the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE). Aliskiren, a novel direct renin...

  13. Can joint sound assess soft and hard endpoints of the Lachman test?: A preliminary study.

    Science.gov (United States)

    Hattori, Koji; Ogawa, Munehiro; Tanaka, Kazunori; Matsuya, Ayako; Uematsu, Kota; Tanaka, Yasuhito

    2016-05-12

    The Lachman test is considered to be a reliable physical examination for anterior cruciate ligament (ACL) injury. Patients with a damaged ACL demonstrate a soft endpoint feeling. However, examiners judge the soft and hard endpoints subjectively. The purpose of our study was to confirm objective performance of the Lachman test using joint auscultation. Human and porcine knee joints were examined. Knee joint sound during the Lachman test (Lachman sound) was analyzed by fast Fourier transformation. As quantitative indices of Lachman sound, the peak sound as the maximum relative amplitude (acoustic pressure) and its frequency were used. The mean Lachman peak sound for healthy volunteer knees was 86.9 ± 12.9 Hz in frequency and -40 ± 2.5 dB in acoustic pressure. The mean Lachman peak sound for intact porcine knees was 84.1 ± 9.4 Hz and -40.5 ± 1.7 dB. Porcine knees with ACL deficiency had a soft endpoint feeling during the Lachman test. The Lachman peak sounds of porcine knees with ACL deficiency were dispersed into four distinct groups, with center frequencies of around 40, 160, 450, and 1600. The Lachman peak sound was capable of assessing soft and hard endpoints of the Lachman test objectively.

  14. Coulometric Titration of Ethylenediaminetetraacetate (EDTA) with Spectrophotometric Endpoint Detection: An Experiment for the Instrumental Analysis Laboratory

    Science.gov (United States)

    Williams, Kathryn R.; Young, Vaneica Y.; Killian, Benjamin J.

    2011-01-01

    Ethylenediaminetetraacetate (EDTA) is commonly used as an anticoagulant in blood-collection procedures. In this experiment for the instrumental analysis laboratory, students determine the quantity of EDTA in commercial collection tubes by coulometric titration with electrolytically generated Cu[superscript 2+]. The endpoint is detected…

  15. Using an Ecosystem Approach to complement protection schemes based on organism-level endpoints

    International Nuclear Information System (INIS)

    Bradshaw, Clare; Kapustka, Lawrence; Barnthouse, Lawrence; Brown, Justin; Ciffroy, Philippe; Forbes, Valery; Geras'kin, Stanislav; Kautsky, Ulrik; Bréchignac, François

    2014-01-01

    Radiation protection goals for ecological resources are focussed on ecological structures and functions at population-, community-, and ecosystem-levels. The current approach to radiation safety for non-human biota relies on organism-level endpoints, and as such is not aligned with the stated overarching protection goals of international agencies. Exposure to stressors can trigger non-linear changes in ecosystem structure and function that cannot be predicted from effects on individual organisms. From the ecological sciences, we know that important interactive dynamics related to such emergent properties determine the flows of goods and services in ecological systems that human societies rely upon. A previous Task Group of the IUR (International Union of Radioecology) has presented the rationale for adding an Ecosystem Approach to the suite of tools available to manage radiation safety. In this paper, we summarize the arguments for an Ecosystem Approach and identify next steps and challenges ahead pertaining to developing and implementing a practical Ecosystem Approach to complement organism-level endpoints currently used in radiation safety. - Highlights: • An Ecosystem Approach to radiation safety complements the organism-level approach. • Emergent properties in ecosystems are not captured by organism-level endpoints. • The proposed Ecosystem Approach better aligns with management goals. • Practical guidance with respect to system-level endpoints is needed. • Guidance on computational model selection would benefit an Ecosystem Approach

  16. Systematic review and consensus definitions for the Standardised Endpoints in Perioperative Medicine (StEP) initiative

    DEFF Research Database (Denmark)

    Myles, P S; Boney, O; Botti, M

    2018-01-01

    Medicine initiative was established to derive a set of standardised endpoints for use in perioperative clinical trials. METHODS: We undertook a systematic review to identify measures of patient comfort used in the anaesthetic, surgical, and other perioperative literature. A multi-round Delphi consensus...

  17. End-point construction and systematic titration error in linear titration curves-complexation reactions

    NARCIS (Netherlands)

    Coenegracht, P.M.J.; Duisenberg, A.J.M.

    The systematic titration error which is introduced by the intersection of tangents to hyperbolic titration curves is discussed. The effects of the apparent (conditional) formation constant, of the concentration of the unknown component and of the ranges used for the end-point construction are

  18. Transmission assessment surveys (TAS) to define endpoints for lymphatic filariasis mass drug administration

    DEFF Research Database (Denmark)

    Chu, Brian K.; Deming, Michael; Biritwum, Nana-Kwadwo

    2013-01-01

    Lymphatic filariasis (LF) is targeted for global elimination through treatment of entire at-risk populations with repeated annual mass drug administration (MDA). Essential for program success is defining and confirming the appropriate endpoint for MDA when transmission is presumed to have reached...

  19. Correlates of protection for rotavirus vaccines: Possible alternative trial endpoints, opportunities, and challenges.

    Science.gov (United States)

    Angel, Juana; Steele, A Duncan; Franco, Manuel A

    2014-01-01

    Rotavirus (RV) is a major vaccine-preventable killer of young children worldwide. Two RV vaccines are globally commercially available and other vaccines are in different stages of development. Due to the absence of a suitable correlate of protection (CoP), all RV vaccine efficacy trials have had clinical endpoints. These trials represent an important challenge since RV vaccines have to be introduced in many different settings, placebo-controlled studies are unethical due to the availability of licensed vaccines, and comparator assessments for new vaccines with clinical endpoints are very large, complex, and expensive to conduct. A CoP as a surrogate endpoint would allow predictions of vaccine efficacy for new RV vaccines and enable a regulatory pathway, contributing to the more rapid development of new RV vaccines. The goal of this review is to summarize experiences from RV natural infection and vaccine studies to evaluate potential CoP for use as surrogate endpoints for assessment of new RV vaccines, and to explore challenges and opportunities in the field.

  20. Application of process analytical technology for monitoring freeze-drying of an amorphous protein formulation: use of complementary tools for real-time product temperature measurements and endpoint detection.

    Science.gov (United States)

    Schneid, Stefan C; Johnson, Robert E; Lewis, Lavinia M; Stärtzel, Peter; Gieseler, Henning

    2015-05-01

    Process analytical technology (PAT) and quality by design have gained importance in all areas of pharmaceutical development and manufacturing. One important method for monitoring of critical product attributes and process optimization in laboratory scale freeze-drying is manometric temperature measurement (MTM). A drawback of this innovative technology is that problems are encountered when processing high-concentrated amorphous materials, particularly protein formulations. In this study, a model solution of bovine serum albumin and sucrose was lyophilized at both conservative and aggressive primary drying conditions. Different temperature sensors were employed to monitor product temperatures. The residual moisture content at primary drying endpoints as indicated by temperature sensors and batch PAT methods was quantified from extracted sample vials. The data from temperature probes were then used to recalculate critical product parameters, and the results were compared with MTM data. The drying endpoints indicated by the temperature sensors were not suitable for endpoint indication, in contrast to the batch methods endpoints. The accuracy of MTM Pice data was found to be influenced by water reabsorption. Recalculation of Rp and Pice values based on data from temperature sensors and weighed vials was possible. Overall, extensive information about critical product parameters could be obtained using data from complementary PAT tools. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

  1. The Impact of Chemoembolization Endpoints on Survival in Hepatocellular Carcinoma Patients

    Science.gov (United States)

    Jin, Brian; Wang, Dingxin; Lewandowski, Robert J.; Riaz, Ahsun; Ryu, Robert K.; Sato, Kent T.; Larson, Andrew C.; Salem, Riad; Omary, Reed A.

    2010-01-01

    OBJECTIVE To investigate the relationship between angiographic embolic endpoints of transarterial chemoembolization (TACE) and survival in patients with hepatocellular carcinoma (HCC). MATERIALS AND METHODS This study retrospectively assessed 105 patients with surgically unresectable HCC who underwent TACE. Patients were classified according to a previously established subjective angiographic chemoembolization endpoint (SACE) scale. Only one patient was classified as SACE level 1 and thus excluded from all subsequent analysis. Survival was evaluated with Kaplan-Meier analysis. Multivariate analysis with Cox’s proportional hazard regression model was used to determine independent prognostic risk factors of survival. RESULTS Overall median survival was 21.1 months (95% confidence interval [CI], 15.9–26.4). Patients embolized to SACE levels 2 and 3 were aggregated and had a significantly higher median survival (25.6 months; 95% CI, 16.2–35.0) than patients embolized to SACE level 4 (17.1 months; 95% CI, 13.3–20.9) (p = 0.035). Multivariate analysis indicated that SACE level 4 (Hazard ratio [HR], 2.49; 95% CI, 1.41–4.42; p = 0.002), European Cooperative Oncology Group performance status > 0 (HR, 1.97; 95% CI, 1.15–3.37; p = 0.013), American Joint Committee on Cancer stage 3 or 4 (HR, 2.42; 95% CI, 1.27–4.60; p = 0.007), and Child-Pugh class B (HR, 1.94; 95% CI, 1.09–3.46; p = 0.025) were all independent negative prognostic indicators of survival. CONCLUSION Embolization to an intermediate, sub-stasis endpoint (SACE levels 2 and 3) during TACE improves survival compared to embolization to a higher, stasis endpoint (SACE level 4). Interventional oncologists should consider targeting these intermediate, sub-stasis angiographic endpoints during TACE. PMID:21427346

  2. Guidelines for time-to-event end-point definitions in trials for pancreatic cancer. Results of the DATECAN initiative (Definition for the Assessment of Time-to-event End-points in CANcer trials)

    NARCIS (Netherlands)

    Bonnetain, Franck; Bonsing, Bert; Conroy, Thierry; Dousseau, Adelaide; Glimelius, Bengt; Haustermans, Karin; Lacaine, François; van Laethem, Jean Luc; Aparicio, Thomas; Aust, Daniela; Bassi, Claudio; Berger, Virginie; Chamorey, Emmanuel; Chibaudel, Benoist; Dahan, Laeticia; de Gramont, Aimery; Delpero, Jean Robert; Dervenis, Christos; Ducreux, Michel; Gal, Jocelyn; Gerber, Erich; Ghaneh, Paula; Hammel, Pascal; Hendlisz, Alain; Jooste, Valérie; Labianca, Roberto; Latouche, Aurelien; Lutz, Manfred; Macarulla, Teresa; Malka, David; Mauer, Muriel; Mitry, Emmanuel; Neoptolemos, John; Pessaux, Patrick; Sauvanet, Alain; Tabernero, Josep; Taieb, Julien; van Tienhoven, Geertjan; Gourgou-Bourgade, Sophie; Bellera, Carine; Mathoulin-Pélissier, Simone; Collette, Laurence

    2014-01-01

    Using potential surrogate end-points for overall survival (OS) such as Disease-Free- (DFS) or Progression-Free Survival (PFS) is increasingly common in randomised controlled trials (RCTs). However, end-points are too often imprecisely defined which largely contributes to a lack of homogeneity across

  3. Defining clinically important perioperative blood loss and transfusion for the Standardised Endpoints for Perioperative Medicine (StEP) collaborative: a protocol for a scoping review.

    Science.gov (United States)

    Bartoszko, Justyna; Vorobeichik, Leon; Jayarajah, Mohandas; Karkouti, Keyvan; Klein, Andrew A; Lamy, Andre; Mazer, C David; Murphy, Mike; Richards, Toby; Englesakis, Marina; Myles, Paul S; Wijeysundera, Duminda N

    2017-06-30

    'Standardised Endpoints for Perioperative Medicine' (StEP) is an international collaboration undertaking development of consensus-based consistent definitions for endpoints in perioperative clinical trials. Inconsistency in endpoint definitions can make interpretation of trial results more difficult, especially if conflicting evidence is present. Furthermore, this inconsistency impedes evidence synthesis and meta-analyses. The goals of StEP are to harmonise definitions for clinically meaningful endpoints and specify standards for endpoint reporting in clinical trials. To help inform this endeavour, we aim to conduct a scoping review to systematically characterise the definitions of clinically important endpoints in the existing published literature on perioperative blood loss and transfusion. The scoping review will be conducted using the widely adopted framework developed by Arksey and O'Malley, with modifications from Levac. We refined our methods with guidance from research librarians as well as researchers and clinicians with content expertise. The electronic literature search will involve several databases including Medline, PubMed-not-Medline and Embase. Our review has three objectives, namely to (1) identify definitions of significant blood loss and transfusion used in previously published large perioperative randomised trials; (2) identify previously developed consensus-based definitions for significant blood loss and transfusion in perioperative medicine and related fields; and (3) describe the association between different magnitudes of blood loss and transfusion with postoperative outcomes. The multistage review process for each question will involve two reviewers screening abstracts, reading full-text articles and performing data extraction. The abstracted data will be organised and subsequently analysed in an iterative process. This scoping review of the previously published literature does not require research ethics approval. The results will be used

  4. Modulation of cigarette smoke-related end-points in mutagenesis and carcinogenesis

    International Nuclear Information System (INIS)

    De Flora, Silvio; D'Agostini, Francesco; Balansky, Roumen; Camoirano, Anna; Bennicelli, Carlo; Bagnasco, Maria; Cartiglia, Cristina; Tampa, Elena; Longobardi, Maria Grazia; Lubet, Ronald A.; Izzotti, Alberto

    2003-01-01

    The epidemic of lung cancer and the increase of other tumours and chronic degenerative diseases associated with tobacco smoking have represented one of the most dramatic catastrophes of the 20th century. The control of this plague is one of the major challenges of preventive medicine for the next decades. The imperative goal is to refrain from smoking. However, chemoprevention by dietary and/or pharmacological agents provides a complementary strategy, which can be targeted not only to current smokers but also to former smokers and passive smokers. This article summarises the results of studies performed in our laboratories during the last 10 years, and provides new data generated in vitro, in experimental animals and in humans. We compared the ability of 63 putative chemopreventive agents to inhibit the bacterial mutagenicity of mainstream cigarette smoke. Modulation by ethanol and the mechanisms involved were also investigated both in vitro and in vivo. Several studies evaluated the effects of dietary chemopreventive agents towards smoke-related intermediate biomarkers in various cells, tissues and organs of rodents. The investigated end-points included metabolic parameters, adducts to haemoglobin, bulky adducts to nuclear DNA, oxidative DNA damage, adducts to mitochondrial DNA, apoptosis, cytogenetic damage in alveolar macrophages, bone marrow and peripheral blood erytrocytes, proliferation markers, and histopathological alterations. The agents tested in vivo included N-acetyl-L-cysteine, 1,2-dithiole-3-thione, oltipraz, phenethyl isothiocyanate, 5,6-benzoflavone, and sulindac. We started applying multigene expression analysis to chemoprevention research, and postulated that an optimal agent should not excessively alter per se the physiological background of gene expression but should be able to attenuate the alterations produced by cigarette smoke or other carcinogens. We are working to develop an animal model for the induction of lung tumours following exposure

  5. Group-Sequential Strategies in Clinical Trials with Multiple Co-Primary Outcomes

    Science.gov (United States)

    Hamasaki, Toshimitsu; Asakura, Koko; Evans, Scott R; Sugimoto, Tomoyuki; Sozu, Takashi

    2015-01-01

    We discuss the decision-making frameworks for clinical trials with multiple co-primary endpoints in a group-sequential setting. The decision-making frameworks can account for flexibilities such as a varying number of analyses, equally or unequally spaced increments of information and fixed or adaptive Type I error allocation among endpoints. The frameworks can provide efficiency, i.e., potentially fewer trial participants, than the fixed sample size designs. We investigate the operating characteristics of the decision-making frameworks and provide guidance on constructing efficient group-sequential strategies in clinical trials with multiple co-primary endpoints. PMID:25844122

  6. The time-dependent "cure-death" model investigating two equally important endpoints simultaneously in trials treating high-risk patients with resistant pathogens.

    Science.gov (United States)

    Sommer, Harriet; Wolkewitz, Martin; Schumacher, Martin

    2017-07-01

    A variety of primary endpoints are used in clinical trials treating patients with severe infectious diseases, and existing guidelines do not provide a consistent recommendation. We propose to study simultaneously two primary endpoints, cure and death, in a comprehensive multistate cure-death model as starting point for a treatment comparison. This technique enables us to study the temporal dynamic of the patient-relevant probability to be cured and alive. We describe and compare traditional and innovative methods suitable for a treatment comparison based on this model. Traditional analyses using risk differences focus on one prespecified timepoint only. A restricted logrank-based test of treatment effect is sensitive to ordered categories of responses and integrates information on duration of response. The pseudo-value regression provides a direct regression model for examination of treatment effect via difference in transition probabilities. Applied to a topical real data example and simulation scenarios, we demonstrate advantages and limitations and provide an insight into how these methods can handle different kinds of treatment imbalances. The cure-death model provides a suitable framework to gain a better understanding of how a new treatment influences the time-dynamic cure and death process. This might help the future planning of randomised clinical trials, sample size calculations, and data analyses. Copyright © 2017 John Wiley & Sons, Ltd.

  7. Reversal of primary root caries lesions after daily intake of milk supplemented with fluoride and probiotic lactobacilli in older adults

    DEFF Research Database (Denmark)

    Petersson, Lars G; Magnusson, Kerstin; Hakestam, Ulf

    2011-01-01

    and group D milk contained only fluoride. Primary endpoints were Root Caries Index (RCI) and electric resistance measurements (ECM) carried out by one blinded single examiner. Secondary endpoints were mutans streptococci and lactobacilli counts in saliva and plaque estimated with chair-side tests. Data were...

  8. Brain tumor - primary - adults

    Science.gov (United States)

    ... Vestibular schwannoma (acoustic neuroma) - adults; Meningioma - adults; Cancer - brain tumor (adults) ... Primary brain tumors include any tumor that starts in the brain. Primary brain tumors can start from brain cells, ...

  9. Free Energy, Enthalpy and Entropy from Implicit Solvent End-Point Simulations.

    Science.gov (United States)

    Fogolari, Federico; Corazza, Alessandra; Esposito, Gennaro

    2018-01-01

    Free energy is the key quantity to describe the thermodynamics of biological systems. In this perspective we consider the calculation of free energy, enthalpy and entropy from end-point molecular dynamics simulations. Since the enthalpy may be calculated as the ensemble average over equilibrated simulation snapshots the difficulties related to free energy calculation are ultimately related to the calculation of the entropy of the system and in particular of the solvent entropy. In the last two decades implicit solvent models have been used to circumvent the problem and to take into account solvent entropy implicitly in the solvation terms. More recently outstanding advancement in both implicit solvent models and in entropy calculations are making the goal of free energy estimation from end-point simulations more feasible than ever before. We review briefly the basic theory and discuss the advancements in light of practical applications.

  10. Adaptive endpoint detection of seismic signal based on auto-correlated function

    International Nuclear Information System (INIS)

    Fan Wanchun; Shi Ren

    2000-01-01

    There are certain shortcomings for the endpoint detection by time-waveform envelope and/or by checking the travel table (both labelled as the artificial detection method). Based on the analysis of the auto-correlation function, the notion of the distance between auto-correlation functions was quoted, and the characterizations of the noise and the signal with noise were discussed by using the distance. Then, the method of auto-adaptable endpoint detection of seismic signal based on auto-correlated similarity was summed up. The steps of implementation and determining of the thresholds were presented in detail. The experimental results that were compared with the methods based on artificial detecting show that this method has higher sensitivity even in a low SNR circumstance

  11. Free Energy, Enthalpy and Entropy from Implicit Solvent End-Point Simulations

    Directory of Open Access Journals (Sweden)

    Federico Fogolari

    2018-02-01

    Full Text Available Free energy is the key quantity to describe the thermodynamics of biological systems. In this perspective we consider the calculation of free energy, enthalpy and entropy from end-point molecular dynamics simulations. Since the enthalpy may be calculated as the ensemble average over equilibrated simulation snapshots the difficulties related to free energy calculation are ultimately related to the calculation of the entropy of the system and in particular of the solvent entropy. In the last two decades implicit solvent models have been used to circumvent the problem and to take into account solvent entropy implicitly in the solvation terms. More recently outstanding advancement in both implicit solvent models and in entropy calculations are making the goal of free energy estimation from end-point simulations more feasible than ever before. We review briefly the basic theory and discuss the advancements in light of practical applications.

  12. Muscle Synergies Heavily Influence the Neural Control of Arm Endpoint Stiffness and Energy Consumption.

    Science.gov (United States)

    Inouye, Joshua M; Valero-Cuevas, Francisco J

    2016-02-01

    Much debate has arisen from research on muscle synergies with respect to both limb impedance control and energy consumption. Studies of limb impedance control in the context of reaching movements and postural tasks have produced divergent findings, and this study explores whether the use of synergies by the central nervous system (CNS) can resolve these findings and also provide insights on mechanisms of energy consumption. In this study, we phrase these debates at the conceptual level of interactions between neural degrees of freedom and tasks constraints. This allows us to examine the ability of experimentally-observed synergies--correlated muscle activations--to control both energy consumption and the stiffness component of limb endpoint impedance. In our nominal 6-muscle planar arm model, muscle synergies and the desired size, shape, and orientation of endpoint stiffness ellipses, are expressed as linear constraints that define the set of feasible muscle activation patterns. Quadratic programming allows us to predict whether and how energy consumption can be minimized throughout the workspace of the limb given those linear constraints. We show that the presence of synergies drastically decreases the ability of the CNS to vary the properties of the endpoint stiffness and can even preclude the ability to minimize energy. Furthermore, the capacity to minimize energy consumption--when available--can be greatly affected by arm posture. Our computational approach helps reconcile divergent findings and conclusions about task-specific regulation of endpoint stiffness and energy consumption in the context of synergies. But more generally, these results provide further evidence that the benefits and disadvantages of muscle synergies go hand-in-hand with the structure of feasible muscle activation patterns afforded by the mechanics of the limb and task constraints. These insights will help design experiments to elucidate the interplay between synergies and the mechanisms

  13. Comparison of mammalian and fish cell line cytotoxicity: impact of endpoint and exposure duration

    International Nuclear Information System (INIS)

    Guelden, Michael; Moerchel, Sabine; Seibert, Hasso

    2005-01-01

    Comparisons of acute toxic concentrations of chemicals to fish in vivo and cytotoxic concentrations to fish cell lines in vitro reveal rather good correlations of the toxic potencies in vitro and in vivo, but a clearly lower sensitivity of the fish cells. To examine whether the low sensitivity is specific for fish cells, cytotoxic potencies of reference chemicals from the Multicenter Evaluation of In Vitro Cytotoxicity program (MEIC) reported for the fish cell lines R1 and RTG-2 were compared with those obtained with the mouse Balb/c 3T3 cell line. Cytotoxic potencies (EC 50 values) for MEIC reference chemicals were determined with exponentially growing Balb/c 3T3 cells using three different test protocols. To assess both endpoints, cell proliferation and cell survival, EC 50 values were measured for the decrease in final cell protein after 24 and 72 h of exposure and for the reduction of cell protein increase during 24 h of exposure. EC 50 values obtained with the fish cell lines R1 and RTG-2 using cell survival as endpoint were taken from the MEIC data base. The comparison of cytotoxic potencies shows that, in general, the fish cell lines and the mammalian cell line are almost equally sensitive towards the cytotoxic action of chemicals. The mammalian cell line assay, however, becomes considerably more sensitive, by factors of 3.4-8.5, than the fish cell line assays, if cell growth instead of cell survival is used as endpoint. It is concluded, that cell proliferation might be a better endpoint than cell survival and that mammalian cell lines might be suited to assess fish acute toxicity

  14. Energy metabolism and biotransformation as endpoints to pre-screen hepatotoxicity using a liver spheroid model

    International Nuclear Information System (INIS)

    Xu Jinsheng; Purcell, Wendy M.

    2006-01-01

    The current study investigated liver spheroid culture as an in vitro model to evaluate the endpoints relevant to the status of energy metabolism and biotransformation after exposure to test toxicants. Mature rat liver spheroids were exposed to diclofenac, galactosamine, isoniazid, paracetamol, m-dinitrobenzene (m-DNB) and 3-nitroaniline (3-NA) for 24 h. Pyruvate uptake, galactose biotransformation, lactate release and glucose secretion were evaluated after exposure. The results showed that pyruvate uptake and lactate release by mature liver spheroids in culture were maintained at a relatively stable level. These endpoints, together with glucose secretion and galactose biotransformation, were related to and could reflect the status of energy metabolism and biotransformation in hepatocytes. After exposure, all of the test agents significantly reduced glucose secretion, which was shown to be the most sensitive endpoint of those evaluated. Diclofenac, isoniazid, paracetamol and galactosamine reduced lactate release (P < 0.01), but m-DNB increased lactate release (P < 0.01). Diclofenac, isoniazid and paracetamol also reduced pyruvate uptake (P < 0.01), while galactosamine had little discernible effect. Diclofenac, galactosamine, paracetamol and m-DNB also reduced galactose biotransformation (P < 0.01), by contrast, isoniazid did not. The metabolite of m-DNB, 3-NA, which served as a negative control, did not cause significant changes in lactate release, pyruvate uptake or galactose biotransformation. It is concluded that pyruvate uptake, galactose biotransformation, lactate release and glucose secretion can be used as endpoints for evaluating the status of energy metabolism and biotransformation after exposure to test agents using the liver spheroid model to pre-screen hepatotoxicity

  15. Kinetic titration with differential thermometric determination of the end-point.

    Science.gov (United States)

    Sajó, I

    1968-06-01

    A method has been described for the determination of concentrations below 10(-4)M by applying catalytic reactions and using thermometric end-point determination. A reference solution, identical with the sample solution except for catalyst, is titrated with catalyst solution until the rates of reaction become the same, as shown by a null deflection on a galvanometer connected via bridge circuits to two opposed thermistors placed in the solutions.

  16. Quantitative 4D Transcatheter Intraarterial Perfusion MR Imaging as a Method to Standardize Angiographic Chemoembolization Endpoints

    Science.gov (United States)

    Jin, Brian; Wang, Dingxin; Lewandowski, Robert J.; Ryu, Robert K.; Sato, Kent T.; Larson, Andrew C.; Salem, Riad; Omary, Reed A.

    2011-01-01

    PURPOSE We aimed to test the hypothesis that subjective angiographic endpoints during transarterial chemoembolization (TACE) of hepatocellular carcinoma (HCC) exhibit consistency and correlate with objective intraprocedural reductions in tumor perfusion as determined by quantitative four dimensional (4D) transcatheter intraarterial perfusion (TRIP) magnetic resonance (MR) imaging. MATERIALS AND METHODS This prospective study was approved by the institutional review board. Eighteen consecutive patients underwent TACE in a combined MR/interventional radiology (MR-IR) suite. Three board-certified interventional radiologists independently graded the angiographic endpoint of each procedure based on a previously described subjective angiographic chemoembolization endpoint (SACE) scale. A consensus SACE rating was established for each patient. Patients underwent quantitative 4D TRIP-MR imaging immediately before and after TACE, from which mean whole tumor perfusion (Fρ) was calculated. Consistency of SACE ratings between observers was evaluated using the intraclass correlation coefficient (ICC). The relationship between SACE ratings and intraprocedural TRIP-MR imaging perfusion changes was evaluated using Spearman’s rank correlation coefficient. RESULTS The SACE rating scale demonstrated very good consistency among all observers (ICC = 0.80). The consensus SACE rating was significantly correlated with both absolute (r = 0.54, P = 0.022) and percent (r = 0.85, P SACE rating scale demonstrates very good consistency between raters, and significantly correlates with objectively measured intraprocedural perfusion reductions during TACE. These results support the use of the SACE scale as a standardized alternative method to quantitative 4D TRIP-MR imaging to classify patients based on embolic endpoints of TACE. PMID:22021520

  17. The Growing Need for Validated Biomarkers and Endpoints for Dry Eye Clinical Research.

    Science.gov (United States)

    Roy, Neeta S; Wei, Yi; Kuklinski, Eric; Asbell, Penny A

    2017-05-01

    Biomarkers with minimally invasive and reproducible objective metrics provide the key to future paradigm shifts in understanding of the underlying causes of dry eye disease (DED) and approaches to treatment of DED. We review biomarkers and their validity in providing objective metrics for DED clinical research and patient care. The English-language literature in PubMed primarily over the last decade was surveyed for studies related to identification of biomarkers of DED: (1) inflammation, (2) point-of-care, (3) ocular imaging, and (4) genetics. Relevant studies in each group were individually evaluated for (1) methodological and analytical details, (2) data and concordance with other similar studies, and (3) potential to serve as validated biomarkers with objective metrics. Significant work has been done to identify biomarkers for DED clinical trials and for patient care. Interstudy variation among studies dealing with the same biomarker type was high. This could be attributed to biologic variations and/or differences in processing, and data analysis. Correlation with other signs and symptoms of DED was not always clear or present. Many of the biomarkers reviewed show the potential to serve as validated and objective metrics for clinical research and patient care in DED. Interstudy variation for a given biomarker emphasizes the need for detailed reporting of study methodology, including information on subject characteristics, quality control, processing, and analysis methods to optimize development of nonsubjective metrics. Biomarker development offers a rich opportunity to significantly move forward clinical research and patient care in DED. DED is an unmet medical need - a chronic pain syndrome associated with variable vision that affects quality of life, is common with advancing age, interferes with the comfortable use of contact lenses, and can diminish results of eye surgeries, such as cataract extraction, LASIK, and glaucoma procedures. It is a worldwide

  18. Automatic sorting of toxicological information into the IUCLID (International Uniform Chemical Information Database) endpoint-categories making use of the semantic search engine Go3R.

    Science.gov (United States)

    Sauer, Ursula G; Wächter, Thomas; Hareng, Lars; Wareing, Britta; Langsch, Angelika; Zschunke, Matthias; Alvers, Michael R; Landsiedel, Robert

    2014-06-01

    The knowledge-based search engine Go3R, www.Go3R.org, has been developed to assist scientists from industry and regulatory authorities in collecting comprehensive toxicological information with a special focus on identifying available alternatives to animal testing. The semantic search paradigm of Go3R makes use of expert knowledge on 3Rs methods and regulatory toxicology, laid down in the ontology, a network of concepts, terms, and synonyms, to recognize the contents of documents. Search results are automatically sorted into a dynamic table of contents presented alongside the list of documents retrieved. This table of contents allows the user to quickly filter the set of documents by topics of interest. Documents containing hazard information are automatically assigned to a user interface following the endpoint-specific IUCLID5 categorization scheme required, e.g. for REACH registration dossiers. For this purpose, complex endpoint-specific search queries were compiled and integrated into the search engine (based upon a gold standard of 310 references that had been assigned manually to the different endpoint categories). Go3R sorts 87% of the references concordantly into the respective IUCLID5 categories. Currently, Go3R searches in the 22 million documents available in the PubMed and TOXNET databases. However, it can be customized to search in other databases including in-house databanks. Copyright © 2013 Elsevier Ltd. All rights reserved.

  19. A New Test Unit for Disintegration End-Point Determination of Orodispersible Films.

    Science.gov (United States)

    Low, Ariana; Kok, Si Ling; Khong, Yuet Mei; Chan, Sui Yung; Gokhale, Rajeev

    2015-11-01

    No standard time or pharmacopoeia disintegration test method for orodispersible films (ODFs) exists. The USP disintegration test for tablets and capsules poses significant challenges for end-point determination when used for ODFs. We tested a newly developed disintegration test unit (DTU) against the USP disintegration test. The DTU is an accessory to the USP disintegration apparatus. It holds the ODF in a horizontal position, allowing top-view of the ODF during testing. A Gauge R&R study was conducted to assign relative contributions of the total variability from the operator, sample or the experimental set-up. Precision was compared using commercial ODF products in different media. Agreement between the two measurement methods was analysed. The DTU showed improved repeatability and reproducibility compared to the USP disintegration system with tighter standard deviations regardless of operator or medium. There is good agreement between the two methods, with the USP disintegration test giving generally longer disintegration times possibly due to difficulty in end-point determination. The DTU provided clear end-point determination and is suitable for quality control of ODFs during product developmental stage or manufacturing. This may facilitate the development of a standardized methodology for disintegration time determination of ODFs. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

  20. End-point impedance measurements across dominant and nondominant hands and robotic assistance with directional damping.

    Science.gov (United States)

    Erden, Mustafa Suphi; Billard, Aude

    2015-06-01

    The goal of this paper is to perform end-point impedance measurements across dominant and nondominant hands while doing airbrush painting and to use the results for developing a robotic assistance scheme. We study airbrush painting because it resembles in many ways manual welding, a standard industrial task. The experiments are performed with the 7 degrees of freedom KUKA lightweight robot arm. The robot is controlled in admittance using a force sensor attached at the end-point, so as to act as a free-mass and be passively guided by the human. For impedance measurements, a set of nine subjects perform 12 repetitions of airbrush painting, drawing a straight-line on a cartoon horizontally placed on a table, while passively moving the airbrush mounted on the robot's end-point. We measure hand impedance during the painting task by generating sudden and brief external forces with the robot. The results show that on average the dominant hand displays larger impedance than the nondominant in the directions perpendicular to the painting line. We find the most significant difference in the damping values in these directions. Based on this observation, we develop a "directional damping" scheme for robotic assistance and conduct a pilot study with 12 subjects to contrast airbrush painting with and without robotic assistance. Results show significant improvement in precision with both dominant and nondominant hands when using robotic assistance.

  1. Using quantitative structure-activity relationships (QSAR) to predict toxic endpoints for polycyclic aromatic hydrocarbons (PAH).

    Science.gov (United States)

    Bruce, Erica D; Autenrieth, Robin L; Burghardt, Robert C; Donnelly, K C; McDonald, Thomas J

    2008-01-01

    Quantitative structure-activity relationships (QSAR) offer a reliable, cost-effective alternative to the time, money, and animal lives necessary to determine chemical toxicity by traditional methods. Additionally, humans are exposed to tens of thousands of chemicals in their lifetimes, necessitating the determination of chemical toxicity and screening for those posing the greatest risk to human health. This study developed models to predict toxic endpoints for three bioassays specific to several stages of carcinogenesis. The ethoxyresorufin O-deethylase assay (EROD), the Salmonella/microsome assay, and a gap junction intercellular communication (GJIC) assay were chosen for their ability to measure toxic endpoints specific to activation-, induction-, and promotion-related effects of polycyclic aromatic hydrocarbons (PAH). Shape-electronic, spatial, information content, and topological descriptors proved to be important descriptors in predicting the toxicity of PAH in these bioassays. Bioassay-based toxic equivalency factors (TEF(B)) were developed for several PAH using the quantitative structure-toxicity relationships (QSTR) developed. Predicting toxicity for a specific PAH compound, such as a bioassay-based potential potency (PP(B)) or a TEF(B), is possible by combining the predicted behavior from the QSTR models. These toxicity estimates may then be incorporated into a risk assessment for compounds that lack toxicity data. Accurate toxicity predictions are made by examining each type of endpoint important to the process of carcinogenicity, and a clearer understanding between composition and toxicity can be obtained.

  2. Individuals versus organisms versus populations in the definition of ecological assessment endpoints.

    Science.gov (United States)

    Suter, Glenn W; Norton, Susan B; Fairbrother, Anne

    2005-11-01

    Discussions and applications of the policies and practices of the U.S. Environmental Protection Agency (USEPA) in ecological risk assessment will benefit from continued clarification of the concepts of assessment endpoints and of levels of biological organization. First, assessment endpoint entities and attributes can be defined at different levels of organization. Hence, an organism-level attribute, such as growth or survival, can be applied collectively to a population-level entity such as the brook trout in a stream. Second, assessment endpoints for ecological risk assessment are often mistakenly described as "individual level," which leads to the idea that such assessments are intended to protect individuals. Finally, populations play a more important role in risk assessments than is generally recognized. Organism-level attributes are used primarily for population-level assessments. In addition, the USEPA and other agencies already are basing management decisions on population or community entities and attributes such as production of fisheries, abundance of migratory bird populations, and aquatic community composition.

  3. Reduction of animal suffering in rabies vaccine potency testing by introduction of humane endpoints.

    Science.gov (United States)

    Takayama-Ito, Mutsuyo; Lim, Chang-Kweng; Nakamichi, Kazuo; Kakiuchi, Satsuki; Horiya, Madoka; Posadas-Herrera, Guillermo; Kurane, Ichiro; Saijo, Masayuki

    2017-03-01

    Potency controls of inactivated rabies vaccines for human use are confirmed by the National Institutes of Health challenge test in which lethal infection with severe neurological symptoms should be observed in approximately half of the mice inoculated with the rabies virus. Weight loss, decreased body temperature, and the presence of rabies-associated neurological signs have been proposed as humane endpoints. The potential for reduction of animal suffering by introducing humane endpoints in the potency test for inactivated rabies vaccine for human use was investigated. The clinical signs were scored and body weight was monitored. The average times to death following inoculation were 10.49 and 10.99 days post-inoculation (dpi) by the potency and challenge control tests, respectively, whereas the average times to showing Score-2 signs (paralysis, trembling, and coma) were 6.26 and 6.55 dpi, respectively. Body weight loss of more than 15% appeared at 5.82 and 6.42 dpi. The data provided here support the introduction of obvious neuronal signs combined with a body weight loss of ≥15% as a humane endpoint to reduce the time of animal suffering by approximately 4 days. Copyright © 2017 International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved.

  4. Ecotoxicological evaluation of the additive butylated hydroxyanisole using a battery with six model systems and eighteen endpoints.

    Science.gov (United States)

    Jos, Angeles; Repetto, Guillermo; Ríos, Juan Carlos; del Peso, Ana; Salguero, Manuel; Hazen, María José; Molero, María Luisa; Fernández-Freire, Paloma; Pérez-Martín, Jose Manuel; Labrador, Verónica; Cameán, Ana

    2005-01-26

    The occurrence and fate of additives in the aquatic environment is an emerging issue in environmental chemistry. This paper describes the ecotoxicological effects of the commonly used additive butylated hydroxyanisole (BHA) using a test battery, comprising of several different organisms and in vitro test systems, representing a proportion of the different trophic levels. The most sensitive system to BHA was the inhibition of bioluminescence in Vibrio fischeri bacteria, which resulted in an acute low observed adverse effect concentration (LOAEC) of 0.28 microM. The next most sensitive system was the immobilization of the cladoceran Daphnia magna followed by: the inhibition of the growth of the unicellular alga Chlorella vulgaris; the endpoints evaluated in Vero (mammalian) cells (total protein content, LDH activity, neutral red uptake and MTT metabolization), mitotic index and root growth inhibition in the terrestrial plant Allium cepa, and finally, the endpoints used on the RTG-2 salmonid fish cell line (neutral red uptake, total protein content, MTS metabolization, lactate dehydrogenase leakage and activity, and glucose-6-phosphate dehydrogenase activity). Morphological alterations in RTG-2 cells were also assessed and these included loss of cells, induction of cellular pleomorphism, hydropic degeneration and induction of apoptosis at high concentrations. The results from this study also indicated that micronuclei were not induced in A.cepa exposed to BHA. The differences in sensitivity for the diverse systems that were used (EC50 ranged from 1.2 to >500 microM) suggest the importance for a test battery approach in the evaluation of the ecological consequences of chemicals. According to the results, the levels of BHA reported in industrial wastewater would elicit adverse effects in the environment. This, coupled with its potential to bioaccumulate, makes BHA a pollutant of concern not only for acute exposures, but also for the long-term.

  5. Modelling the long-term consequences of a hypothetical dispersal of radioactivity in an urban area including remediation alternatives

    DEFF Research Database (Denmark)

    Thiessen, K.M.; Andersson, Kasper Grann; Batandjieva, B.

    2009-01-01

    The Urban Remediation Working Group of the International Atomic Energy Agency's EMRAS (Environmental Modelling for Radiation Safety) program was organized to address issues of remediation assessment modelling for urban areas contaminated with dispersed radionuclides. The present paper describes...... the second of two modelling exercises. This exercise was based on a hypothetical dispersal of radioactivity in an urban area from a radiological dispersal device, with reference surface contamination at selected sites used as the primary input information. Modelling endpoints for the exercise included...... radionuclide concentrations and external dose rates at specified locations, contributions to the dose rates from individual surfaces, and annual and cumulative external doses to specified reference individuals. Model predictions were performed for a "no action" situation (with no remedial measures...

  6. New seismograph includes filters

    Energy Technology Data Exchange (ETDEWEB)

    1979-11-02

    The new Nimbus ES-1210 multichannel signal enhancement seismograph from EG and G geometrics has recently been redesigned to include multimode signal fillers on each amplifier. The ES-1210F is a shallow exploration seismograph for near subsurface exploration such as in depth-to-bedrock, geological hazard location, mineral exploration, and landslide investigations.

  7. Angiographic core laboratory reproducibility analyses: implications for planning clinical trials using coronary angiography and left ventriculography end-points.

    Science.gov (United States)

    Steigen, Terje K; Claudio, Cheryl; Abbott, David; Schulzer, Michael; Burton, Jeff; Tymchak, Wayne; Buller, Christopher E; John Mancini, G B

    2008-06-01

    To assess reproducibility of core laboratory performance and impact on sample size calculations. Little information exists about overall reproducibility of core laboratories in contradistinction to performance of individual technicians. Also, qualitative parameters are being adjudicated increasingly as either primary or secondary end-points. The comparative impact of using diverse indexes on sample sizes has not been previously reported. We compared initial and repeat assessments of five quantitative parameters [e.g., minimum lumen diameter (MLD), ejection fraction (EF), etc.] and six qualitative parameters [e.g., TIMI myocardial perfusion grade (TMPG) or thrombus grade (TTG), etc.], as performed by differing technicians and separated by a year or more. Sample sizes were calculated from these results. TMPG and TTG were also adjudicated by a second core laboratory. MLD and EF were the most reproducible, yielding the smallest sample size calculations, whereas percent diameter stenosis and centerline wall motion require substantially larger trials. Of the qualitative parameters, all except TIMI flow grade gave reproducibility characteristics yielding sample sizes of many 100's of patients. Reproducibility of TMPG and TTG was only moderately good both within and between core laboratories, underscoring an intrinsic difficulty in assessing these. Core laboratories can be shown to provide reproducibility performance that is comparable to performance commonly ascribed to individual technicians. The differences in reproducibility yield huge differences in sample size when comparing quantitative and qualitative parameters. TMPG and TTG are intrinsically difficult to assess and conclusions based on these parameters should arise only from very large trials.

  8. The ladies trial: laparoscopic peritoneal lavage or resection for purulent peritonitisA and Hartmann's procedure or resection with primary anastomosis for purulent or faecal peritonitisB in perforated diverticulitis (NTR2037

    Directory of Open Access Journals (Sweden)

    Bruin Sjoerd C

    2010-10-01

    Full Text Available Abstract Background Recently, excellent results are reported on laparoscopic lavage in patients with purulent perforated diverticulitis as an alternative for sigmoidectomy and ostomy. The objective of this study is to determine whether LaparOscopic LAvage and drainage is a safe and effective treatment for patients with purulent peritonitis (LOLA-arm and to determine the optimal resectional strategy in patients with a purulent or faecal peritonitis (DIVA-arm: perforated DIVerticulitis: sigmoidresection with or without Anastomosis. Methods/Design In this multicentre randomised trial all patients with perforated diverticulitis are included. Upon laparoscopy, patients with purulent peritonitis are treated with laparoscopic lavage and drainage, Hartmann's procedure or sigmoidectomy with primary anastomosis in a ratio of 2:1:1 (LOLA-arm. Patients with faecal peritonitis will be randomised 1:1 between Hartmann's procedure and resection with primary anastomosis (DIVA-arm. The primary combined endpoint of the LOLA-arm is major morbidity and mortality. A sample size of 132:66:66 patients will be able to detect a difference in the primary endpoint from 25% in resectional groups compared to 10% in the laparoscopic lavage group (two sided alpha = 5%, power = 90%. Endpoint of the DIVA-arm is stoma free survival one year after initial surgery. In this arm 212 patients are needed to significantly demonstrate a difference of 30% (log rank test two sided alpha = 5% and power = 90% in favour of the patients with resection with primary anastomosis. Secondary endpoints for both arms are the number of days alive and outside the hospital, health related quality of life, health care utilisation and associated costs. Discussion The Ladies trial is a nationwide multicentre randomised trial on perforated diverticulitis that will provide evidence on the merits of laparoscopic lavage and drainage for purulent generalised peritonitis and on the optimal resectional strategy

  9. Analytic device including nanostructures

    KAUST Repository

    Di Fabrizio, Enzo M.; Fratalocchi, Andrea; Totero Gongora, Juan Sebastian; Coluccio, Maria Laura; Candeloro, Patrizio; Cuda, Gianni

    2015-01-01

    A device for detecting an analyte in a sample comprising: an array including a plurality of pixels, each pixel including a nanochain comprising: a first nanostructure, a second nanostructure, and a third nanostructure, wherein size of the first nanostructure is larger than that of the second nanostructure, and size of the second nanostructure is larger than that of the third nanostructure, and wherein the first nanostructure, the second nanostructure, and the third nanostructure are positioned on a substrate such that when the nanochain is excited by an energy, an optical field between the second nanostructure and the third nanostructure is stronger than an optical field between the first nanostructure and the second nanostructure, wherein the array is configured to receive a sample; and a detector arranged to collect spectral data from a plurality of pixels of the array.

  10. Saskatchewan resources. [including uranium

    Energy Technology Data Exchange (ETDEWEB)

    1979-09-01

    The production of chemicals and minerals for the chemical industry in Saskatchewan are featured, with some discussion of resource taxation. The commodities mentioned include potash, fatty amines, uranium, heavy oil, sodium sulfate, chlorine, sodium hydroxide, sodium chlorate and bentonite. Following the successful outcome of the Cluff Lake inquiry, the uranium industry is booming. Some developments and production figures for Gulf Minerals, Amok, Cenex and Eldorado are mentioned.

  11. Comparison of a 'freeze-all' strategy including GnRH agonist trigger versus a 'fresh transfer' strategy including hCG trigger in assisted reproductive technology (ART)

    DEFF Research Database (Denmark)

    Stormlund, Sacha; Løssl, Kristine; Zedeler, Anne

    2017-01-01

    and single blastocyst transfer in the fresh (stimulated) cycle. The primary endpoint is to compare ongoing pregnancy rates per randomised patient in the two treatment groups after the first single blastocyst transfer. ETHICS AND DISSEMINATION: The study will be performed in accordance with the ethical...... principles in the Helsinki Declaration. The study is approved by the Scientific Ethical Committees in Denmark and Sweden. The results of the study will be publically disseminated. TRIAL REGISTRATION NUMBER: NCT02746562; Pre-results....

  12. Energetic endpoints provide early indicators of life history effects in a freshwater gastropod exposed to the fungicide, pyraclostrobin

    International Nuclear Information System (INIS)

    Fidder, Bridgette N.; Reátegui-Zirena, Evelyn G.; Olson, Adric D.; Salice, Christopher J.

    2016-01-01

    Organismal energetics provide important insights into the effects of environmental toxicants. We aimed to determine the effects of pyraclostrobin on Lymnaea stagnalis by examining energy allocation patterns and life history traits. Juvenile snails exposed to pyraclostrobin decreased feeding rate and increased apparent avoidance behaviors at environmentally relevant concentrations. In adults, we found that sublethal concentrations of pyraclostrobin did not affect reproductive output, however, there were significant effects on developmental endpoints with longer time to hatch and decreased hatching success in pyraclostrobin-exposed egg masses. Further, there were apparent differences in developmental effects depending on whether mothers were also exposed to pyraclostrobin suggesting this chemical can exert intergenerational effects. Pyraclostrobin also affected protein and carbohydrate content of eggs in mothers that were exposed to pyraclostrobin. Significant effects on macronutrient content of eggs occurred at lower concentrations than effects on gross endpoints such as hatching success and time to hatch suggesting potential value for these endpoints as early indicators of ecologically relevant stress. These results provide important insight into the effects of a common fungicide on important endpoints for organismal energetics and life history. - Highlights: • We exposed a freshwater snail to relevant concentrations of pyraclostrobin. • We monitored energetic and life history endpoints. • Pyraclostrobin affected feeding, hatching success and egg macronutrient content. • Energetic-based endpoints may provide valuable insight to toxic effects. - The fungicide pyraclostrobin at environmentally relevant concentrations effects a range of life history and energetic endpoints in the freshwater snail, Lymnaea stagnalis.

  13. Amenorrhea - primary

    Science.gov (United States)

    ... of periods - primary Images Primary amenorrhea Normal uterine anatomy (cut section) Absence of menstruation (amenorrhea) References Bulun SE. The physiology and pathology of the female reproductive axis. In: ...

  14. Being Included and Excluded

    DEFF Research Database (Denmark)

    Korzenevica, Marina

    2016-01-01

    Following the civil war of 1996–2006, there was a dramatic increase in the labor mobility of young men and the inclusion of young women in formal education, which led to the transformation of the political landscape of rural Nepal. Mobility and schooling represent a level of prestige that rural...... politics. It analyzes how formal education and mobility either challenge or reinforce traditional gendered norms which dictate a lowly position for young married women in the household and their absence from community politics. The article concludes that women are simultaneously excluded and included from...... community politics. On the one hand, their mobility and decision-making powers decrease with the increase in the labor mobility of men and their newly gained education is politically devalued when compared to the informal education that men gain through mobility, but on the other hand, schooling strengthens...

  15. Evaluation of a two-generation reproduction toxicity study adding endpoints to detect endocrine disrupting activity using vinclozolin.

    Science.gov (United States)

    Matsuura, Ikuo; Saitoh, Tetsuji; Ashina, Michiko; Wako, Yumi; Iwata, Hiroshi; Toyota, Naoto; Ishizuka, Yoshihito; Namiki, Masato; Hoshino, Nobuhito; Tsuchitani, Minoru

    2005-12-01

    A two-generation reproduction toxicity study in rats adding extra endpoints to detect endocrine disrupting activity was conducted using vinclozolin by dietary administration at 0, 40, 200, and 1000 ppm, for investigation of its utility. The extra endpoints included anogenital distance (AGD), nipple development, sexual maturation (vaginal opening and preputial separation), estrous cycle, spermatogenesis, sex organ weights, and blood hormone concentrations (thyroid and sex hormones). Hepatic drug-metabolizing enzyme activities were also measured. The results revealed changes due to vinclozolin in the AGD, nipple development, sexual maturation, sex organ weights, and blood sex hormone concentrations in males of both parental animals and offspring, even at the lowest dose of 40 ppm, confirmed by results for the classical endpoints of histopathological examination at 200 ppm and mating at 1000 ppm. The effects on parental males included increased pituitary and testis weights, and decreased epididymis weights at 1000 ppm in both generations, and decreased prostate and epididymis weights at 200 and 1000 ppm and seminal vesicle weights at 1000 ppm in F1 males. Histopathological examination revealed hypertrophy of the basophilic cells in the pituitary at these two doses, and diffuse hyperplasia of the testicular interstitial cells and atrophy of the seminal vesicle mucosa at 1000 ppm in F0 and F1 males. In addition, F1 males demonstrated decrease in prostate fluid at 200 and 1000 ppm. Blood hormone analysis revealed increases in LH, FSH, testosterone, and DHT in F0 and F1 males at 1000 ppm. General toxicological effects included suppressed body weight gain in F0 and F1 females and in F1 males, and reduced food consumption in F0 and F1 females at 1000 ppm. Histopathological examination revealed centrilobular hepatocellular hypertrophy in males at 200 and 1000 ppm and in females at 1000 ppm, increased lipid droplets in the adrenal zona fasciculata and zona glomerulosa in

  16. Signal transduction profile of chemical sensitisers in dendritic cells: An endpoint to be included in a cell-based in vitro alternative approach to hazard identification?

    International Nuclear Information System (INIS)

    Neves, Bruno Miguel; Goncalo, Margarida; Figueiredo, Americo; Duarte, Carlos B.; Lopes, Maria Celeste; Cruz, Maria Teresa

    2011-01-01

    The development of non-animal testing methods for the assessment of skin sensitisation potential is an urgent challenge within the framework of existing and forthcoming legislation. Efforts have been made to replace current animal tests, but so far no alternative methods have been developed. It is widely recognised that alternatives to animal testing cannot be accomplished with a single approach, but rather will require the integration of results obtained from different in vitro and in silico assays. The argument subjacent to the development of in vitro dendritic cell (DC)-based assays is that sensitiser-induced changes in the DC phenotype can be differentiated from those induced by irritants. This assumption is derived from the unique capacity of DC to convert environmental signals encountered at the skin into a receptor expression pattern (MHC class II molecules, co-stimulatory molecules, chemokine receptors) and a soluble mediator release profile that will stimulate T lymphocytes. Since signal transduction cascades precede changes in surface marker expression and cytokine/chemokine secretion, these phenotypic modifications are a consequence of a signal transduction profile that is specifically triggered by sensitisers and not by irritants. A limited number of studies have addressed this subject and the present review attempts to summarise and highlight all of the signalling pathways modulated by skin sensitisers and irritants. Furthermore, we conclude this review by focusing on the most promising strategies suitable for inclusion into a cell-based in vitro alternative approach to hazard identification.

  17. Use of barusiban in a novel study design for evaluation of tocolytic agents in pregnant and neonatal monkeys, including behavioural and immunological endpoints

    DEFF Research Database (Denmark)

    Rasmussen, Allan D; Nelson, Joyce K; Chellman, Gary J

    2007-01-01

    infants entailed the design of a unique protocol to investigate all aspects of maternal and offspring well-being. Barusiban was administered to the mothers from gestation day 85 until delivery with daily subcutaneous dosages up to 2.5mg/kg body weight/day. There were no test article-related effects seen...

  18. Pharmacogenetic meta-analysis of baseline risk factors, pharmacodynamic, efficacy and tolerability endpoints from two large global cardiovascular outcomes trials for darapladib.

    Directory of Open Access Journals (Sweden)

    Astrid Yeo

    Full Text Available Darapladib, a lipoprotein-associated phospholipase A2 (Lp-PLA2 inhibitor, failed to demonstrate efficacy for the primary endpoints in two large phase III cardiovascular outcomes trials, one in stable coronary heart disease patients (STABILITY and one in acute coronary syndrome (SOLID-TIMI 52. No major safety signals were observed but tolerability issues of diarrhea and odor were common (up to 13%. We hypothesized that genetic variants associated with Lp-PLA2 activity may influence efficacy and tolerability and therefore performed a comprehensive pharmacogenetic analysis of both trials. We genotyped patients within the STABILITY and SOLID-TIMI 52 trials who provided a DNA sample and consent (n = 13,577 and 10,404 respectively, representing 86% and 82% of the trial participants using genome-wide arrays with exome content and performed imputation using a 1000 Genomes reference panel. We investigated baseline and change from baseline in Lp-PLA2 activity, two efficacy endpoints (major coronary events and myocardial infarction as well as tolerability parameters at genome-wide and candidate gene level using a meta-analytic approach. We replicated associations of published loci on baseline Lp-PLA2 activity (APOE, CELSR2, LPA, PLA2G7, LDLR and SCARB1 and identified three novel loci (TOMM5, FRMD5 and LPL using the GWAS-significance threshold P≤5E-08. Review of the PLA2G7 gene (encoding Lp-PLA2 within these datasets identified V279F null allele carriers as well as three other rare exonic null alleles within various ethnic groups, however none of these variants nor any other loci associated with Lp-PLA2 activity at baseline were associated with any of the drug response endpoints. The analysis of darapladib efficacy endpoints, despite low power, identified six low frequency loci with main genotype effect (though with borderline imputation scores and one common locus (minor allele frequency 0.24 with genotype by treatment interaction effect passing the GWAS

  19. Phase II Trials for Heterogeneous Patient Populations with a Time-to-Event Endpoint.

    Science.gov (United States)

    Jung, Sin-Ho

    2017-07-01

    In this paper, we consider a single-arm phase II trial with a time-to-event end-point. We assume that the study population has multiple subpopulations with different prognosis, but the study treatment is expected to be similarly efficacious across the subpopulations. We review a stratified one-sample log-rank test and present its sample size calculation method under some practical design settings. Our sample size method requires specification of the prevalence of subpopulations. We observe that the power of the resulting sample size is not very sensitive to misspecification of the prevalence.

  20. On weighted hardy inequalities on semiaxis for functions vanishing at the endpoints

    Directory of Open Access Journals (Sweden)

    Vladimir Stepanov

    1997-01-01

    Full Text Available We study the weighted Hardy inequalities on the semiaxis of the form ‖Fu‖2≤C‖F(kv‖2  (1 for functions vanishing at the endpoints together with derivatives up to the order k−1. The case k=2 is completely characterized.

  1. Adaptive endpoint detection of seismic signal based on auto-correlated function

    International Nuclear Information System (INIS)

    Fan Wanchun; Shi Ren

    2001-01-01

    Based on the analysis of auto-correlation function, the notion of the distance between auto-correlation function was quoted, and the characterization of the noise and the signal with noise were discussed by using the distance. Then, the method of auto- adaptable endpoint detection of seismic signal based on auto-correlated similarity was summed up. The steps of implementation and determining of the thresholds were presented in detail. The experimental results that were compared with the methods based on artificial detecting show that this method has higher sensitivity even in a low signal with noise ratio circumstance

  2. Giant Magnetic Fluctuations at the Critical Endpoint in Insulating HoMnO3

    Science.gov (United States)

    Choi, Y. J.; Lee, N.; Sharma, P. A.; Kim, S. B.; Vajk, O. P.; Lynn, J. W.; Oh, Y. S.; Cheong, S.-W.

    2013-04-01

    Although abundant research has focused recently on the quantum criticality of itinerant magnets, critical phenomena of insulating magnets in the vicinity of critical endpoints (CEP’s) have rarely been revealed. Here we observe an emergent CEP at 2.05 T and 2.2 K with a suppressed thermal conductivity and concomitant strong critical fluctuations evident via a divergent magnetic susceptibility (e.g., χ''(2.05T,2.2K)/χ''(3T,2.2K)≈23,500%, comparable to the critical opalescence in water) in the hexagonal insulating antiferromagnet HoMnO3.

  3. Detection of Bordetella pertussis from Clinical Samples by Culture and End-Point PCR in Malaysian Patients.

    Science.gov (United States)

    Ting, Tan Xue; Hashim, Rohaidah; Ahmad, Norazah; Abdullah, Khairul Hafizi

    2013-01-01

    Pertussis or whooping cough is a highly infectious respiratory disease caused by Bordetella pertussis. In vaccinating countries, infants, adolescents, and adults are relevant patients groups. A total of 707 clinical specimens were received from major hospitals in Malaysia in year 2011. These specimens were cultured on Regan-Lowe charcoal agar and subjected to end-point PCR, which amplified the repetitive insertion sequence IS481 and pertussis toxin promoter gene. Out of these specimens, 275 were positive: 4 by culture only, 6 by both end-point PCR and culture, and 265 by end-point PCR only. The majority of the positive cases were from ≤3 months old patients (77.1%) (P 0.05). Our study showed that the end-point PCR technique was able to pick up more positive cases compared to culture method.

  4. Definitions and validation criteria for biomarkers and surrogate endpoints: development and testing of a quantitative hierarchical levels of evidence schema

    DEFF Research Database (Denmark)

    Lassere, Marissa N; Johnson, Kent R; Boers, Maarten

    2007-01-01

    endpoints, and leading indicators, a quantitative surrogate validation schema was developed and subsequently evaluated at a stakeholder workshop. RESULTS: The search identified several classification schema and definitions. Components of these were incorporated into a new quantitative surrogate validation...... of the National Institutes of Health definitions of biomarker, surrogate endpoint, and clinical endpoint was useful. CONCLUSION: Further development and application of this schema provides incentives and guidance for effective biomarker and surrogate endpoint research, and more efficient drug discovery...... are then applied if there is serious counterevidence. A total score (0 to 15) determines the level of evidence, with Level 1 the strongest and Level 5 the weakest. It was proposed that the term "surrogate" be restricted to markers attaining Levels 1 or 2 only. Most stakeholders agreed that this operationalization...

  5. Does bisphenol A induce superfeminization in Marisa cornuarietis? Part I: intra- and inter-laboratory variability in test endpoints.

    Science.gov (United States)

    Forbes, Valery E; Selck, Henriette; Palmqvist, Annemette; Aufderheide, John; Warbritton, Ryan; Pounds, Nadine; Thompson, Roy; van der Hoeven, Nelly; Caspers, Norbert

    2007-03-01

    It has been claimed that bisphenol A (BPA) induces superfeminization in the freshwater gastropod, Marisa cornuarietis. To explore the reproducibility of prior work, here we present results from a three-laboratory study, the objectives of which were to determine the mean and variability in test endpoints (i.e., adult fecundity, egg hatchability, and juvenile growth) under baseline conditions and to identify the sources of variability. A major source of variability for all of the measured endpoints was due to differences within and among individuals. With few exceptions, variability among laboratories and among replicate tanks within laboratories contributed little to the observed variability in endpoints. The results highlight the importance of obtaining basic knowledge of husbandry requirements and baseline information on life-history traits of potential test species prior to designing toxicity test protocols. Understanding of the levels and sources of endpoint variability is essential so that statistically robust and ecologically relevant tests of chemicals can be conducted.

  6. Definitions and validation criteria for biomarkers and surrogate endpoints: development and testing of a quantitative hierarchical levels of evidence schema

    DEFF Research Database (Denmark)

    Lassere, Marissa N; Johnson, Kent R; Boers, Maarten

    2007-01-01

    endpoints, and leading indicators, a quantitative surrogate validation schema was developed and subsequently evaluated at a stakeholder workshop. RESULTS: The search identified several classification schema and definitions. Components of these were incorporated into a new quantitative surrogate validation...... level of evidence schema that evaluates biomarkers along 4 domains: Target, Study Design, Statistical Strength, and Penalties. Scores derived from 3 domains the Target that the marker is being substituted for, the Design of the (best) evidence, and the Statistical strength are additive. Penalties...... of the National Institutes of Health definitions of biomarker, surrogate endpoint, and clinical endpoint was useful. CONCLUSION: Further development and application of this schema provides incentives and guidance for effective biomarker and surrogate endpoint research, and more efficient drug discovery...

  7. Factors Influencing Depression Endpoints Research (FINDER: baseline results of Italian patients with depression

    Directory of Open Access Journals (Sweden)

    Grassi Luigi

    2009-05-01

    Full Text Available Abstract Background Factors Influencing Depression Endpoints Research (FINDER is a 6-month, prospective, observational study carried out in 12 European countries aimed at investigating health-related quality of life (HRQoL in outpatients receiving pharmacological treatment for a first or new depressive episode. Baseline characteristics of patients enrolled in Italy are presented. Methods All treatment decisions were at the discretion of the investigator. Data were collected at baseline and after 3 and 6 months of treatment. Baseline evaluations included demographics, medical and psychiatric history, and medications used in the last 24 months and prescribed at enrolment. The Hospital Anxiety and Depression Scale (HADS, was adopted to evaluate depressive symptoms, while somatic and painful physical symptoms were assessed by using the Somatic Symptom Inventory (SSI and a 0 to 100 mm visual analogue scale (VAS, HRQoL via 36-item Short Form Health Survey (SF-36, and the European Quality of Life 5-Dimensions (EQ-5D instrument. Results A total of 513 patients were recruited across 38 sites. The mean ± standard deviation (SD age at first depressive episode was 38.7 ± 15.9 years, the mean duration of depression 10.6 ± 12.3 years. The most common psychiatric comorbidities in the previous 24 months were anxiety/panic (72.6% and obsessive/compulsive disorders (13.4%, while 35.9% had functional somatic syndromes. Most patients (65.1% reported pain from any cause. Monotherapy with selective serotonin reuptake inhibitors (SSRIs and tricyclic antidepressants (TCAs was prescribed at enrolment in 64.5% and 6.4% of the cases, respectively. The most commonly prescribed agents were sertraline (17.3%, escitalopram (16.2%, venlaflaxine (15.6% and paroxetine (14.8%. The mean HADS subscores for depression and anxiety were 13.3 ± 4.2 and 12.2 ± 3.9, respectively; 76.4% of patients could be defined as being 'probable cases' for depression and 66.2% for anxiety. The

  8. Air pollution, cardiovascular endpoints and susceptibility by stress and material resources: a systematic review of the evidence.

    Science.gov (United States)

    Fuller, Christina H; Feeser, Karla R; Sarnat, Jeremy A; O'Neill, Marie S

    2017-06-14

    Evidence shows that both the physical and social environments play a role in the development of cardiovascular disease. The purpose of this systematic review is two-fold: First, we summarize research from the past 12 years from the growing number of studies focused on effect modification of the relationships between air pollution and cardiovascular disease (CVD) outcomes by socioeconomic position (SEP) and; second, we identify research gaps throughout the published literature on this topic and opportunities for addressing these gaps in future study designs. We identified 30 articles that examined the modifying effects of either material resources or psychosocial stress (both related to SEP) on associations between short and long-term air pollution exposure and CVD endpoints. Although 18 articles identified at least one interaction between an air pollutant and material resource indicator, 11 others did not. Support for susceptibility to air pollution by psychosocial stress was weaker; however, only three articles tested this hypothesis. Further studies are warranted to investigate how air pollution and SEP together may influence CVD. We recommend that such research include thorough assessment of air pollution and SEP correlations, including spatial correlation; investigate air pollution indices or multi-pollutant models; use standardized metrics of SEP to enhance comparability across studies; and evaluate potentially susceptible populations.

  9. Definitions and validation criteria for biomarkers and surrogate endpoints: development and testing of a quantitative hierarchical levels of evidence schema.

    Science.gov (United States)

    Lassere, Marissa N; Johnson, Kent R; Boers, Maarten; Tugwell, Peter; Brooks, Peter; Simon, Lee; Strand, Vibeke; Conaghan, Philip G; Ostergaard, Mikkel; Maksymowych, Walter P; Landewe, Robert; Bresnihan, Barry; Tak, Paul-Peter; Wakefield, Richard; Mease, Philip; Bingham, Clifton O; Hughes, Michael; Altman, Doug; Buyse, Marc; Galbraith, Sally; Wells, George

    2007-03-01

    There are clear advantages to using biomarkers and surrogate endpoints, but concerns about clinical and statistical validity and systematic methods to evaluate these aspects hinder their efficient application. Our objective was to review the literature on biomarkers and surrogates to develop a hierarchical schema that systematically evaluates and ranks the surrogacy status of biomarkers and surrogates; and to obtain feedback from stakeholders. After a systematic search of Medline and Embase on biomarkers, surrogate (outcomes, endpoints, markers, indicators), intermediate endpoints, and leading indicators, a quantitative surrogate validation schema was developed and subsequently evaluated at a stakeholder workshop. The search identified several classification schema and definitions. Components of these were incorporated into a new quantitative surrogate validation level of evidence schema that evaluates biomarkers along 4 domains: Target, Study Design, Statistical Strength, and Penalties. Scores derived from 3 domains the Target that the marker is being substituted for, the Design of the (best) evidence, and the Statistical strength are additive. Penalties are then applied if there is serious counterevidence. A total score (0 to 15) determines the level of evidence, with Level 1 the strongest and Level 5 the weakest. It was proposed that the term "surrogate" be restricted to markers attaining Levels 1 or 2 only. Most stakeholders agreed that this operationalization of the National Institutes of Health definitions of biomarker, surrogate endpoint, and clinical endpoint was useful. Further development and application of this schema provides incentives and guidance for effective biomarker and surrogate endpoint research, and more efficient drug discovery, development, and approval.

  10. Patient-specific dosimetric endpoints based treatment plan quality control in radiotherapy

    International Nuclear Information System (INIS)

    Song, Ting; Zhou, Linghong; Staub, David; Chen, Mingli; Lu, Weiguo; Tian, Zhen; Jia, Xun; Li, Yongbao; Jiang, Steve B; Gu, Xuejun

    2015-01-01

    In intensity modulated radiotherapy (IMRT), the optimal plan for each patient is specific due to unique patient anatomy. To achieve such a plan, patient-specific dosimetric goals reflecting each patient’s unique anatomy should be defined and adopted in the treatment planning procedure for plan quality control. This study is to develop such a personalized treatment plan quality control tool by predicting patient-specific dosimetric endpoints (DEs). The incorporation of patient specific DEs is realized by a multi-OAR geometry-dosimetry model, capable of predicting optimal DEs based on the individual patient’s geometry. The overall quality of a treatment plan is then judged with a numerical treatment plan quality indicator and characterized as optimal or suboptimal. Taking advantage of clinically available prostate volumetric modulated arc therapy (VMAT) treatment plans, we built and evaluated our proposed plan quality control tool. Using our developed tool, six of twenty evaluated plans were identified as sub-optimal plans. After plan re-optimization, these suboptimal plans achieved better OAR dose sparing without sacrificing the PTV coverage, and the dosimetric endpoints of the re-optimized plans agreed well with the model predicted values, which validate the predictability of the proposed tool. In conclusion, the developed tool is able to accurately predict optimally achievable DEs of multiple OARs, identify suboptimal plans, and guide plan optimization. It is a useful tool for achieving patient-specific treatment plan quality control. (paper)

  11. Hairy black holes and the endpoint of AdS{sub 4} charged superradiance

    Energy Technology Data Exchange (ETDEWEB)

    Dias, Óscar J.C.; Masachs, Ramon [STAG research centre and Mathematical Sciences, University of Southampton,Southampton (United Kingdom)

    2017-02-24

    We construct hairy black hole solutions that merge with the anti-de Sitter (AdS{sub 4}) Reissner-Nordström black hole at the onset of superradiance. These hairy black holes have, for a given mass and charge, higher entropy than the corresponding AdS{sub 4}-Reissner-Nordström black hole. Therefore, they are natural candidates for the endpoint of the charged superradiant instability. On the other hand, hairy black holes never dominate the canonical and grand-canonical ensembles. The zero-horizon radius of the hairy black holes is a soliton (i.e. a boson star under a gauge transformation). We construct our solutions perturbatively, for small mass and charge, so that the properties of hairy black holes can be used to testify and compare with the endpoint of initial value simulations. We further discuss the near-horizon scalar condensation instability which is also present in global AdS{sub 4}-Reissner-Nordström black holes. We highlight the different nature of the near-horizon and superradiant instabilities and that hairy black holes ultimately exist because of the non-linear instability of AdS.

  12. Transgenerational endpoints provide increased sensitivity and insight into multigenerational responses of Lymnaea stagnalis exposed to cadmium.

    Science.gov (United States)

    Reátegui-Zirena, Evelyn G; Fidder, Bridgette N; Olson, Adric D; Dawson, Daniel E; Bilbo, Thomas R; Salice, Christopher J

    2017-05-01

    Ecotoxicology provides data to inform environmental management. Many testing protocols do not consider offspring fitness and toxicant sensitivity. Cadmium (Cd) is a well-studied and ubiquitous toxicant but little is known about the effects on offspring of exposed parents (transgenerational effects). This study had three objectives: to identify endpoints related to offspring performance; to determine whether parental effects would manifest as a change in Cd tolerance in offspring and how parental exposure duration influenced the manifestation of parental effects. Adult snails were exposed to Cd 0, 25, 50, 100, 200 and 400 μg Cd/L for eight weeks. There were effects on adult endpoints (e.g., growth, reproduction) but only at the highest concentrations (>100 μg/L). Alternatively, we observed significant transgenerational effects at all Cd concentrations. Surprisingly, we found increased Cd tolerance in hatchlings from all parental Cd exposure concentrations even though eggs and hatchlings were in Cd-free conditions for 6 weeks. Explicit consideration of offspring performance adds value to current toxicity testing protocols. Parental exposure duration has important implications for offspring effects and that contaminant concentrations that are not directly toxic to parents can cause transgenerational changes in resistance that have significant implications for toxicity testing and adaptive responses. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. A patient and community-centered approach selecting endpoints for a randomized trial of a novel advance care planning tool

    Directory of Open Access Journals (Sweden)

    Bridges JFP

    2018-02-01

    Full Text Available John FP Bridges,1,2 Norah L Crossnohere,2 Anne L Schuster,1 Judith A Miller,3 Carolyn Pastorini,3,† Rebecca A Aslakson2,4,5 1Department of Health Policy and Management, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 2Department of Health, Behavior, and Society, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 3Patient-Centered Outcomes Research Institute (PCORI Project, Baltimore, MD, 4Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins School of Medicine, Baltimore, MD, 5Armstrong Institute for Patient Safety and Quality, The Johns Hopkins School of Medicine, Baltimore, MD, USA †Carolyn Pastorini passed away on August 24, 2015 Background: Despite a movement toward patient-centered outcomes, best practices on how to gather and refine patients’ perspectives on research endpoints are limited. Advanced care planning (ACP is inherently patient centered and would benefit from patient prioritization of endpoints for ACP-related tools and studies.Objective: This investigation sought to prioritize patient-centered endpoints for the content and evaluation of an ACP video being developed for patients undergoing major surgery. We also sought to highlight an approach using complementary engagement and research strategies to document priorities and preferences of patients and other stakeholders.Materials and methods: Endpoints identified from a previously published environmental scan were operationalized following rating by a caregiver co-investigator, refinement by a patient co-investigator, review by a stakeholder committee, and validation by patients and family members. Finalized endpoints were taken to a state fair where members of the public who indicated that they or a loved one had undergone major surgery prioritized their most relevant endpoints and provided comments.Results: Of the initial 50 ACP endpoints identified from the review, 12 endpoints were selected for public

  14. Combined effects of gamma irradiation and cadmium on cellular and population-level endpoints of the micro-alga Pseudokirchneriella subcapitata

    Energy Technology Data Exchange (ETDEWEB)

    Bradshaw, C. [Stockholm University (Sweden); Abdul Meseh, D.; Alasawi, H.; Qiang, M.; Nascimento, F. [Dept of Ecology, Environment and Plant Sciences (Sweden)

    2014-07-01

    A major challenge in evaluating the risks of radiation to organisms is that radioactive substances often co-occur with other contaminants in the environment. The combined effects of multiple contaminants is poorly understood, particularly where radiation is involved, but mixture toxicity can give rise to synergistic, antagonistic or additive effects. The challenge of understanding mixture toxicity in a radiation context is the focus of one of the work packages of the STAR EU Network of Excellence in Radioecology, of which this study is a part. This paper presents results from an experiment where the green micro-alga Pseudokirchneriella subcapitata was exposed to both acute external gamma irradiation and the toxic metal cadmium (Cd) (over 72 hours); the experiment had a fully factorial design with 4 gamma doses and 4 Cd concentrations. The endpoints measured were chosen to reflect subcellular, cellular and population-level effects: antioxidant enzyme expression; membrane damage; protein, vitamin and pigment content of the cells; individual cell biomass and growth; population growth (biomass per ml and cells per ml). Preliminary results suggest effects of both Cd and gamma on some of the cellular and subcellular endpoints such as thiamine (vitamin B1) and chlorophyll concentrations in the cells, and individual cell biomass. In some cases interactive effects of the combined Cd and gamma treatments were seen, and these appeared to be dose level dependent. This lack of a consistent pattern of interactive mixture toxicity effects across the endpoints measured means that such effects would be very hard to predict in a risk assessment context. The lack of measurable effects at the population level was probably due to the short experimental duration (72 hours). Other experiments in our research group on the same micro-alga species that have looked at longer term effects (weeks) have shown that effects may not manifest themselves until at least a week after an acute gamma

  15. Towards better environmental performance of wastewater sludge treatment using endpoint approach in LCA methodology

    Directory of Open Access Journals (Sweden)

    Isam Alyaseri

    2017-03-01

    Full Text Available The aim of this study is to use the life cycle assessment method to measure the environmental performance of the sludge incineration process in a wastewater treatment plant and to propose an alternative that can reduce the environmental impact. To show the damages caused by the treatment processes, the study aimed to use an endpoint approach in evaluating impacts on human health, ecosystem quality, and resources due to the processes. A case study was taken at Bissell Point Wastewater Treatment Plant in Saint Louis, Missouri, U.S. The plant-specific data along with literature data from technical publications were used to build an inventory, and then analyzed the environmental burdens from sludge handling unit in the year 2011. The impact assessment method chosen was ReCipe 2008. The existing scenario (dewatering-multiple hearth incineration-ash to landfill was evaluated and three alternative scenarios (fluid bed incineration and anaerobic digestion with and without land application with energy recovery from heat or biogas were proposed and analyzed to find the one with the least environmental impact. The existing scenario shows that the most significant impacts are related to depletion in resources and damage to human health. These impacts mainly came from the operation phase (electricity and fuel consumption and emissions related to combustion. Alternatives showed better performance than the existing scenario. Using ReCipe endpoint methodology, and among the three alternatives tested, the anaerobic digestion had the best overall environmental performance. It is recommended to convert to fluid bed incineration if the concerns were more about human health or to anaerobic digestion if the concerns were more about depletion in resources. The endpoint approach may simplify the outcomes of this study as follows: if the plant is converted to fluid bed incineration, it could prevent an average of 43.2 DALYs in human life, save 0.059 species in the area

  16. Comparison between amperometric and true potentiometric end-point detection in the determination of water by the Karl Fischer method.

    Science.gov (United States)

    Cedergren, A

    1974-06-01

    A rapid and sensitive method using true potentiometric end-point detection has been developed and compared with the conventional amperometric method for Karl Fischer determination of water. The effect of the sulphur dioxide concentration on the shape of the titration curve is shown. By using kinetic data it was possible to calculate the course of titrations and make comparisons with those found experimentally. The results prove that the main reaction is the slow step, both in the amperometric and the potentiometric method. Results obtained in the standardization of the Karl Fischer reagent showed that the potentiometric method, including titration to a preselected potential, gave a standard deviation of 0.001(1) mg of water per ml, the amperometric method using extrapolation 0.002(4) mg of water per ml and the amperometric titration to a pre-selected diffusion current 0.004(7) mg of water per ml. Theories and results dealing with dilution effects are presented. The time of analysis was 1-1.5 min for the potentiometric and 4-5 min for the amperometric method using extrapolation.

  17. SIMULATION FROM ENDPOINT-CONDITIONED, CONTINUOUS-TIME MARKOV CHAINS ON A FINITE STATE SPACE, WITH APPLICATIONS TO MOLECULAR EVOLUTION.

    Science.gov (United States)

    Hobolth, Asger; Stone, Eric A

    2009-09-01

    Analyses of serially-sampled data often begin with the assumption that the observations represent discrete samples from a latent continuous-time stochastic process. The continuous-time Markov chain (CTMC) is one such generative model whose popularity extends to a variety of disciplines ranging from computational finance to human genetics and genomics. A common theme among these diverse applications is the need to simulate sample paths of a CTMC conditional on realized data that is discretely observed. Here we present a general solution to this sampling problem when the CTMC is defined on a discrete and finite state space. Specifically, we consider the generation of sample paths, including intermediate states and times of transition, from a CTMC whose beginning and ending states are known across a time interval of length T. We first unify the literature through a discussion of the three predominant approaches: (1) modified rejection sampling, (2) direct sampling, and (3) uniformization. We then give analytical results for the complexity and efficiency of each method in terms of the instantaneous transition rate matrix Q of the CTMC, its beginning and ending states, and the length of sampling time T. In doing so, we show that no method dominates the others across all model specifications, and we give explicit proof of which method prevails for any given Q, T, and endpoints. Finally, we introduce and compare three applications of CTMCs to demonstrate the pitfalls of choosing an inefficient sampler.

  18. A Review of Clinical Trial Endpoints of Patients with Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension and How They Relate to Patient Outcomes in the United States.

    Science.gov (United States)

    Divers, Christine; Platt, David; Wang, Edward; Lin, Jay; Lingohr-Smith, Melissa; Mathai, Stephen C

    2017-01-01

    Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are subgroups of pulmonary hypertension and are considered rare diseases. Understanding how endpoints of clinical trials (and patient registry studies) of patients with PAH and CTEPH are associated with patient outcomes is important in order to address the concerns of patients, health care providers, decision makers, and payers. The purpose of this review was to examine how endpoints used in clinical trials and patient registry studies are associated with outcomes of patients with PAH and CTEPH. A PubMed literature search was conducted to retrieve published studies, including randomized phase III clinical trials and observational studies, from years 2000 to May 2015 that evaluated the associations between change in 6-minute walking distance (6MWD), 6MWD thresholds, change in World Health Organization functional class (WHO-FC), and time to clinical worsening with outcomes of patients with PAH and CTEPH. Based on this review of published literature, a reduction in 6MWD as a criterion for PAH worsening, a deterioration in WHO-FC, and delay in the time to clinical worsening are clinically meaningful trial endpoints and are associated with outcomes of patients with PAH and CTEPH. Utilization and standardization of these endpoints will be useful for comparing interventions of clinical trials and therapies. Hospitalizations are frequent among patients with PAH and CTEPH, and total health care costs are high. From a U.S. payer perspective, clinical worsening is an important composite endpoint in that it includes hospitalization, which can be transformed into a preventative cost value associated with efficacious treatment of patients with PAH and CTEPH. In view of the greater number of medications available to treat PAH, the introduction of the first approved therapy to treat CTEPH, and the increasing use of combination pharmacotherapy, reliable prognostic markers of treatment

  19. The Comparison of the Outcomes between Primary PCI, Fibrinolysis, and No Reperfusion in Patients ≥ 75 Years Old with ST-Segment Elevation Myocardial Infarction: Results from the Chinese Acute Myocardial Infarction (CAMI Registry.

    Directory of Open Access Journals (Sweden)

    He Peiyuan

    Full Text Available Only a few randomized trials have analyzed the clinical outcomes of elderly ST-segment elevation myocardial infarction (STEMI patients (≥ 75 years old. Therefore, the best reperfusion strategy has not been well established. An observational study focused on clinical outcomes was performed in this population.Based on the national registry on STEMI patients, the in-hospital outcomes of elderly patients with different reperfusion strategies were compared. The primary endpoint was defined as death. Secondary endpoints included recurrent myocardial infarction, ischemia driven revascularization, myocardial infarction related complications, and major bleeding. Multivariable regression analysis was performed to adjust for the baseline disparities between the groups.Patients who had primary percutaneous coronary intervention (PCI or fibrinolysis were relatively younger. They came to hospital earlier, and had lower risk of death compared with patients who had no reperfusion. The guideline recommended medications were more frequently used in patients with primary PCI during the hospitalization and at discharge. The rates of death were 7.7%, 15.0%, and 19.9% respectively, with primary PCI, fibrinolysis, and no reperfusion (P 0.05. In the multivariable regression analysis, primary PCI outweighs no reperfusion in predicting the in-hospital death in patients ≥ 75 years old. However, fibrinolysis does not.Early reperfusion, especially primary PCI was safe and effective with absolute reduction of mortality compared with no reperfusion. However, certain randomized trials were encouraged to support the conclusion.

  20. Multiple-endpoint assay provides a detailed mechanistic view of responses to herbicide exposure in Chlamydomonas reinhardtii

    International Nuclear Information System (INIS)

    Nestler, Holger; Groh, Ksenia J.; Schönenberger, René; Behra, Renata; Schirmer, Kristin; Eggen, Rik I.L.; Suter, Marc J.-F.

    2012-01-01

    The release of herbicides into the aquatic environment raises concerns about potential detrimental effects on ecologically important non-target species, such as unicellular algae, necessitating ecotoxicological risk assessment. Algal toxicity tests based on growth, a commonly assessed endpoint, are integrative, and hence do not provide information about underlying toxic mechanisms and effects. This limitation may be overcome by measuring more specific biochemical and physiological endpoints. In the present work, we developed and applied a novel multiple-endpoint assay, and analyzed the effects of the herbicides paraquat, diuron and norflurazon, each representing a specific mechanism of toxic action, on the single celled green alga Chlamydomonas reinhardtii. The endpoints added to assessment of growth were pigment content, maximum and effective photosystem II quantum yield, ATP content, esterase and oxidative activity. All parameters were measured at 2, 6 and 24 h of exposure, except for growth and pigment content, which were determined after 6 and 24 h only. Effective concentrations causing 50% of response (EC50s) and lowest observable effect concentrations (LOECs) were determined for all endpoints and exposure durations where possible. The assay provided a detailed picture of the concentration- and time-dependent development of effects elicited by the analyzed herbicides, thus improving the understanding of the underlying toxic mechanisms. Furthermore, the response patterns were unique to the respective herbicide and reflected the different mechanisms of toxicity. The comparison of the endpoint responses and sensitivities revealed that several physiological and biochemical parameters reacted earlier or stronger to disturbances than growth. Overall, the presented multiple-endpoint assay constitutes a promising basis for investigating stressor and toxicant effects in green algae.

  1. Multiple-endpoint assay provides a detailed mechanistic view of responses to herbicide exposure in Chlamydomonas reinhardtii

    Energy Technology Data Exchange (ETDEWEB)

    Nestler, Holger [Eawag, Swiss Federal Institute of Aquatic Science and Technology, Ueberlandstrasse 133, 8600 Duebendorf (Switzerland); ETH Zurich, Swiss Federal Institute of Technology, Institute of Biogeochemistry and Pollutant Dynamics, Universitaetstrasse 16, 8092 Zurich (Switzerland); Groh, Ksenia J.; Schoenenberger, Rene; Behra, Renata [Eawag, Swiss Federal Institute of Aquatic Science and Technology, Ueberlandstrasse 133, 8600 Duebendorf (Switzerland); Schirmer, Kristin [Eawag, Swiss Federal Institute of Aquatic Science and Technology, Ueberlandstrasse 133, 8600 Duebendorf (Switzerland); ETH Zurich, Swiss Federal Institute of Technology, Institute of Biogeochemistry and Pollutant Dynamics, Universitaetstrasse 16, 8092 Zurich (Switzerland); EPF Lausanne, School of Architecture, Civil and Environmental Engineering, 1015 Lausanne (Switzerland); Eggen, Rik I.L. [Eawag, Swiss Federal Institute of Aquatic Science and Technology, Ueberlandstrasse 133, 8600 Duebendorf (Switzerland); ETH Zurich, Swiss Federal Institute of Technology, Institute of Biogeochemistry and Pollutant Dynamics, Universitaetstrasse 16, 8092 Zurich (Switzerland); Suter, Marc J.-F., E-mail: suter@eawag.ch [Eawag, Swiss Federal Institute of Aquatic Science and Technology, Ueberlandstrasse 133, 8600 Duebendorf (Switzerland); ETH Zurich, Swiss Federal Institute of Technology, Institute of Biogeochemistry and Pollutant Dynamics, Universitaetstrasse 16, 8092 Zurich (Switzerland)

    2012-04-15

    The release of herbicides into the aquatic environment raises concerns about potential detrimental effects on ecologically important non-target species, such as unicellular algae, necessitating ecotoxicological risk assessment. Algal toxicity tests based on growth, a commonly assessed endpoint, are integrative, and hence do not provide information about underlying toxic mechanisms and effects. This limitation may be overcome by measuring more specific biochemical and physiological endpoints. In the present work, we developed and applied a novel multiple-endpoint assay, and analyzed the effects of the herbicides paraquat, diuron and norflurazon, each representing a specific mechanism of toxic action, on the single celled green alga Chlamydomonas reinhardtii. The endpoints added to assessment of growth were pigment content, maximum and effective photosystem II quantum yield, ATP content, esterase and oxidative activity. All parameters were measured at 2, 6 and 24 h of exposure, except for growth and pigment content, which were determined after 6 and 24 h only. Effective concentrations causing 50% of response (EC50s) and lowest observable effect concentrations (LOECs) were determined for all endpoints and exposure durations where possible. The assay provided a detailed picture of the concentration- and time-dependent development of effects elicited by the analyzed herbicides, thus improving the understanding of the underlying toxic mechanisms. Furthermore, the response patterns were unique to the respective herbicide and reflected the different mechanisms of toxicity. The comparison of the endpoint responses and sensitivities revealed that several physiological and biochemical parameters reacted earlier or stronger to disturbances than growth. Overall, the presented multiple-endpoint assay constitutes a promising basis for investigating stressor and toxicant effects in green algae.

  2. On the Higher Moments of Particle Multiplicity, Chemical Freeze-Out, and QCD Critical Endpoint

    Directory of Open Access Journals (Sweden)

    A. Tawfik

    2013-01-01

    Full Text Available We calculate the first six nonnormalized moments of particle multiplicity within the framework of the hadron resonance gas model. In terms of the lower order moments and corresponding correlation functions, general expressions of higher order moments are derived. Thermal evolution of the first four normalized moments and their products (ratios are studied at different chemical potentials, so that it is possible to evaluate them at chemical freeze-out curve. It is found that a nonmonotonic behaviour reflecting the dynamical fluctuation and strong correlation of particles starts to appear from the normalized third order moment. We introduce novel conditions for describing the chemical freeze-out curve. Although the hadron resonance gas model does not contain any information on the criticality related to the chiral dynamics and singularity in the physical observables, we are able to find out the location of the QCD critical endpoint at μ ~ 350  MeV and temperature T ~ 162  MeV.

  3. Comparison endpoint study of process plasma and secondary electron beam exciter optical emission spectroscopy

    Energy Technology Data Exchange (ETDEWEB)

    Stephan Thamban, P. L.; Yun, Stuart; Padron-Wells, Gabriel; Hosch, Jimmy W.; Goeckner, Matthew J. [Department of Mechanical Engineering, University of Texas at Dallas, 800W Campbell Road, Richardson, Texas 75080 (United States); Department of Electrical Engineering, University of Texas at Dallas, 800W Campbell Road, Richardson, Texas 75080 (United States); Verity Instruments, Inc., 2901 Eisenhower Street, Carrollton, Texas 75007 (United States); Department of Mathematical Sciences, University of Texas at Dallas, 800 W Campbell Road, Richardson, Texas 75080 (United States)

    2012-11-15

    Traditionally process plasmas are often studied and monitored by optical emission spectroscopy. Here, the authors compare experimental measurements from a secondary electron beam excitation and direct process plasma excitation to discuss and illustrate its distinctiveness in the study of process plasmas. They present results that show excitations of etch process effluents in a SF{sub 6} discharge and endpoint detection capabilities in dark plasma process conditions. In SF{sub 6} discharges, a band around 300 nm, not visible in process emission, is observed and it can serve as a good indicator of etch product emission during polysilicon etches. Based on prior work reported in literature the authors believe this band is due to SiF{sub 4} gas phase species.

  4. Impact of copula directional specification on multi-trial evaluation of surrogate endpoints

    Science.gov (United States)

    Renfro, Lindsay A.; Shang, Hongwei; Sargent, Daniel J.

    2014-01-01

    Evaluation of surrogate endpoints using patient-level data from multiple trials is the gold standard, where multi-trial copula models are used to quantify both patient-level and trial-level surrogacy. While limited consideration has been given in the literature to copula choice (e.g., Clayton), no prior consideration has been given to direction of implementation (via survival versus distribution functions). We demonstrate that evenwith the “correct” copula family, directional misspecification leads to biased estimates of patient-level and trial-level surrogacy. We illustrate with a simulation study and a re-analysis of disease-free survival as a surrogate for overall survival in early stage colon cancer. PMID:24905465

  5. Simultaneous small-sample comparisons in longitudinal or multi-endpoint trials using multiple marginal models

    DEFF Research Database (Denmark)

    Pallmann, Philip; Ritz, Christian; Hothorn, Ludwig A

    2018-01-01

    , however only asymptotically. In this paper, we show how to make the approach also applicable to small-sample data problems. Specifically, we discuss the computation of adjusted P values and simultaneous confidence bounds for comparisons of randomised treatment groups as well as for levels......Simultaneous inference in longitudinal, repeated-measures, and multi-endpoint designs can be onerous, especially when trying to find a reasonable joint model from which the interesting effects and covariances are estimated. A novel statistical approach known as multiple marginal models greatly...... simplifies the modelling process: the core idea is to "marginalise" the problem and fit multiple small models to different portions of the data, and then estimate the overall covariance matrix in a subsequent, separate step. Using these estimates guarantees strong control of the family-wise error rate...

  6. Determination of the Acidity of Oils Using Paraformaldehyde as a Thermometric End-Point Indicator

    Directory of Open Access Journals (Sweden)

    Carneiro Mário J. D.

    2002-01-01

    Full Text Available The determination of the acidity of oils by catalytic thermometric titrimetry using paraformaldehyde as the thermometric end-point indicator was investigated. The sample solvent was a 1:1 (v/v mixture of toluene and 2-propanol and the titrant was 0.1 mol L-1 aqueous sodium hydroxide. Paraformaldehyde, being insoluble in the sample solvent, does not present the inconvenience of other indicators that change the properties of the solvent due to composition changes. The titration can therefore be done effectively in the same medium as the standard potentiometric and visual titration methods. The results of the application of the method to both non-refined and refined oils are presented herein. The proposed method has advantages in relation to the potentiometric method in terms of speed and simplicity.

  7. End-Point Contact Force Control with Quantitative Feedback Theory for Mobile Robots

    Directory of Open Access Journals (Sweden)

    Shuhuan Wen

    2012-12-01

    Full Text Available Robot force control is an important issue for intelligent mobile robotics. The end-point stiffness of a robot is a key and open problem in the research community. The control strategies are mostly dependent on both the specifications of the task and the environment of the robot. Due to the limited stiffness of the end-effector, we may adopt inherent torque to feedback the oscillations of the controlled force. This paper proposes an effective control strategy which contains a controller using quantitative feedback theory. The nested loop controllers take into account the physical limitation of the system's inner variables and harmful interference. The biggest advantage of the method is its simplicity in both the design process and the implementation of the control algorithm in engineering practice. Taking the one-link manipulator as an example, numerical experiments are carried out to verify the proposed control method. The results show the satisfactory performance.

  8. Elastic collisions of classical point particles on a finite frictionless linear track with perfectly reflecting endpoints

    Science.gov (United States)

    DeLuca, R.

    2006-03-01

    Repeated elastic collisions of point particles on a finite frictionless linear track with perfectly reflecting endpoints are considered. The problem is analysed by means of an elementary linear algebra approach. It is found that, starting with a state consisting of a projectile particle in motion at constant velocity and a target particle at rest in a fixed known position, the points at which collisions occur on track, when plotted versus progressive numerals, corresponding to the collisions themselves, show periodic patterns for a rather large choice of values of the initial position x(0) and on the mass ratio r. For certain values of these parameters, however, only regular behaviour over a large number of collisions is detected.

  9. Patient-reported outcomes in insomnia: development of a conceptual framework and endpoint model.

    Science.gov (United States)

    Kleinman, Leah; Buysse, Daniel J; Harding, Gale; Lichstein, Kenneth; Kalsekar, Anupama; Roth, Thomas

    2013-01-01

    This article describes qualitative research conducted with patients with clinical diagnoses of insomnia and focuses on the development of a conceptual framework and endpoint model that identifies a hierarchy and interrelationships of potential outcomes in insomnia research. Focus groups were convened to discuss how patients experience insomnia and to generate items for patient-reported questionnaires on insomnia and associated daytime consequences. Results for the focus group produced two conceptual frameworks: one for sleep and one for daytime impairment. Each conceptual framework consists of hypothesized domains and items in each domain based on patient language taken from the focus group. These item pools may ultimately serve as a basis to develop new questionnaires to assess insomnia.

  10. Radiological impacts analysis with use of new endpoint as complementary safety indicators

    International Nuclear Information System (INIS)

    Peralta Vital, J.L.; Gil Castillo, R.; Fleitas Estevez, G.G.; Olivera Acosta, J.

    2015-01-01

    The paper shows the new safety indicators on risk assessment (safety assessment) to radioactive waste environmental management implementation (concentrations and fluxes of naturally occurring radioactive materials (NORM)). The endpoint obtained, allow the best analysis of the radiological impact associated to radioactive waste isolation system. The common safety indicators for safety assessment purpose, dose and risk, are very time dependent, increasing the uncertainties in the results for long term assessment. The complementary and new proposed endpoints are more stable and they are not affected by changes in the critical group, pathways, etc. The NORM values on facility site were obtained as result of national surveys, the natural concentrations of U, Ra, Th, K has been associated with the variation of the lithologies in 3 geographical areas of the Country (Occidental, Central and Oriental). The results obtained are related with the safety assessment topics and allowed to apply the new complementary safety indicators, by comparisons between the natural concentrations and fluxes on site and its calculated values for the conceptual repository design. In order to normalize the concentration results, the analysis was realized adopting the criteria of the Repository Equivalent Rock Volume (RERV). The preliminary comparison showed that the calculated concentrations and fluxes in the Cuban conceptual radioactive waste repository are not higher than the natural values in the host rock. According to the application of new safety indicators, the reference disposal facility does not increase the natural activity concentration and fluxes in the environment. In order to implement these new safety indicator it has been used the current 226 Ra inventory of the Repository and the 226 Ra as natural concentration on the site. (authors)

  11. Log-gamma directed polymer with fixed endpoints via the replica Bethe Ansatz

    International Nuclear Information System (INIS)

    Thiery, Thimothée; Le Doussal, Pierre

    2014-01-01

    We study the model of a discrete directed polymer (DP) on a square lattice with homogeneous inverse gamma distribution of site random Boltzmann weights, introduced by Seppalainen (2012 Ann. Probab. 40 19–73). The integer moments of the partition sum, Z n -bar , are studied using a transfer matrix formulation, which appears as a generalization of the Lieb–Liniger quantum mechanics of bosons to discrete time and space. In the present case of the inverse gamma distribution the model is integrable in terms of a coordinate Bethe Ansatz, as discovered by Brunet. Using the Brunet-Bethe eigenstates we obtain an exact expression for the integer moments of Z n -bar for polymers of arbitrary lengths and fixed endpoint positions. Although these moments do not exist for all integer n, we are nevertheless able to construct a generating function which reproduces all existing integer moments and which takes the form of a Fredholm determinant (FD). This suggests an analytic continuation via a Mellin–Barnes transform and we thereby propose a FD ansatz representation for the probability distribution function (PDF) of Z and its Laplace transform. In the limit of a very long DP, this ansatz yields that the distribution of the free energy converges to the Gaussian unitary ensemble (GUE) Tracy-Widom distribution up to a non-trivial average and variance that we calculate. Our asymptotic predictions coincide with a result by Borodin et al (2013 Commun. Math. Phys. 324 215–32) based on a formula obtained by Corwin et al (2011 arXiv:1110.3489) using the geometric Robinson–Schensted–Knuth (gRSK) correspondence. In addition we obtain the dependence on the endpoint position and the exact elastic coefficient at a large time. We argue the equivalence between our formula and that of Borodin et al. As we will discuss, this provides a connection between quantum integrability and tropical combinatorics. (paper)

  12. Cadmium phytotoxicity: Quantitative sensitivity relationships between classical endpoints and antioxidative enzyme biomarkers

    Energy Technology Data Exchange (ETDEWEB)

    Rosa Correa, Albertina Xavier da [Centro de Ciencias Tecnologicas da Terra e do Mar, Universidade do Vale do Itajai, Rua Uruguai, 458, 88302-202 Itajai SC (Brazil); Roerig, Leonardo Rubi [Centro de Ciencias Tecnologicas da Terra e do Mar, Universidade do Vale do Itajai, Rua Uruguai, 458, 88302-202 Itajai SC (Brazil); Verdinelli, Miguel A. [Centro de Ciencias Tecnologicas da Terra e do Mar, Universidade do Vale do Itajai, Rua Uruguai, 458, 88302-202 Itajai SC (Brazil); Cotelle, Sylvie [Centre des Sciences de l' Environnement, Universite de Metz, 57000 Metz (France); Ferard, Jean-Francois [Centre des Sciences de l' Environnement, Universite de Metz, 57000 Metz (France); Radetski, Claudemir Marcos [Centro de Ciencias Tecnologicas da Terra e do Mar, Universidade do Vale do Itajai, Rua Uruguai, 458, 88302-202 Itajai SC (Brazil)]. E-mail: radetski@univali.br

    2006-03-15

    In this work, cadmium phytotoxicity and quantitative sensitivity relationships between different hierarchical endpoints in plants cultivated in a contaminated soil were studied. Thus, germination rate, biomass growth and antioxidative enzyme activity (i.e. superoxide dismutase, peroxidase, catalase and glutathione reductase) in three terrestrial plants (Avena sativa L., Brassica campestris L. cv. Chinensis, Lactuca sativa L. cv. hanson) were analyzed. Plant growth tests were carried out according to an International Standard Organization method and the results were analyzed by ANOVA followed by Williams' test. The concentration of Cd{sup 2+} that had the smallest observed significant negative effect (LOEC) on plant biomass was 6.25, 12.5 and 50 mg Cd/kg dry soil for lettuce, oat and Chinese cabbage, respectively. Activity of all enzymes studied increased significantly compared to enzyme activity in plant controls. For lettuce, LOEC values (mg Cd/kg dry soil) for enzymic activity ranged from 0.05 (glutathione reductase) to 0.39 (catalase). For oat, LOEC values (mg Cd/kg dry soil) ranged from 0.19 (for superoxide dismutase and glutathione reductase) to 0.39 (for catalase and peroxidase). For Chinese cabbage, LOEC values (mg Cd/kg dry soil) ranged from 0.19 (peroxidase, catalase and glutathione reductase) to 0.39 (superoxide dismutase). Classical (i.e. germination and biomass) and biochemical (i.e. enzyme activity) endpoints were compared to establish a sensitivity ranking, which was: enzyme activity > biomass > germination rate. For cadmium-soil contamination, the determination of quantitative sensitivity relationships (QSR) between classical and antioxidative enzyme biomarkers showed that the most sensitive plant species have, generally, the lowest QSR values.

  13. Cadmium phytotoxicity: Quantitative sensitivity relationships between classical endpoints and antioxidative enzyme biomarkers

    International Nuclear Information System (INIS)

    Rosa Correa, Albertina Xavier da; Roerig, Leonardo Rubi; Verdinelli, Miguel A.; Cotelle, Sylvie; Ferard, Jean-Francois; Radetski, Claudemir Marcos

    2006-01-01

    In this work, cadmium phytotoxicity and quantitative sensitivity relationships between different hierarchical endpoints in plants cultivated in a contaminated soil were studied. Thus, germination rate, biomass growth and antioxidative enzyme activity (i.e. superoxide dismutase, peroxidase, catalase and glutathione reductase) in three terrestrial plants (Avena sativa L., Brassica campestris L. cv. Chinensis, Lactuca sativa L. cv. hanson) were analyzed. Plant growth tests were carried out according to an International Standard Organization method and the results were analyzed by ANOVA followed by Williams' test. The concentration of Cd 2+ that had the smallest observed significant negative effect (LOEC) on plant biomass was 6.25, 12.5 and 50 mg Cd/kg dry soil for lettuce, oat and Chinese cabbage, respectively. Activity of all enzymes studied increased significantly compared to enzyme activity in plant controls. For lettuce, LOEC values (mg Cd/kg dry soil) for enzymic activity ranged from 0.05 (glutathione reductase) to 0.39 (catalase). For oat, LOEC values (mg Cd/kg dry soil) ranged from 0.19 (for superoxide dismutase and glutathione reductase) to 0.39 (for catalase and peroxidase). For Chinese cabbage, LOEC values (mg Cd/kg dry soil) ranged from 0.19 (peroxidase, catalase and glutathione reductase) to 0.39 (superoxide dismutase). Classical (i.e. germination and biomass) and biochemical (i.e. enzyme activity) endpoints were compared to establish a sensitivity ranking, which was: enzyme activity > biomass > germination rate. For cadmium-soil contamination, the determination of quantitative sensitivity relationships (QSR) between classical and antioxidative enzyme biomarkers showed that the most sensitive plant species have, generally, the lowest QSR values

  14. A conscious mouse model of gastric ileus using clinically relevant endpoints

    Directory of Open Access Journals (Sweden)

    Shao Yuanlin

    2005-06-01

    Full Text Available Abstract Background Gastric ileus is an unsolved clinical problem and current treatment is limited to supportive measures. Models of ileus using anesthetized animals, muscle strips or isolated smooth muscle cells do not adequately reproduce the clinical situation. Thus, previous studies using these techniques have not led to a clear understanding of the pathophysiology of ileus. The feasibility of using food intake and fecal output as simple, clinically relevant endpoints for monitoring ileus in a conscious mouse model was evaluated by assessing the severity and time course of various insults known to cause ileus. Methods Delayed food intake and fecal output associated with ileus was monitored after intraperitoneal injection of endotoxin, laparotomy with bowel manipulation, thermal injury or cerulein induced acute pancreatitis. The correlation of decreased food intake after endotoxin injection with gastric ileus was validated by measuring gastric emptying. The effect of endotoxin on general activity level and feeding behavior was also determined. Small bowel transit was measured using a phenol red marker. Results Each insult resulted in a transient and comparable decrease in food intake and fecal output consistent with the clinical picture of ileus. The endpoints were highly sensitive to small changes in low doses of endotoxin, the extent of bowel manipulation, and cerulein dose. The delay in food intake directly correlated with delayed gastric emptying. Changes in general activity and feeding behavior were insufficient to explain decreased food intake. Intestinal transit remained unchanged at the times measured. Conclusion Food intake and fecal output are sensitive markers of gastric dysfunction in four experimental models of ileus. In the mouse, delayed gastric emptying appears to be the major cause of the anorexic effect associated with ileus. Gastric dysfunction is more important than small bowel dysfunction in this model. Recovery of

  15. Correlates of protection for inactivated enterovirus 71 vaccine: the analysis of immunological surrogate endpoints.

    Science.gov (United States)

    Zhu, Wenbo; Jin, Pengfei; Li, Jing-Xin; Zhu, Feng-Cai; Liu, Pei

    2017-09-01

    Inactivated Enterovirus 71 (EV71) vaccines showed significant efficacy against the diseases associated with EV71 and a neutralizing antibody (NTAb) titer of 1:16-1:32 was suggested as the correlates of the vaccine protection. This paper aims to further estimate the immunological surrogate endpoints for the protection of inactivated EV71 vaccines and the effect factors. Pre-vaccination NTAb against EV71 at baseline (day 0), post-vaccination NTAb against EV71 at day 56, and the occurrence of laboratory-confirmed EV71-associated diseases during a 24-months follow-up period were collected from a phase 3 efficacy trial of an inactivated EV71 vaccine. We used the mixed-scaled logit model and the absolute sigmoid function by some extensions in continuous models to estimate the immunological surrogate endpoint for the EV71 vaccine protection, respectively. For children with a negative baseline of EV71 NTAb titers, an antibody level of 26.6 U/ml (1:30) was estimated to provide at least a 50% protection for 12 months, and an antibody level of 36.2 U/ml (1:42) may be needed to achieve a 50% protective level of the population for 24 months. Both the pre-vaccination NTAb level and the vaccine protective period could affect the estimation of the immunological surrogate for EV71 vaccine. A post-vaccination NTAb titer of 1:42 or more may be needed for long-term protection. NCT01508247.

  16. Establishment of Early Endpoints in Mouse Total-Body Irradiation Model.

    Directory of Open Access Journals (Sweden)

    Amory Koch

    Full Text Available Acute radiation sickness (ARS following exposure to ionizing irradiation is characterized by radiation-induced multiorgan dysfunction/failure that refers to progressive dysfunction of two or more organ systems, the etiological agent being radiation damage to cells and tissues over time. Radiation sensitivity data on humans and animals has made it possible to describe the signs associated with ARS. A mouse model of total-body irradiation (TBI has previously been developed that represents the likely scenario of exposure in the human population. Herein, we present the Mouse Intervention Scoring System (MISS developed at the Veterinary Sciences Department (VSD of the Armed Forces Radiobiology Research Institute (AFRRI to identify moribund mice and decrease the numbers of mice found dead, which is therefore a more humane refinement to death as the endpoint. Survival rates were compared to changes in body weights and temperatures in the mouse (CD2F1 male TBI model (6-14 Gy, 60Co γ-rays at 0.6 Gy min-1, which informed improvements to the Scoring System. Individual tracking of animals via implanted microchips allowed for assessment of criteria based on individuals rather than by group averages. From a total of 132 mice (92 irradiated, 51 mice were euthanized versus only four mice that were found dead (7% of non-survivors. In this case, all four mice were found dead after overnight periods between observations. Weight loss alone was indicative of imminent succumbing to radiation injury, however mice did not always become moribund within 24 hours while having weight loss >30%. Only one survivor had a weight loss of greater than 30%. Temperature significantly dropped only 2-4 days before death/euthanasia in 10 and 14 Gy animals. The score system demonstrates a significant refinement as compared to using subjective assessment of morbidity or death as the endpoint for these survival studies.

  17. Sodium chloride as a reference substance for the three growth endpoints used in the Lemna minor L. (1753 test

    Directory of Open Access Journals (Sweden)

    Aline Andrade Godoy

    2017-01-01

    Full Text Available Lemna sp. growth inhibition test standardized protocols suggest the use of compounds such as 3,5-dichlorophenol as reference substances for checking the test organism’s sensitivity routinely. However, this and other recommended chemicals present risks to human health and to the environment. Sodium chloride (NaCl appears as a less toxic alternative reference substance which has been successfully used in routine ecotoxicological tests. However, the evaluation of this compound in multiple growth endpoints used in the L. minor test, which is required for recommending it as a reference substance for this test organism, has not yet been reported. In the present study, NaCl was tested with L. minor for the growth endpoints frond number, total frond area and fresh weight. Results showed acceptable sensitivity and reproducibility (coefficient of variance < 15.0% for all three of the measured endpoints. Statistically significant differences were observed between the EC50 values calculated based on the three endpoints (p < 0.05. Total frond area was the most sensitive one, with average EC50 value of 2742.80 ± 245.7 mg L-1. It was anticipated that NaCl can be a suitable alternative reference substance and that total frond area should be the endpoint of choice for sensitivity toxicity tests using NaCl.

  18. Fall Prevention in a Primary Care Setting.

    Science.gov (United States)

    Siegrist, Monika; Freiberger, Ellen; Geilhof, Barbara; Salb, Johannes; Hentschke, Christian; Landendoerfer, Peter; Linde, Klause; Halle, Martin; Blank, Wolfgang A

    2016-05-27

    Falls and fall-related injuries are common in community-dwelling elderly people. Effective multifactorial fall prevention programs in the primary care setting may be a promising approach to reduce the incidence rate of falls. In a cluster randomized trial in 33 general practices 378 people living independently and at high risk of falling (65 to 94 years old; 285 women) were allocated to either a 16 week exercise-based fall prevention program including muscle strengthening and challenging balance training exercises, combined with a 12 week home-based exercise program (222 participants), or to usual care (156 participants). The main outcome was number of falls over a period of 12 months. Secondary outcomes were the number of fall-related injuries, physical function (Timed-Up-and-Go-Test, TUG, Chair-Stand-Test, CST, modified Romberg Test), and fear of falling. In the intervention group (n=222 patients in 17 general practices) 291 falls occurred, compared to 367 falls in the usual care group (n=156 patients in 16 general practices). We observed a lower incidence rate for falls in the intervention group (incidence rate ratio/IRR: 0.54; 95% confidence interval (CI): [0.35; 0.84], p=0.007) and for fall-related injuries (IRR: 0.66; [0.42; 0.94], p=0.033). Additionally, patients in the intervention group showed significant improvements in secondary endpoints (TUG: -2.39 s, [-3.91; -0.87], p=0.014; mRomberg: 1.70 s, [0.35; 3.04], p=0.037; fear of falling: -2.28 points, [-3.87; -0.69], p=0.022) compared to usual care. A complex falls prevention program in a primary care setting was effective in reducing falls and fall-related injuries in community dwelling older adults at risk.

  19. Osteoprotegerin predicts long-term outcome in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention

    DEFF Research Database (Denmark)

    Pedersen, Sune Folke; Bjerre, Mette; Mogelvang, Rasmus

    2012-01-01

    : 1.03-1.59; p = 0.03), repeat myocardial infarction (HR: 1.30; CI: 1.00-1.68; p = 0.05) and admission with heart failure (HR: 1.50; CI: 1.18-1.90; p = 0.001). Conclusion: This study shows that OPG independently predicts long-term outcome in STEMI patients treated with pPCI. Eventually, this knowledge...... in patients with ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (pPCI). Methods: We included 716 consecutive STEMI patients admitted to a single high-volume invasive heart center from September 2006 to December 2008. Endpoints were all...

  20. Primary fibromyalgia

    DEFF Research Database (Denmark)

    Jacobsen, S; Jensen, L T; Foldager, M

    1990-01-01

    Serum concentrations of procollagen type III aminoterminal peptide have previously been reported to be low in some patients with primary fibromyalgia and the aim of this study was to determine if such patients differ clinically from primary fibromyalgia patients with normal levels of procollagen...... type III aminoterminal peptide. Subjective symptoms, tender points and dynamic muscle strength in 45 women with primary fibromyalgia were related to serum concentrations of procollagen type III aminoterminal peptide. Patients with low serum concentrations of procollagen type III aminoterminal peptide...... concentrations of procollagen type III aminoterminal peptide of primary fibromyalgia patients are connected to the disease impact....

  1. UST-ID robotics: Wireless communication and minimum conductor technology, and end-point tracking technology surveys

    International Nuclear Information System (INIS)

    Holliday, M.A.

    1993-10-01

    This report is a technology review of the current state-of-the-art in two technologies applicable to the Underground Storage Tank (UST) program at the Hanford Nuclear Reservation. The first review is of wireless and minimal conductor technologies for in-tank communications. The second review is of advanced concepts for independent tool-point tracking. This study addresses the need to provide wireless transmission media or minimum conductor technology for in-tank communications and robot control. At present, signals are conducted via contacting transmission media, i.e., cables. Replacing wires with radio frequencies or invisible light are commonplace in the communication industry. This technology will be evaluated for its applicability to the needs of robotics. Some of these options are radio signals, leaky coax, infrared, microwave, and optical fiber systems. Although optical fiber systems are contacting transmission media, they will be considered because of their ability to reduce the number of conductors. In this report we will identify, evaluate, and recommend the requirements for wireless and minimum conductor technology to replace the present cable system. The second section is a technology survey of concepts for independent end-point tracking (tracking the position of robot end effectors). The position of the end effector in current industrial robots is determined by computing that position from joint information, which is basically a problem of locating a point in three-dimensional space. Several approaches are presently being used in industrial robotics, including: stereo-triangulation with a theodolite network and electrocamera system, photogrammetry, and multiple-length measurement with laser interferometry and wires. The techniques that will be evaluated in this survey are advanced applications of the aforementioned approaches. These include laser tracking (3-D and 5-D), ultrasonic tracking, vision-guided servoing, and adaptive robotic visual tracking

  2. Using Primary Source Documents.

    Science.gov (United States)

    Mintz, Steven

    2003-01-01

    Explores the use of primary sources when teaching about U.S. slavery. Includes primary sources from the Gilder Lehrman Documents Collection (New York Historical Society) to teach about the role of slaves in the Revolutionary War, such as a proclamation from Lord Dunmore offering freedom to slaves who joined his army. (CMK)

  3. Medics in Primary School

    Science.gov (United States)

    Press, Colin

    2003-01-01

    Some time ago a flyer on "Medics in Primary School" came the author's way. It described a programme for making placements in primary schools available to medical students. The benefits of the program to medical students and participating schools were highlighted, including opportunities to develop communication skills and demystify…

  4. A Phase 2, Double-Blind, Placebo-Controlled, Randomized Study of Fresolimumab in Patients With Steroid-Resistant Primary Focal Segmental Glomerulosclerosis

    Directory of Open Access Journals (Sweden)

    Flavio Vincenti

    2017-09-01

    Discussion: The study was underpowered and did not meet the primary or secondary endpoints. However, fresolimumab was well tolerated and is appropriate for continued evaluation in larger studies with adequate power.

  5. Radiometric titration of officinal radiopharmaceuticals using radioactive kryptonates as end-point indicators. I. Salicylic, acetylosalicylic, benzoic acids

    Energy Technology Data Exchange (ETDEWEB)

    Toelgyessy, J; Dillinger, P [Slovenska Vysoka Skola Technicka, Bratislava (Czechoslovakia). Chemickotechnologicka Fakulta; Harangozo, M; Jombik, J [Komenskeho Univ., Bratislava (Czechoslovakia). Farmaceuticka Fakulta

    1980-01-01

    A method for the determination of salicylic, acetylsalicylic and benzoic acids in officinal pharmaceutical based on radiometric titration with 0.1 mol.l/sup -1/ NaOH was developed. The end-point was detected with the aid of radioactive glass kryptonate. After the end-point, the excess titrant attacks the glass surface layers and this results in releasing /sup 85/Kr, and consequently, in decreasing the radioactivity of the kryptonate employed. The radioactive kryptonate used as an indicator was prepared by the bombardment of glass with accelerated /sup 85/Kr ions. The developed method is simple, accurate and correct.

  6. Effectiveness of Traditional Chinese Medicine Compound JieDuTongLuoShengJin Granules Treatment in Primary Sjögren’s Syndrome: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial

    Directory of Open Access Journals (Sweden)

    Ben Li

    2017-01-01

    Full Text Available Objective. To evaluate the clinical therapeutic efficacy and safety of JieDuTongLuoShengJin granules + HCQ in patients with pSS. Methods. 40 patients with low-activity-level pSS and without visceral involvement participated in this study and were randomized to receive either JieDuTongLuoShengJin granules with HCQ or placebo with HCQ. Patients and investigators were blinded to treatment allocation. The primary endpoint was week 12 ESSPRI score, while secondary endpoints included ESSDAI, salivary and lacrimal gland function, and some laboratory variables. Safety-related data were also assessed. Results. Comparing with the placebo group, the treatment group experienced statistically significant improvement in the mean change from baseline for the primary endpoint of ESSPRI score and also in PGA. Moreover, in comparison with baseline values, the treatment group had significantly improved ESSDAI score, unstimulated saliva flow rate, and several laboratory variables. However, upon comparison of the two groups, there were no significant differences for them. The incidence of AEs was 10.0%, one in treatment group and three in placebo group. Conclusion. Treatment with a combination of JieDuTongLuoShengJin granules with HCQ is effective in improving patients’ subjective symptoms and some objective indicators of pSS. These results indicate that JieDuTongLuoShengJin is promising as a safe and effective treatment of pSS.

  7. A polysomnographic placebo-controlled evaluation of the efficacy and safety of eszopiclone relative to placebo and zolpidem in the treatment of primary insomnia.

    Science.gov (United States)

    Erman, Milton K; Zammit, Gary; Rubens, Robert; Schaefer, Kendyl; Wessel, Thomas; Amato, David; Caron, Judy; Walsh, James K

    2008-06-15

    To evaluate the polysomnographic efficacy and the safety of a range of doses of eszopiclone relative to placebo in patients with primary insomnia. Zolpidem 10 mg was included as an active control. This multicenter, randomized, crossover study enrolled patients aged 21-64 years meeting the DSM-IV criteria for primary insomnia (n = 65). Patients received 2 nights treatment each with placebo, eszopiclone 1 mg, 2 mg, 2.5 mg, or 3 mg, and zolpidem 10 mg after randomization to one of 6 treatment sequences. Visits were separated by a 3-7 day washout. Objective efficacy was assessed by polysomnography (PSG). The primary endpoint was latency to persistent sleep (LPS); key secondary endpoints were sleep efficiency (SE) and wake time after sleep onset (WASO); other endpoints included wake time during sleep (WTDS) and number of awakenings (NAW), as well as patient-reported variables. LPS and SE were significantly different than placebo for all active treatments (p zolpidem 10 mg or the other eszopiclone doses. The incidence of central nervous system adverse events was 23.4% for zolpidem 10 mg, 6.2% to 12.5% for the eszopiclone doses, and 7.9% for placebo. Relative to placebo, all active treatments were effective in reducing LPS and increasing SE. Eszopiclone 3 mg was significantly different from placebo on the 3 PSG measures of sleep maintenance (WASO, WTDS, and NAW). Significant differences between zolpidem 10 mg and eszopiclone (2 mg or 3 mg) were not observed for PSG-measured outcomes, although the study was not powered to detect differences between the active drug conditions.

  8. Primary infertility (image)

    Science.gov (United States)

    Primary infertility is a term used to describe a couple that has never been able to conceive a pregnancy ... to do so through unprotected intercourse. Causes of infertility include a wide range of physical as well ...

  9. Comparative Analysis of Dynamic Cell Viability, Migration and Invasion Assessments by Novel Real-Time Technology and Classic Endpoint Assays

    Science.gov (United States)

    Limame, Ridha; Wouters, An; Pauwels, Bea; Fransen, Erik; Peeters, Marc; Lardon, Filip; De Wever, Olivier; Pauwels, Patrick

    2012-01-01

    Background Cell viability and motility comprise ubiquitous mechanisms involved in a variety of (patho)biological processes including cancer. We report a technical comparative analysis of the novel impedance-based xCELLigence Real-Time Cell Analysis detection platform, with conventional label-based endpoint methods, hereby indicating performance characteristics and correlating dynamic observations of cell proliferation, cytotoxicity, migration and invasion on cancer cells in highly standardized experimental conditions. Methodology/Principal Findings Dynamic high-resolution assessments of proliferation, cytotoxicity and migration were performed using xCELLigence technology on the MDA-MB-231 (breast cancer) and A549 (lung cancer) cell lines. Proliferation kinetics were compared with the Sulforhodamine B (SRB) assay in a series of four cell concentrations, yielding fair to good correlations (Spearman's Rho 0.688 to 0.964). Cytotoxic action by paclitaxel (0–100 nM) correlated well with SRB (Rho>0.95) with similar IC50 values. Reference cell migration experiments were performed using Transwell plates and correlated by pixel area calculation of crystal violet-stained membranes (Rho 0.90) and optical density (OD) measurement of extracted dye (Rho>0.95). Invasion was observed on MDA-MB-231 cells alone using Matrigel-coated Transwells as standard reference method and correlated by OD reading for two Matrigel densities (Rho>0.95). Variance component analysis revealed increased variances associated with impedance-based detection of migration and invasion, potentially caused by the sensitive nature of this method. Conclusions/Significance The xCELLigence RTCA technology provides an accurate platform for non-invasive detection of cell viability and motility. The strong correlations with conventional methods imply a similar observation of cell behavior and interchangeability with other systems, illustrated by the highly correlating kinetic invasion profiles on different

  10. Comparative analysis of dynamic cell viability, migration and invasion assessments by novel real-time technology and classic endpoint assays.

    Directory of Open Access Journals (Sweden)

    Ridha Limame

    Full Text Available BACKGROUND: Cell viability and motility comprise ubiquitous mechanisms involved in a variety of (pathobiological processes including cancer. We report a technical comparative analysis of the novel impedance-based xCELLigence Real-Time Cell Analysis detection platform, with conventional label-based endpoint methods, hereby indicating performance characteristics and correlating dynamic observations of cell proliferation, cytotoxicity, migration and invasion on cancer cells in highly standardized experimental conditions. METHODOLOGY/PRINCIPAL FINDINGS: Dynamic high-resolution assessments of proliferation, cytotoxicity and migration were performed using xCELLigence technology on the MDA-MB-231 (breast cancer and A549 (lung cancer cell lines. Proliferation kinetics were compared with the Sulforhodamine B (SRB assay in a series of four cell concentrations, yielding fair to good correlations (Spearman's Rho 0.688 to 0.964. Cytotoxic action by paclitaxel (0-100 nM correlated well with SRB (Rho>0.95 with similar IC(50 values. Reference cell migration experiments were performed using Transwell plates and correlated by pixel area calculation of crystal violet-stained membranes (Rho 0.90 and optical density (OD measurement of extracted dye (Rho>0.95. Invasion was observed on MDA-MB-231 cells alone using Matrigel-coated Transwells as standard reference method and correlated by OD reading for two Matrigel densities (Rho>0.95. Variance component analysis revealed increased variances associated with impedance-based detection of migration and invasion, potentially caused by the sensitive nature of this method. CONCLUSIONS/SIGNIFICANCE: The xCELLigence RTCA technology provides an accurate platform for non-invasive detection of cell viability and motility. The strong correlations with conventional methods imply a similar observation of cell behavior and interchangeability with other systems, illustrated by the highly correlating kinetic invasion profiles on

  11. Elimination of endpoint-discontinuity artifacts in the analysis of spectra in reciprocal space

    International Nuclear Information System (INIS)

    Yoo, S. D.; Aspnes, D. E.

    2001-01-01

    Reciprocal-space analysis offers several advantages for determining critical point parameters in optical and other spectra, for example the separation of baseline effects, information, and noise in low-, medium-, and high-index Fourier coefficients, respectively. However, endpoint-discontinuity artifacts can obscure much of the information when segments are isolated for analysis. We developed a procedure for eliminating these artifacts and recovering buried information by minimizing in the white-noise region the mean-square deviation between the Fourier coefficients of the data and those of low-order polynomials, then subtracting the resulting coefficients from the data over the entire range. We find that spectral analysis is optimized if no false data are used, i.e., when the number of points transformed equals the number of actual data points in the segment. Using fractional differentiation we develop a simple derivation of the variation of the reciprocal-space coefficients with index n for Lorentzian and Gaussian line shapes in direct space. More generally, we show that the definition of critical point energies in terms of phase coherence of the Fourier coefficients allows these energies to be determined for a broad class of line shapes even if the direct-space line shapes themselves are not known. Limitations for undersampled or highly broadened spectra are discussed, along with extensions to two- or higher-dimensional arrays of data. [copyright] 2001 American Institute of Physics

  12. Center-Within-Trial Versus Trial-Level Evaluation of Surrogate Endpoints

    Science.gov (United States)

    Renfro, Lindsay A.; Shi, Qian; Xue, Yuan; Li, Junlong; Shang, Hongwei; Sargent, Daniel J.

    2014-01-01

    Evaluation of candidate surrogate endpoints using individual patient data from multiple clinical trials is considered the gold standard approach to validate surrogates at both patient and trial levels. However, this approach assumes the availability of patient-level data from a relatively large collection of similar trials, which may not be possible to achieve for a given disease application. One common solution to the problem of too few similar trials involves performing trial-level surrogacy analyses on trial sub-units (e.g., centers within trials), thereby artificially increasing the trial-level sample size for feasibility of the multi-trial analysis. To date, the practical impact of treating trial sub-units (centers) identically to trials in multi-trial surrogacy analyses remains unexplored, and conditions under which this ad hoc solution may in fact be reasonable have not been identified. We perform a simulation study to identify such conditions, and demonstrate practical implications using a multi-trial dataset of patients with early stage colon cancer. PMID:25061255

  13. End-Point Immobilization of Recombinant Thrombomodulin via Sortase-Mediated Ligation

    Science.gov (United States)

    Jiang, Rui; Weingart, Jacob; Zhang, Hailong; Ma, Yong; Sun, Xue-Long

    2012-01-01

    We report an enzymatic end-point modification and immobilization of recombinant human thrombomodulin (TM), a cofactor for activation of anticoagulant protein C pathway via thrombin. First, a truncated TM mutant consisting of epidermal growth factor-like domains 4–6 (TM456) with a conserved pentapeptide LPETG motif at its C-terminal was expressed and purified in E. coli. Next, the truncated TM456 derivative was site-specifically modified with N-terminal diglycine containing molecules such as biotin and the fluorescent probe dansyl via sortase A (SrtA) mediated ligation (SML). The successful ligations were confirmed by SDS-PAGE and fluorescence imaging. Finally, the truncated TM456 was immobilized onto N-terminal diglycine-functionalized glass slide surface via SML directly. Alternatively, the truncated TM456 was biotinylated via SML and then immobilized onto streptavidin-functionalized glass slide surface indirectly. The successful immobilizations were confirmed by fluorescence imaging. The bioactivity of the immobilized truncated TM456 was further confirmed by protein C activation assay, in which enhanced activation of protein C by immobilized recombinant TM was observed. The sortase A-catalyzed surface ligation took place under mild conditions and is rapid occurring in a single step without prior chemical modification of the target protein. This site-specific covalent modification leads to molecules being arranged in a definitively ordered fashion and facilitating the preservation of the protein’s biological activity. PMID:22372933

  14. Update of the International Consensus on Palliative Radiotherapy Endpoints for Future Clinical Trials in Bone Metastases

    Energy Technology Data Exchange (ETDEWEB)

    Chow, Edward, E-mail: Edward.Chow@sunnybrook.ca [Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON (Canada); Hoskin, Peter [Mount Vernon Centre for Cancer Treatment, Mount Vernon Hospital, Northwood, Middlesex (United Kingdom); Mitera, Gunita; Zeng Liang [Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON (Canada); Lutz, Stephen [Department of Radiation Oncology, Blanchard Valley Regional Cancer Center, Findlay, OH (United States); Roos, Daniel [Department of Radiation Oncology, Royal Adelaide Hospital, Adelaide, South Australia (Australia); Hahn, Carol [Department of Radiation Oncology, Duke University Medical Center, Durham, NC (United States); Linden, Yvette van der [Radiotherapeutic Institute Friesland, Leeuwarden (Netherlands); Hartsell, William [Department of Radiation Oncology, Advocate Good Samaritan Cancer Center, Downers Grove, IL (United States); Kumar, Eshwar [Department of Oncology, Atlantic Health Sciences Cancer Centre, Saint John Regional Hospital, Saint John, NB (Canada)

    2012-04-01

    Purpose: To update the international consensus on palliative radiotherapy endpoints for future clinical trials in bone metastases by surveying international experts regarding previous uncertainties within the 2002 consensus, changes that may be necessary based on practice pattern changes and research findings since that time. Methods and Materials: A two-phase survey was used to determine revisions and new additions to the 2002 consensus. A total of 49 experts from the American Society for Radiation Oncology, the European Society for Therapeutic Radiology and Oncology, the Faculty of Radiation Oncology of the Royal Australian and New Zealand College of Radiologists, and the Canadian Association of Radiation Oncology who are directly involved in the care of patients with bone metastases participated in this survey. Results: Consensus was established in areas involving response definitions, eligibility criteria for future trials, reirradiation, changes in systemic therapy, radiation techniques, parameters at follow-up, and timing of assessments. Conclusion: An outline for trials in bone metastases was updated based on survey and consensus. Investigators leading trials in bone metastases are encouraged to adopt the revised guideline to promote consistent reporting. Areas for future research were identified. It is intended for the consensus to be re-examined in the future on a regular basis.

  15. Determining significant endpoints for ecological risk analyses. 1997 annual progress report

    Energy Technology Data Exchange (ETDEWEB)

    Hinton, T.G.; Congdon, J.; Rowe, C.; Scott, D. [Univ. of Georgia, Aiken, SC (US). Savannah River Ecology Lab.; Bedford, J.; Whicker, F.W. [Colorado State Univ., Fort Collins, CO (US)

    1997-11-01

    'This report summarizes the first year''s progress of research funded under the Department of Energy''s Environmental Management Science Program. The research was initiated to better determine ecological risks from toxic and radioactive contaminants. More precisely, the research is designed to determine the relevancy of sublethal cellular damage to the performance of individuals and to identify characteristics of non-human populations exposed to chronic, low-level radiation, as is typically found on many DOE sites. The authors propose to establish a protocol to assess risks to non-human species at higher levels of biological organization by relating molecular damage to more relevant responses that reflect population health. They think that they can achieve this by coupling changes in metabolic rates and energy allocation patterns to meaningful population response variables, and by using novel biological dosimeters in controlled, manipulative dose/effects experiments. They believe that a scientifically defensible endpoint for measuring ecological risks can only be determined once its understood the extent to which molecular damage from contaminant exposure is detrimental at the individual and population levels of biological organization.'

  16. The interpolation method based on endpoint coordinate for CT three-dimensional image

    International Nuclear Information System (INIS)

    Suto, Yasuzo; Ueno, Shigeru.

    1997-01-01

    Image interpolation is frequently used to improve slice resolution to reach spatial resolution. Improved quality of reconstructed three-dimensional images can be attained with this technique as a result. Linear interpolation is a well-known and widely used method. The distance-image method, which is a non-linear interpolation technique, is also used to convert CT value images to distance images. This paper describes a newly developed method that makes use of end-point coordinates: CT-value images are initially converted to binary images by thresholding them and then sequences of pixels with 1-value are arranged in vertical or horizontal directions. A sequence of pixels with 1-value is defined as a line segment which has starting and end points. For each pair of adjacent line segments, another line segment was composed by spatial interpolation of the start and end points. Binary slice images are constructed from the composed line segments. Three-dimensional images were reconstructed from clinical X-ray CT images, using three different interpolation methods and their quality and processing speed were evaluated and compared. (author)

  17. Speech endpoint detection with non-language speech sounds for generic speech processing applications

    Science.gov (United States)

    McClain, Matthew; Romanowski, Brian

    2009-05-01

    Non-language speech sounds (NLSS) are sounds produced by humans that do not carry linguistic information. Examples of these sounds are coughs, clicks, breaths, and filled pauses such as "uh" and "um" in English. NLSS are prominent in conversational speech, but can be a significant source of errors in speech processing applications. Traditionally, these sounds are ignored by speech endpoint detection algorithms, where speech regions are identified in the audio signal prior to processing. The ability to filter NLSS as a pre-processing step can significantly enhance the performance of many speech processing applications, such as speaker identification, language identification, and automatic speech recognition. In order to be used in all such applications, NLSS detection must be performed without the use of language models that provide knowledge of the phonology and lexical structure of speech. This is especially relevant to situations where the languages used in the audio are not known apriori. We present the results of preliminary experiments using data from American and British English speakers, in which segments of audio are classified as language speech sounds (LSS) or NLSS using a set of acoustic features designed for language-agnostic NLSS detection and a hidden-Markov model (HMM) to model speech generation. The results of these experiments indicate that the features and model used are capable of detection certain types of NLSS, such as breaths and clicks, while detection of other types of NLSS such as filled pauses will require future research.

  18. End-point detection in potentiometric titration by continuous wavelet transform.

    Science.gov (United States)

    Jakubowska, Małgorzata; Baś, Bogusław; Kubiak, Władysław W

    2009-10-15

    The aim of this work was construction of the new wavelet function and verification that a continuous wavelet transform with a specially defined dedicated mother wavelet is a useful tool for precise detection of end-point in a potentiometric titration. The proposed algorithm does not require any initial information about the nature or the type of analyte and/or the shape of the titration curve. The signal imperfection, as well as random noise or spikes has no influence on the operation of the procedure. The optimization of the new algorithm was done using simulated curves and next experimental data were considered. In the case of well-shaped and noise-free titration data, the proposed method gives the same accuracy and precision as commonly used algorithms. But, in the case of noisy or badly shaped curves, the presented approach works good (relative error mainly below 2% and coefficients of variability below 5%) while traditional procedures fail. Therefore, the proposed algorithm may be useful in interpretation of the experimental data and also in automation of the typical titration analysis, specially in the case when random noise interfere with analytical signal.

  19. Analysing data from patient-reported outcome and quality of life endpoints for cancer clinical trials

    DEFF Research Database (Denmark)

    Bottomley, Andrew; Pe, Madeline; Sloan, Jeff

    2016-01-01

    Measures of health-related quality of life (HRQOL) and other patient-reported outcomes generate important data in cancer randomised trials to assist in assessing the risks and benefits of cancer therapies and fostering patient-centred cancer care. However, the various ways these measures are anal......Measures of health-related quality of life (HRQOL) and other patient-reported outcomes generate important data in cancer randomised trials to assist in assessing the risks and benefits of cancer therapies and fostering patient-centred cancer care. However, the various ways these measures...... are analysed and interpreted make it difficult to compare results across trials, and hinders the application of research findings to inform publications, product labelling, clinical guidelines, and health policy. To address these problems, the Setting International Standards in Analyzing Patient......-Reported Outcomes and Quality of Life Endpoints Data (SISAQOL) initiative has been established. This consortium, directed by the European Organisation for Research and Treatment of Cancer (EORTC), was convened to provide recommendations on how to standardise the analysis of HRQOL and other patient-reported outcomes...

  20. Update of the International Consensus on Palliative Radiotherapy Endpoints for Future Clinical Trials in Bone Metastases

    International Nuclear Information System (INIS)

    Chow, Edward; Hoskin, Peter; Mitera, Gunita; Zeng Liang; Lutz, Stephen; Roos, Daniel; Hahn, Carol; Linden, Yvette van der; Hartsell, William; Kumar, Eshwar

    2012-01-01

    Purpose: To update the international consensus on palliative radiotherapy endpoints for future clinical trials in bone metastases by surveying international experts regarding previous uncertainties within the 2002 consensus, changes that may be necessary based on practice pattern changes and research findings since that time. Methods and Materials: A two-phase survey was used to determine revisions and new additions to the 2002 consensus. A total of 49 experts from the American Society for Radiation Oncology, the European Society for Therapeutic Radiology and Oncology, the Faculty of Radiation Oncology of the Royal Australian and New Zealand College of Radiologists, and the Canadian Association of Radiation Oncology who are directly involved in the care of patients with bone metastases participated in this survey. Results: Consensus was established in areas involving response definitions, eligibility criteria for future trials, reirradiation, changes in systemic therapy, radiation techniques, parameters at follow-up, and timing of assessments. Conclusion: An outline for trials in bone metastases was updated based on survey and consensus. Investigators leading trials in bone metastases are encouraged to adopt the revised guideline to promote consistent reporting. Areas for future research were identified. It is intended for the consensus to be re-examined in the future on a regular basis.

  1. CaFE: a tool for binding affinity prediction using end-point free energy methods.

    Science.gov (United States)

    Liu, Hui; Hou, Tingjun

    2016-07-15

    Accurate prediction of binding free energy is of particular importance to computational biology and structure-based drug design. Among those methods for binding affinity predictions, the end-point approaches, such as MM/PBSA and LIE, have been widely used because they can achieve a good balance between prediction accuracy and computational cost. Here we present an easy-to-use pipeline tool named Calculation of Free Energy (CaFE) to conduct MM/PBSA and LIE calculations. Powered by the VMD and NAMD programs, CaFE is able to handle numerous static coordinate and molecular dynamics trajectory file formats generated by different molecular simulation packages and supports various force field parameters. CaFE source code and documentation are freely available under the GNU General Public License via GitHub at https://github.com/huiliucode/cafe_plugin It is a VMD plugin written in Tcl and the usage is platform-independent. tingjunhou@zju.edu.cn. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  2. Fourier-transform infrared spectroscopy as a novel approach to providing effect-based endpoints in duckweed toxicity testing.

    Science.gov (United States)

    Hu, Li-Xin; Ying, Guang-Guo; Chen, Xiao-Wen; Huang, Guo-Yong; Liu, You-Sheng; Jiang, Yu-Xia; Pan, Chang-Gui; Tian, Fei; Martin, Francis L

    2017-02-01

    Traditional duckweed toxicity tests only measure plant growth inhibition as an endpoint, with limited effects-based data. The present study aimed to investigate whether Fourier-transform infrared (FTIR) spectroscopy could enhance the duckweed (Lemna minor L.) toxicity test. Four chemicals (Cu, Cd, atrazine, and acetochlor) and 4 metal-containing industrial wastewater samples were tested. After exposure of duckweed to the chemicals, standard toxicity endpoints (frond number and chlorophyll content) were determined; the fronds were also interrogated using FTIR spectroscopy under optimized test conditions. Biochemical alterations associated with each treatment were assessed and further analyzed by multivariate analysis. The results showed that comparable x% of effective concentration (ECx) values could be achieved based on FTIR spectroscopy in comparison with those based on traditional toxicity endpoints. Biochemical alterations associated with different doses of toxicant were mainly attributed to lipid, protein, nucleic acid, and carbohydrate structural changes, which helped to explain toxic mechanisms. With the help of multivariate analysis, separation of clusters related to different exposure doses could be achieved. The present study is the first to show successful application of FTIR spectroscopy in standard duckweed toxicity tests with biochemical alterations as new endpoints. Environ Toxicol Chem 2017;36:346-353. © 2016 SETAC. © 2016 SETAC.

  3. Updated standardized endpoint definitions for transcatheter aortic valve implantation: The Valve Academic Research Consortium-2 consensus document

    NARCIS (Netherlands)

    A.P. Kappetein (Arie Pieter); S.J. Head (Stuart); P. Généreux (Philippe); N. Piazza (Nicolo); N.M. van Mieghem (Nicolas); E.H. Blackstone (Eugene); T.G. Brott (Thomas); D.J. Cohen (David J.); D.E. Cutlip (Donald); G.A. van Es (Gerrit Anne); R.T. Hahn (Rebecca); A.J. Kirtane (Ajay); M. Krucoff (Mitchell); S. Kodali (Susheel); M.J. Mack (Michael); R. Mehran (Roxana); J. Rodés-Cabau (Josep); P. Vranckx (Pascal); J.G. Webb (John); S.W. Windecker (Stephan); P.W.J.C. Serruys (Patrick); M.B. Leon (Martin)

    2012-01-01

    textabstractObjectives: The aim of the current Valvular Academic Research Consortium (VARC)-2 initiative was to revisit the selection and definitions of transcatheter aortic valve implantation (TAVI)- clinical endpoints to make them more suitable to the present and future needs of clinical trials.

  4. Definitions and validation criteria for biomarkers and surrogate endpoints: development and testing of a quantitative hierarchical levels of evidence schema

    NARCIS (Netherlands)

    Lassere, Marissa N.; Johnson, Kent R.; Boers, Maarten; Tugwell, Peter; Brooks, Peter; Simon, Lee; Strand, Vibeke; Conaghan, Philip G.; Ostergaard, Mikkel; Maksymowych, Walter P.; Landewe, Robert; Bresnihan, Barry; Tak, Paul-Peter; Wakefield, Richard; Mease, Philip; Bingham, Clifton O.; Hughes, Michael; Altman, Doug; Buyse, Marc; Galbraith, Sally; Wells, George

    2007-01-01

    OBJECTIVE: There are clear advantages to using biomarkers and surrogate endpoints, but concerns about clinical and statistical validity and systematic methods to evaluate these aspects hinder their efficient application. Our objective was to review the literature on biomarkers and surrogates to

  5. Energetic endpoints provide early indicators of life history effects in a freshwater gastropod exposed to the fungicide, pyraclostrobin.

    Science.gov (United States)

    Fidder, Bridgette N; Reátegui-Zirena, Evelyn G; Olson, Adric D; Salice, Christopher J

    2016-04-01

    Organismal energetics provide important insights into the effects of environmental toxicants. We aimed to determine the effects of pyraclostrobin on Lymnaea stagnalis by examining energy allocation patterns and life history traits. Juvenile snails exposed to pyraclostrobin decreased feeding rate and increased apparent avoidance behaviors at environmentally relevant concentrations. In adults, we found that sublethal concentrations of pyraclostrobin did not affect reproductive output, however, there were significant effects on developmental endpoints with longer time to hatch and decreased hatching success in pyraclostrobin-exposed egg masses. Further, there were apparent differences in developmental effects depending on whether mothers were also exposed to pyraclostrobin suggesting this chemical can exert intergenerational effects. Pyraclostrobin also affected protein and carbohydrate content of eggs in mothers that were exposed to pyraclostrobin. Significant effects on macronutrient content of eggs occurred at lower concentrations than effects on gross endpoints such as hatching success and time to hatch suggesting potential value for these endpoints as early indicators of ecologically relevant stress. These results provide important insight into the effects of a common fungicide on important endpoints for organismal energetics and life history. Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. The Impact of Multiple Endpoint Dependency on "Q" and "I"[superscript 2] in Meta-Analysis

    Science.gov (United States)

    Thompson, Christopher Glen; Becker, Betsy Jane

    2014-01-01

    A common assumption in meta-analysis is that effect sizes are independent. When correlated effect sizes are analyzed using traditional univariate techniques, this assumption is violated. This research assesses the impact of dependence arising from treatment-control studies with multiple endpoints on homogeneity measures "Q" and…

  7. Primary productivity

    Digital Repository Service at National Institute of Oceanography (India)

    Verlecar, X.N.; Parulekar, A.H.

    Photosynthetic production in the oceans in relation to light, nutrients and mixing processes is discussed. Primary productivity in the estuarine region is reported to be high in comparison to coastal and oceanic waters. Upwelling phenomenon...

  8. Primary Hyperparathyroidism

    Science.gov (United States)

    ... Neoplasia Type 1 Thyroid Disease & Pregnancy Primary Hyperparathyroidism Prolactinoma National Hormone and Pituitary Program (NHPP): Information for ... qualified health care provider nearby. Eating, Diet, and Nutrition Eating, diet, and nutrition have not been shown ...

  9. Prediction of outcome of bright light treatment in patients with seasonal affective disorder: Discarding the early response, confirming a higher atypical balance, and uncovering a higher body mass index at baseline as predictors of endpoint outcome.

    Science.gov (United States)

    Dimitrova, Tzvetelina D; Reeves, Gloria M; Snitker, Soren; Lapidus, Manana; Sleemi, Aamar R; Balis, Theodora G; Manalai, Partam; Tariq, Muhammad M; Cabassa, Johanna A; Karim, Naila N; Johnson, Mary A; Langenberg, Patricia; Rohan, Kelly J; Miller, Michael; Stiller, John W; Postolache, Teodor T

    2017-11-01

    We tested the hypothesis that the early improvement in mood after the first hour of bright light treatment compared to control dim-red light would predict the outcome at six weeks of bright light treatment for depressed mood in patients with Seasonal Affective Disorder (SAD). We also analyzed the value of Body Mass Index (BMI) and atypical symptoms of depression at baseline in predicting treatment outcome. Seventy-eight adult participants were enrolled. The first treatment was controlled crossover, with randomized order, and included one hour of active bright light treatment and one hour of control dim-red light, with one-hour washout. Depression was measured on the Structured Interview Guide for the Hamilton Rating Scale for Depression-SAD version (SIGH-SAD). The predictive association of depression scores changes after the first session. BMI and atypical score balance with treatment outcomes at endpoint were assessed using multivariable linear and logistic regressions. No significant prediction by changes in depression scores after the first session was found. However, higher atypical balance scores and BMI positively predicted treatment outcome. Absence of a control intervention for the six-weeks of treatment (only the first session in the laboratory was controlled). Exclusion of patients with comorbid substance abuse, suicidality and bipolar I disorder, and patients on antidepressant medications, reducing the generalizability of the study. Prediction of outcome by early response to light treatment was not replicated, and the previously reported prediction of baseline atypical balance was confirmed. BMI, a parameter routinely calculated in primary care, was identified as a novel predictor, and calls for replication and then exploration of possible mediating mechanisms. Published by Elsevier B.V.

  10. Percutaneous lower-extremity arterial interventions with primary balloon angioplasty versus Silverhawk atherectomy and adjunctive balloon angioplasty: randomized trial.

    Science.gov (United States)

    Shammas, Nicolas W; Coiner, Denise; Shammas, Gail A; Dippel, Eric J; Christensen, Lori; Jerin, Michael

    2011-09-01

    Target lesion revascularization (TLR) with primary percutaneous transluminal angioplasty (PTA) versus SilverHawk atherectomy and adjunctive PTA of de novo infrainguinal disease has not been well defined. This study was conducted to compare the two approaches. In this prospective, two-center randomized trial of PTA versus atherectomy of infrainguinal vessels, the primary endpoint of TLR was evaluated at 1 year. Secondary endpoints included the rate of "bailout" stent placement for suboptimal acute angiographic results and the rate of target vessel revascularization (TVR). Fifty-eight patients were included in the study. Of these, 29 (36 vessels) were randomized to the atherectomy arm and 29 (48 vessels) to the PTA arm. Final acute angiographic success rates were 100% in the PTA arm and 97.2% in the atherectomy arm (P value not significant). There was no statistical difference in TLR (16.7% vs 11.1%) or TVR (21.4% vs 11.1%) between the PTA and atherectomy groups, respectively. Bailout stent placement was performed in 18 of 29 patients (62.1%) in the PTA arm and eight of 29 patients (27.6%) in the atherectomy arm (P = .017). Major adverse events were similar between the PTA and atherectomy arms. Finally, when embolic filter protection was used, distal macroembolization occurred in 11 of 17 patients (64.7%) treated with atherectomy versus none of 10 in the PTA group (P atherectomy and primary PTA. Atherectomy reduced the need for bailout stent placement compared with primary PTA. Copyright © 2011 SIR. Published by Elsevier Inc. All rights reserved.

  11. Acute effects of a prooxidant herbicide on the microalga Chlamydomonas reinhardtii: Screening cytotoxicity and genotoxicity endpoints

    International Nuclear Information System (INIS)

    Esperanza, Marta; Cid, Ángeles; Herrero, Concepción; Rioboo, Carmen

    2015-01-01

    Highlights: • Mitochondrial membrane potential constituted the most sensitive parameter assayed. • Several genotoxicity methods were applied for first time in ecotoxicological studies. • Oxidative DNA base damage (8-OHdG) was induced by paraquat exposure. • Cells with DNA strand breakage and subG1-nuclei increased in treated cultures. • Typical apoptosis hallmarks were observed in microalgal cells exposed to paraquat. - Abstract: Since recent evidence has demonstrated that many types of chemicals exhibit oxidative and/or genotoxic potential on living organisms, reactive oxygen species (ROS) formation and DNA damage are currently the best accepted paradigms to assess the potential hazardous biological effects of a wide range of contaminants. The goal of this study was to evaluate the sensitivity of different cytotoxicity and genotoxicity responses on the model microalga Chlamydomonas reinhardtii exposed to the prooxidant herbicide paraquat. In addition to the growth endpoint, cell viability, mitochondrial membrane potential and presence of reactive oxygen species (ROS) were assayed as potential markers of cytotoxicity using flow cytometry (FCM). To study the effects of paraquat on C. reinhardtii DNA, several genotoxicity approaches were implemented for the first time in an ecotoxicological study on microalgae. Oxidative DNA base damage was analysed by measuring the oxidative DNA lesion 8-OHdG by FCM. DNA fragmentation was analysed by different methods: comet assay, and cell cycle analysis by FCM, with a particular focus on the presence of subG1-nuclei. Finally, effects on morphology of nuclei were monitored through DAPI staining. The evaluation of these endpoints showed that several physiological and biochemical parameters reacted to oxidative stress disturbances with greater sensitivity than integrative parameters such as growth rates or cell viability. The experiments revealed concentration-dependent cytotoxicity (ROS formation, depolarization of

  12. Acute effects of a prooxidant herbicide on the microalga Chlamydomonas reinhardtii: Screening cytotoxicity and genotoxicity endpoints

    Energy Technology Data Exchange (ETDEWEB)

    Esperanza, Marta; Cid, Ángeles; Herrero, Concepción; Rioboo, Carmen, E-mail: carmen.rioboo@udc.es

    2015-08-15

    Highlights: • Mitochondrial membrane potential constituted the most sensitive parameter assayed. • Several genotoxicity methods were applied for first time in ecotoxicological studies. • Oxidative DNA base damage (8-OHdG) was induced by paraquat exposure. • Cells with DNA strand breakage and subG1-nuclei increased in treated cultures. • Typical apoptosis hallmarks were observed in microalgal cells exposed to paraquat. - Abstract: Since recent evidence has demonstrated that many types of chemicals exhibit oxidative and/or genotoxic potential on living organisms, reactive oxygen species (ROS) formation and DNA damage are currently the best accepted paradigms to assess the potential hazardous biological effects of a wide range of contaminants. The goal of this study was to evaluate the sensitivity of different cytotoxicity and genotoxicity responses on the model microalga Chlamydomonas reinhardtii exposed to the prooxidant herbicide paraquat. In addition to the growth endpoint, cell viability, mitochondrial membrane potential and presence of reactive oxygen species (ROS) were assayed as potential markers of cytotoxicity using flow cytometry (FCM). To study the effects of paraquat on C. reinhardtii DNA, several genotoxicity approaches were implemented for the first time in an ecotoxicological study on microalgae. Oxidative DNA base damage was analysed by measuring the oxidative DNA lesion 8-OHdG by FCM. DNA fragmentation was analysed by different methods: comet assay, and cell cycle analysis by FCM, with a particular focus on the presence of subG1-nuclei. Finally, effects on morphology of nuclei were monitored through DAPI staining. The evaluation of these endpoints showed that several physiological and biochemical parameters reacted to oxidative stress disturbances with greater sensitivity than integrative parameters such as growth rates or cell viability. The experiments revealed concentration-dependent cytotoxicity (ROS formation, depolarization of

  13. Novel joint selection methods can reduce sample size for rheumatoid arthritis clinical trials with ultrasound endpoints.

    Science.gov (United States)

    Allen, John C; Thumboo, Julian; Lye, Weng Kit; Conaghan, Philip G; Chew, Li-Ching; Tan, York Kiat

    2018-03-01

    To determine whether novel methods of selecting joints through (i) ultrasonography (individualized-ultrasound [IUS] method), or (ii) ultrasonography and clinical examination (individualized-composite-ultrasound [ICUS] method) translate into smaller rheumatoid arthritis (RA) clinical trial sample sizes when compared to existing methods utilizing predetermined joint sites for ultrasonography. Cohen's effect size (ES) was estimated (ES^) and a 95% CI (ES^L, ES^U) calculated on a mean change in 3-month total inflammatory score for each method. Corresponding 95% CIs [nL(ES^U), nU(ES^L)] were obtained on a post hoc sample size reflecting the uncertainty in ES^. Sample size calculations were based on a one-sample t-test as the patient numbers needed to provide 80% power at α = 0.05 to reject a null hypothesis H 0 : ES = 0 versus alternative hypotheses H 1 : ES = ES^, ES = ES^L and ES = ES^U. We aimed to provide point and interval estimates on projected sample sizes for future studies reflecting the uncertainty in our study ES^S. Twenty-four treated RA patients were followed up for 3 months. Utilizing the 12-joint approach and existing methods, the post hoc sample size (95% CI) was 22 (10-245). Corresponding sample sizes using ICUS and IUS were 11 (7-40) and 11 (6-38), respectively. Utilizing a seven-joint approach, the corresponding sample sizes using ICUS and IUS methods were nine (6-24) and 11 (6-35), respectively. Our pilot study suggests that sample size for RA clinical trials with ultrasound endpoints may be reduced using the novel methods, providing justification for larger studies to confirm these observations. © 2017 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.

  14. First observation of bald patches in a filament channel and at a barb endpoint

    Science.gov (United States)

    López Ariste, A.; Aulanier, G.; Schmieder, B.; Sainz Dalda, A.

    2006-09-01

    The 3D magnetic field topology of solar filaments/prominences is strongly debated, because it is not directly measureable in the corona. Among various prominence models, several are consistent with many observations, but their related topologies are very different. We conduct observations to address this paradigm. We measure the photospheric vector magnetic field in several small flux concentrations surrounding a filament observed far from disc center. Our objective is to test for the presence/absence of magnetic dips around/below the filament body/barb, which is a strong constraint on prominence models, and that is still untested by observations. Our observations are performed with the THEMIS/MTR instrument. The four Stokes parameters are extracted, from which the vector magnetic fields are calculated using a PCA inversion. The resulting vector fields are then deprojected onto the photospheric plane. The 180° ambiguity is then solved by selecting the only solution that matches filament chirality rules. Considering the weakness of the resulting magnetic fields, a careful analysis of the inversion procedure and its error bars was performed, to avoid over-interpretation of noisy or ambiguous Stokes profiles. Thanks to the simultaneous multi-wavelength THEMIS observations, the vector field maps are coaligned with the Hα image of the filament. By definition, photospheric dips are identifiable where the horizontal component of the magnetic field points from a negative toward a positive polarity. Among six bipolar regions analyzed in the filament channel, four at least display photospheric magnetic dips, i.e. bald patches. For barbs, the topology of the endpoint is that of a bald patch located next to a parasitic polarity, not of an arcade pointing within the polarity. The observed magnetic field topology in the photosphere tends to support models of prominence based on magnetic dips located within weakly twisted flux tubes. Their underlying and lateral extensions form

  15. Comparison of the sensitivity of different toxicological endpoints in Caco-2 cells after cadmium chloride treatment

    Energy Technology Data Exchange (ETDEWEB)

    Boveri, M.; Pazos, P.; Gennari, A.; Casado, J.; Hartung, T.; Prieto, P. [ECVAM, Inst. for Health and Consumer Protection, Joint Research Centre, European Commission, Ispra (Italy)

    2004-04-01

    The human colorectal adenocarcinoma cell line Caco-2 is a widely used in vitro model of the intestinal barrier. Cadmium chloride (CdCl{sub 2}) is a highly toxic metal compound, ubiquitous in the biosphere, able to enter the food chain and to reach the intestinal epithelium, causing structural and functional damages. The aim of this work was to characterise cadmium toxicity in Caco-2 cells and, in particular, to compare the sensitivity of different endpoints revealing damage both on the epithelial barrier and at the cellular or molecular level. After 24-h exposure of the cells to CdCl{sub 2}, lactate dehydrogenase (LDH) leakage showed cadmium-induced cell toxicity, significant from 25 {mu}M CdCl{sub 2} and above, and analysis of different cell death pathways indicated the presence of necrosis after treatment with 50 {mu}M CdCl{sub 2}. At the molecular level, we observed an increase in the protective protein heat shock protein 70 (HSP70), starting at 10 {mu}M CdCl{sub 2}. At the barrier level, transepithelial electrical resistance (TEER) decreased while paracellular permeability (PCP) significantly increased after the treatment, showing an EC{sub 50} of 6 and 16 {mu}M CdCl{sub 2}, respectively, and indicating the loss of barrier integrity. In conclusion, our data reveal that CdCl{sub 2} toxicity in Caco-2 cells can be detected at the barrier level at very low concentrations; also, HSP70 was shown to be a sensitive marker for detecting in vitro cadmium-induced toxicity. (orig.)

  16. Predictive validity of endpoints used in electrophysiological modelling of migraine in the trigeminovascular system.

    Science.gov (United States)

    Farkas, Bence; Kardos, Péter; Orosz, Szabolcs; Tarnawa, István; Csekő, Csongor; Lévay, György; Farkas, Sándor; Lendvai, Balázs; Kovács, Péter

    2015-11-02

    The trigeminovascular system has a pivotal role in the pathomechanism of migraine. The aim of the present study was to further develop existing models of migraine making them more suitable for testing the effects of compounds with presumed antimigraine activity in anaesthetised rats. Simultaneous recording of ongoing activity of spontaneously active neurons in the trigeminocervical complex as well as their discharges evoked by electrical stimulation of the dura mater via activation of A- and C-sensory fibres were carried out. Effects of sumatriptan, propranolol and topiramate were evaluated prior to and after application of a mixture containing inflammatory mediators on the dura. Propranolol (10 mg/kg s.c) and topiramate (30 mg/kg s.c.) resulted in a tendency to decrease the level of both spontaneous and evoked activity, while sumatriptan (1 mg/kg s.c.) did not exhibit any effect on recorded parameters. Application of an inflammatory soup to the dura mater boosted up spontaneous activity, which could be significantly attenuated by propranolol and topiramate but not by sumatriptan. In addition, all compounds prevented the delayed increase of spontaneous firing. In contrast to the ongoing activity, evoked responses were not augmented by inflammatory mediators. Nevertheless, inhibitory effect of propranolol and topiramate was evident when considering A- or C-fibre responses. Findings do not support the view that electrically evoked responses are useful for the measurement of trigeminal sensitization. It is proposed however, that inhibition of enhanced firing (immediate and/or delayed) evoked by inflammatory mediators as an endpoint have higher predictive validity regarding the clinical effectiveness of compounds. Copyright © 2015 Elsevier B.V. All rights reserved.

  17. Determining significant endpoints for ecological risk analyses. 1998 annual progress report

    Energy Technology Data Exchange (ETDEWEB)

    Hinton, T.G.; Congdon, J.; Scott, D. [Univ. of Georgia, Aiken, SC (US). Savannah River Ecology Lab.; Rowe, C. [Univ. of Puerto Rico, San Juan (PR); Bedford, J.; Whicker, W. [Colorado State Univ., Fort Collins, CO (US)

    1998-06-01

    'The goal of this report is to establish a protocol for assessing risks to non-human populations exposed to environmental stresses typically found on many DOE sites. The authors think that they can achieve this by using novel biological dosimeters in controlled, manipulative dose/effects experiments, and by coupling changes in metabolic rates and energy allocation patterns to meaningful population response variables (such as age-specific survivorship, reproductive output, age at maturity and longevity). This research is needed to determine the relevancy of sublethal cellular damage to the performance of individuals and populations exposed to chronic, low-level radiation, and radiation with concomitant exposure to chemicals. They believe that a scientifically defensible endpoint for measuring ecological risks can only be determined once its understood the extent to which molecular damage from contaminant exposure is detrimental at the individual and population levels of biological organization. The experimental facility will allow them to develop a credible assessment tool for appraising ecological risks, and to evaluate the effects of radionuclide/chemical synergisms on non-human species. This report summarizes work completed midway of a 3-year project that began in November 1996. Emphasis to date has centered on three areas: (1) developing a molecular probe to measure stable chromosomal aberrations known as reciprocal translocations, (2) constructing an irradiation facility where the statistical power inherent in replicated mesocosms can be used to address the response of non-human organisms to exposures from low levels of radiation and metal contaminants, and (3) quantifying responses of organisms living in contaminated mesocosms and field sites.'

  18. NEOCENT: a randomised feasibility and translational study comparing neoadjuvant endocrine therapy with chemotherapy in ER-rich postmenopausal primary breast cancer.

    Science.gov (United States)

    Palmieri, C; Cleator, S; Kilburn, L S; Kim, S B; Ahn, S-H; Beresford, M; Gong, G; Mansi, J; Mallon, E; Reed, S; Mousa, K; Fallowfield, L; Cheang, M; Morden, J; Page, K; Guttery, D S; Rghebi, B; Primrose, L; Shaw, J A; Thompson, A M; Bliss, J M; Coombes, R C

    2014-12-01

    Neoadjuvant endocrine therapy is an alternative to chemotherapy for women with oestrogen receptor (ER)-positive early breast cancer (BC). We aimed to assess feasibility of recruiting patients to a study comparing chemotherapy versus endocrine therapy in postmenopausal women with ER-rich primary BC, and response as well as translational endpoints were assessed. Patients requiring neoadjuvant therapy were randomised to chemotherapy: 6 × 3-weekly cycles FE₁₀₀C or endocrine therapy: letrozole 2.5 mg, daily for 18-23 weeks. Primary endpoints were recruitment feasibility and tissue collection. Secondary endpoints included clinical, radiological and pathological response rates, quality of life and translational endpoints. 63/80 patients approached were eligible, of those 44 (70, 95% CI 57-81) were randomised. 12 (54.5, 95% CI 32.2-75.6) chemotherapy patients showed radiological objective response compared with 13 (59.1, 95% CI 36.4-79.3) letrozole patients. Compared with baseline, mean Ki-67 levels fell in both groups at days 2-4 and at surgery [fold change: 0.24 (95% CI 0.12-0.51) and 0.24; (95% CI 0.15-0.37), respectively]. Plasma total cfDNA levels rose from baseline to week 8 [fold change: chemotherapy 2.10 (95% CI 1.47-3.00), letrozole 1.47(95% CI 0.98-2.20)], and were maintained at surgery in the chemotherapy group [chemotherapy 2.63; 95% CI 1.56-4.41), letrozole 0.95 (95% CI 0.71-1.26)]. An increase in plasma let-7a miRNA was seen at surgery for patients with objective radiological response to chemotherapy. Recruitment and tissue collection endpoints were met; however, a larger trial was deemed unfeasible due to slow accrual. Both regimens were equally efficacious. Dynamic changes were seen in Ki-67 and circulating biomarkers in both groups with increases in cfDNA and let-7a miRNA persisting until surgery for chemotherapy patients.

  19. Prophylactic antibiotics after acute stroke for reducing pneumonia in patients with dysphagia (STROKE-INF): a prospective, cluster-randomised, open-label, masked endpoint, controlled clinical trial.

    Science.gov (United States)

    Kalra, Lalit; Irshad, Saddif; Hodsoll, John; Simpson, Matthew; Gulliford, Martin; Smithard, David; Patel, Anita; Rebollo-Mesa, Irene

    2015-11-07

    Post-stroke pneumonia is associated with increased mortality and poor functional outcomes. This study assessed the effectiveness of antibiotic prophylaxis for reducing pneumonia in patients with dysphagia after acute stroke. We did a prospective, multicentre, cluster-randomised, open-label controlled trial with masked endpoint assessment of patients older than 18 years with dysphagia after new stroke recruited from 48 stroke units in the UK, accredited and included in the UK National Stroke Audit. We excluded patients with contraindications to antibiotics, pre-existing dysphagia, or known infections, or who were not expected to survive beyond 14 days. We randomly assigned the units (1:1) by computer to give either prophylactic antibiotics for 7 days plus standard stroke unit care or standard stroke unit care only to patients clustered in the units within 48 h of stroke onset. We did the randomisation with minimisation to stratify for number of admissions and access to specialist care. Patient and staff who did the assessments and analyses were masked to stroke unit allocation. The primary outcome was post-stroke pneumonia in the first 14 days, assessed with both a criteria-based, hierarchical algorithm and by physician diagnosis in the intention-to-treat population. Safety was also analysed by intention to treat. This trial is closed to new participants and is registered with isrctn.com, number ISRCTN37118456. Between April 21, 2008, and May 17, 2014, we randomly assigned 48 stroke units (and 1224 patients clustered within the units) to the two treatment groups: 24 to antibiotics and 24 to standard care alone (control). 11 units and seven patients withdrew after randomisation before 14 days, leaving 1217 patients in 37 units for the intention-to-treat analysis (615 patients in the antibiotics group, 602 in control). Prophylactic antibiotics did not affect the incidence of algorithm-defined post-stroke pneumonia (71 [13%] of 564 patients in antibiotics group vs 52

  20. Primary care ... where?

    Science.gov (United States)

    Adcock, G B

    1999-07-01

    Corporate-based nurse managed centers are not the national norm. More prevalent is the use of an occupational health or physician-directed medical model of care. The author describes how a 14-year-old primary care center at a North Carolina computer software company is just "business as usual" when viewed in the context of the company's philosophy, goals, and culture. Included are considerations for nurse practitioners interested in the successful transplantation of this primary care model to other settings.

  1. Lethal and sublethal endpoints observed for Artemia exposed to two reference toxicants and an ecotoxicological concern organic compound.

    Science.gov (United States)

    Manfra, Loredana; Canepa, Sara; Piazza, Veronica; Faimali, Marco

    2016-01-01

    Swimming speed alteration and mortality assays with the marine crustacean Artemia franciscana were carried out. EC50 and LC50 values after 24-48h exposures were calculated for two reference toxicants, copper sulphate pentahydrate (CuSO4·5H2O) and Sodium Dodecyl Sulphate (SDS), and an ecotoxicological concern organic compound, Diethylene Glycol (DEG). Different end-points have been evaluated, in order to point out their sensitivity levels. The swimming speed alteration (SSA) was compared to mortality values and also to the hatching rate inhibition (literature data). SSA resulted to be more sensitive than the mortality and with a sensitivity comparable to (or even higher than) the hatching rate endpoint. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. New drugs and patient-centred end-points in old age: setting the wheels in motion.

    Science.gov (United States)

    Mangoni, Arduino A; Pilotto, Alberto

    2016-01-01

    Older patients with various degrees of frailty and disability, a key population target of pharmacological interventions in acute and chronic disease states, are virtually neglected in pre-marketing studies assessing the efficacy and safety of investigational drugs. Moreover, aggressively pursuing established therapeutic targets in old age, e.g. blood pressure, serum glucose or cholesterol concentrations, is not necessarily associated with the beneficial effects, and the acceptable safety, reported in younger patient cohorts. Measures of self-reported health and functional status might represent additional, more meaningful, therapeutic end-points in the older population, particularly in patients with significant frailty and relatively short life expectancy, e.g. in the presence of cancer and/or neurodegenerative disease conditions. Strategies enhancing early knowledge about key pharmacological characteristics of investigational drugs targeting older adults are discussed, together with the rationale for incorporating non-traditional, patient-centred, end-points in this ever-increasing group.

  3. Optimal descriptor as a translator of eclectic data into endpoint prediction: mutagenicity of fullerene as a mathematical function of conditions.

    Science.gov (United States)

    Toropov, Andrey A; Toropova, Alla P

    2014-06-01

    The experimental data on the bacterial reverse mutation test on C60 nanoparticles (TA100) is examined as an endpoint. By means of the optimal descriptors calculated with the Monte Carlo method a mathematical model of the endpoint has been built up. The model is the mathematical function of (i) dose (g/plate); (ii) metabolic activation (i.e. with S9 mix or without S9 mix); and (iii) illumination (i.e. dark or irradiation). The statistical quality of the model is the following: n=10, r(2)=0.7549, q(2)=0.5709, s=7.67, F=25 (Training set); n=5, r(2)=0.8987, s=18.4 (Calibration set); and n=5, r(2)=0.6968, s=10.9 (Validation set). Copyright © 2013 Elsevier Ltd. All rights reserved.

  4. QED contribution to the color-singlet J/ψ production in Υ decay near the endpoint

    International Nuclear Information System (INIS)

    Liu Xiaohui

    2010-01-01

    A recent study indicates that the α 2 α s 2 order QED processes of Υ→J/ψ+X decay are compatible with those of QCD processes. However, in the endpoint region, the nonrelativistic QED calculation breaks down since the collinear degrees of freedom are missing under the framework of this effective theory. In this paper we apply the soft-collinear effective theory (SCET) to study the color-singlet QED process at the kinematic limit. Within this approach we are able to sum the kinematic logarithms by running operators using the renormalization group equations of soft-collinear effective theory, which will lead to a dramatic change in the momentum distribution near the endpoint and the spectrum shape consistent with the experimental results.

  5. Study protocol: Rehabilitation including Social and Physical activity and Education in Children and Teenagers with Cancer (RESPECT).

    Science.gov (United States)

    Thorsteinsson, Troels; Helms, Anne Sofie; Adamsen, Lis; Andersen, Lars Bo; Andersen, Karen Vitting; Christensen, Karl Bang; Hasle, Henrik; Heilmann, Carsten; Hejgaard, Nete; Johansen, Christoffer; Madsen, Marianne; Madsen, Svend Aage; Simovska, Venka; Strange, Birgit; Thing, Lone Friis; Wehner, Peder Skov; Schmiegelow, Kjeld; Larsen, Hanne Baekgaard

    2013-11-14

    During cancer treatment children have reduced contact with their social network of friends, and have limited participation in education, sports, and leisure activities. During and following cancer treatment, children describe school related problems, reduced physical fitness, and problems related to interaction with peers. The RESPECT study is a nationwide population-based prospective, controlled, mixed-methods intervention study looking at children aged 6-18 years newly diagnosed with cancer in eastern Denmark (n=120) and a matched control group in western Denmark (n=120). RESPECT includes Danish-speaking children diagnosed with cancer and treated at pediatric oncology units in Denmark. Primary endpoints are the level of educational achievement one year after the cessation of first-line cancer therapy, and the value of VO2max one year after the cessation of first-line cancer therapy. Secondary endpoints are quality of life measured by validated questionnaires and interviews, and physical performance. RESPECT includes a multimodal intervention program, including ambassador-facilitated educational, physical, and social interventions. The educational intervention includes an educational program aimed at the child with cancer, the child's schoolteachers and classmates, and the child's parents. Children with cancer will each have two ambassadors assigned from their class. The ambassadors visit the child with cancer at the hospital at alternating 2-week intervals and participate in the intervention program. The physical and social intervention examines the effect of early, structured, individualized, and continuous physical activity from diagnosis throughout the treatment period. The patients are tested at diagnosis, at 3 and 6 months after diagnosis, and one year after the cessation of treatment. The study is powered to quantify the impact of the combined educational, physical, and social intervention programs. RESPECT is the first population-based study to examine the

  6. Influence of nutrient medium composition on uranium toxicity and choice of the most sensitive growth related endpoint in Lemna minor.

    Science.gov (United States)

    Horemans, Nele; Van Hees, May; Saenen, Eline; Van Hoeck, Arne; Smolders, Valérie; Blust, Ronny; Vandenhove, Hildegarde

    2016-01-01

    Uranium (U) toxicity is known to be highly dependent on U speciation and bioavailability. To assess the impact of uranium on plants, a growth inhibition test was set up in the freshwater macrophyte Lemna minor. First growth media with different compositions were tested in order to find a medium fit for testing U toxicity in L. minor. Following arguments were used for medium selection: the ability to sustain L. minor growth, a high solubility of U in the medium and a high percentage of the more toxic U-species namely UO2(2+). Based on these selection criteria a with a low phosphate concentration of 0.5 mg L(-1) and supplemented with 5 mM MES (2-(N-morpholino)ethanesulfonic acid) to ensure pH stability was chosen. This medium also showed highest U toxicity compared to the other tested media. Subsequently a full dose response curve for U was established by exposing L. minor plants to U concentrations ranging from 0.05 μM up to 150 μM for 7 days. Uranium was shown to adversely affect growth of L. minor in a dose dependent manner with EC10, EC30 and EC50 values ranging between 1.6 and 4.8 μM, 7.7-16.4 μM and 19.4-37.2 μM U, respectively, depending on the growth endpoint. Four different growth related endpoints were tested: frond area, frond number, fresh weight and dry weight. Although differences in relative growth rates and associated ECx-values calculated on different endpoints are small (maximal twofold difference), frond area is recommended to be used to measure U-induced growth effects as it is a sensitive growth endpoint and easy to measure in vivo allowing for measurements over time. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. How "humane" is your endpoint? Refining the science-driven approach for termination of animal studies of chronic infection.

    OpenAIRE

    Nuno H Franco; Margarida Correia-Neves; I Anna S Olsson

    2012-01-01

    Public concern on issues such as animal welfare or the scientific validity and clinical value of animal research is growing, resulting in increasing regulatory demands for animal research. Abiding to the most stringent animal welfare standards, while having scientific objectives as the main priority, is often challenging. To do so, endpoints of studies involving severe, progressive diseases need to be established considering how early in the disease process the scientific objectives can be ac...

  8. Improved Survival Endpoints With Adjuvant Radiation Treatment in Patients With High-Risk Early-Stage Endometrial Carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Elshaikh, Mohamed A., E-mail: melshai1@hfhs.org [Department of Radiation Oncology, Henry Ford Hospital, Detroit, Michigan (United States); Vance, Sean; Suri, Jaipreet S. [Department of Radiation Oncology, Henry Ford Hospital, Detroit, Michigan (United States); Mahan, Meredith [Public Health Science, Henry Ford Hospital, Detroit, Michigan (United States); Munkarah, Adnan [Division of Gynecologic Oncology, Department of Women' s Health Services, Henry Ford Hospital, Detroit, Michigan (United States)

    2014-02-01

    Purpose/Objective(s): To determine the impact of adjuvant radiation treatment (RT) on recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS) in patients with high-risk 2009 International Federation of Gynecology and Obstetrics stage I-II endometrial carcinoma. Methods and Materials: We identified 382 patients with high-risk EC who underwent hysterectomy. RFS, DSS, and OS were calculated from the date of hysterectomy by use of the Kaplan-Meier method. Cox regression modeling was used to explore the risks associated with various factors on survival endpoints. Results: The median follow-up time for the study cohort was 5.4 years. The median age was 71 years. All patients underwent hysterectomy and salpingo-oophorectomy, 93% had peritoneal cytology, and 85% underwent lymphadenectomy. Patients with endometrioid histology constituted 72% of the study cohort, serous in 16%, clear cell in 7%, and mixed histology in 4%. Twenty-three percent of patients had stage II disease. Adjuvant management included RT alone in 220 patients (57%), chemotherapy alone in 25 patients (7%), and chemoradiation therapy in 27 patients (7%); 110 patients (29%) were treated with close surveillance. The 5-year RFS, DSS, and OS were 76%, 88%, and 73%, respectively. On multivariate analysis, adjuvant RT was a significant predictor of RFS (P<.001) DSS (P<.001), and OS (P=.017). Lymphovascular space involvement was a significant predictor of RFS and DSS (P<.001). High tumor grade was a significant predictor for RFS (P=.038) and DSS (P=.025). Involvement of the lower uterine segment was also a predictor of RFS (P=.049). Age at diagnosis and lymphovascular space involvement were significant predictors of OS: P<.001 and P=.002, respectively. Conclusion: In the treatment of patients with high-risk features, our study suggests that adjuvant RT significantly improves recurrence-free, disease-specific, and overall survival in patients with early-stage endometrial carcinoma

  9. Pharmaceutics, Drug Delivery and Pharmaceutical Technology: A New Test Unit for Disintegration End-Point Determination of Orodispersible Films.

    Science.gov (United States)

    Low, Ariana; Kok, Si Ling; Khong, Yuetmei; Chan, Sui Yung; Gokhale, Rajeev

    2015-11-01

    No standard time or pharmacopoeia disintegration test method for orodispersible films (ODFs) exists. The USP disintegration test for tablets and capsules poses significant challenges for end-point determination when used for ODFs. We tested a newly developed disintegration test unit (DTU) against the USP disintegration test. The DTU is an accessory to the USP disintegration apparatus. It holds the ODF in a horizontal position, allowing top-view of the ODF during testing. A Gauge R&R study was conducted to assign relative contributions of the total variability from the operator, sample or the experimental set-up. Precision was compared using commercial ODF products in different media. Agreement between the two measurement methods was analysed. The DTU showed improved repeatability and reproducibility compared to the USP disintegration system with tighter standard deviations regardless of operator or medium. There is good agreement between the two methods, with the USP disintegration test giving generally longer disintegration times possibly due to difficulty in end-point determination. The DTU provided clear end-point determination and is suitable for quality control of ODFs during product developmental stage or manufacturing. This may facilitate the development of a standardized methodology for disintegration time determination of ODFs. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:3893-3903, 2015. Copyright © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

  10. The role of categorization and scale endpoint comparisons in numerical information processing: A two-process model.

    Science.gov (United States)

    Tao, Tao; Wyer, Robert S; Zheng, Yuhuang

    2017-03-01

    We propose a two-process conceptualization of numerical information processing to describe how people form impressions of a score that is described along a bounded scale. According to the model, people spontaneously categorize a score as high or low. Furthermore, they compare the numerical discrepancy between the score and the endpoint of the scale to which it is closer, if they are not confident of their categorization, and use implications of this comparison as a basis for judgment. As a result, their evaluation of the score is less extreme when the range of numbers along the scale is large (e.g., from 0 to 100) than when it is small (from 0 to 10). Six experiments support this two-process model and demonstrate its generalizability. Specifically, the magnitude of numbers composing the scale has less impact on judgments (a) when the score being evaluated is extreme, (b) when individuals are unmotivated to engage in endpoint comparison processes (i.e., they are low in need for cognition), and (c) when they are unable to do so (i.e., they are under cognitive load). Moreover, the endpoint to which individuals compare the score can depend on their regulatory focus. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  11. Investigation of allergenicity of some cosmetic mixtures by using ex vivo local lymph node assay-BrdU endpoints.

    Science.gov (United States)

    Ulker, Ozge Cemiloglu; Kaymak, Yesim; Karakaya, Asuman

    2014-01-01

    Balsam of Peru and fragrance mix are commonly used in cosmetic products. Allergy to fragrance is the most common cause of cosmetic contact dermatitis. In the present study, ex vivo local lymph node assay-5-bromo-2'-deoxyuridine (LLNA-BrdU) was used to evaluate the dermal sensitization potential of these cosmetic mixtures. The stimulation index values and estimated concentration (EC3) values were calculated and the potency classification was found for each mixture. At the same time, in order to measure the irritant effect without having to use additional animals, a combination of ex vivo LLNA-BrdU and the irritancy assay was conducted. Th1 [interleukin (IL)-2, interferon-γ] and Th2 cytokine (IL-4, IL-5) releases from lymph node cell culture were investigated as non-radioactive endpoints. According to the results of ex vivo LLNA-BrdU assays, EC3 values were found to be 3.09% (moderate) for balsam of Peru and 4.44% (moderate) for fragrance mix. Cytokine analysis results indicate that both Th1 and Th2 cytokines are involved in the regulation of murine contact allergy and can be considered as useful endpoints. In conclusion, according to our results, fragrance mix and balsam of Peru can be considered as moderate sensitizers; however, in high concentrations, both of them have irritation properties. The cytokines investigated can be considered as the endpoints of the ex vivo LLNA-BrdU assay. © 2014 S. Karger AG, Basel.

  12. A Comparison of Real-Time and Endpoint Cell Viability Assays for Improved Synthetic Lethal Drug Validation.

    Science.gov (United States)

    Single, Andrew; Beetham, Henry; Telford, Bryony J; Guilford, Parry; Chen, Augustine

    2015-12-01

    Cell viability assays fulfill a central role in drug discovery studies. It is therefore important to understand the advantages and disadvantages of the wide variety of available assay methodologies. In this study, we compared the performance of three endpoint assays (resazurin reduction, CellTiter-Glo, and nuclei enumeration) and two real-time systems (IncuCyte and xCELLigence). Of the endpoint approaches, both the resazurin reduction and CellTiter-Glo assays showed higher cell viabilities when compared directly to stained nuclei counts. The IncuCyte and xCELLigence real-time systems were comparable, and both were particularly effective at tracking the effects of drug treatment on cell proliferation at sub-confluent growth. However, the real-time systems failed to evaluate contrasting cell densities between drug-treated and control-treated cells at full growth confluency. Here, we showed that using real-time systems in combination with endpoint assays alleviates the disadvantages posed by each approach alone, providing a more effective means to evaluate drug toxicity in monolayer cell cultures. Such approaches were shown to be effective in elucidating the toxicity of synthetic lethal drugs in an isogenic pair of MCF10A breast cell lines. © 2015 Society for Laboratory Automation and Screening.

  13. Scenario-targeted toxicity assessment through multiple endpoint bioassays in a soil posing unacceptable environmental risk according to regulatory screening values.

    Science.gov (United States)

    Rodriguez-Ruiz, A; Etxebarria, J; Boatti, L; Marigómez, I

    2015-09-01

    Lanestosa is a chronically polluted site (derelict mine) where the soil (Lanestosa (LA) soil) exceeds screening values (SVs) of regulatory policies in force (Basque Country; Europe) for Zn, Pb and Cd. A scenario-targeted toxicity assessment was carried out on the basis of a multi-endpoint bioassay approach. Acute and chronic toxicity bioassays were conducted with selected test species (Vibrio fischeri, Dictyostelium discoideum, Lactuca sativa, Raphanus sativus and Eisenia fetida) in combination with chemical analysis of soils and elutriates and with bioaccumulation studies in earthworms. Besides, the toxicity profile was compared with that of the mine runoff (RO) soil and of a fresh artificially polluted soil (LAAPS) resembling LA soil pollutant profile. Extractability studies in LA soil revealed that Pb, Zn and Cd were highly available for exchange and/or release into the environment. Indeed, Pb and Zn were accumulated in earthworms and LA soil resulted to be toxic. Soil respiration, V. fischeri, vegetative and developmental cycles of D. discoideum and survival and juvenile production of E. fetida were severely affected. These results confirmed that LA soil had unacceptable environmental risk and demanded intervention. In contrast, although Pb and Zn concentrations in RO soil revealed also unacceptable risk, both metal extractability and toxicity were much lower than in LA soil. Thus, within the polluted site, the need for intervention varied between areas that posed dissimilar risk. Besides, since LAAPS, with a high exchangeable metal fraction, was the most toxic, ageing under in situ natural conditions seemingly contributed to attenuate LA soil risk. As a whole, combining multi-endpoint bioassays with scenario-targeted analysis (including leaching and ageing) provides reliable risk assessment in soils posing unacceptable environmental risk according to SVs, which is useful to optimise the required intervention measures.

  14. Design and endpoints of clinical and translational trials in advanced colorectal cancer. a proposal from GROUP Español Multidisciplinar en Cancer Digestivo (GEMCAD).

    Science.gov (United States)

    Carrera, Gemma; Garcia-Albeniz, Xabier; Ayuso, Juan Ramón; Aparicio, Jorge; Castells, Antoni; Codony-Servat, Jordi; Feliu, Jaime; Fuster, David; Gallego, Rosa; Pagés, Mario; Torres, Ferran; Maurel, Joan

    2011-05-01

    Meta-analytic reviews of Randomized Clinical Trials (RCT) have reached contradictory conclusions regarding the benefit of medical interventions in Advanced Colorectal Cancer (ACRC). Surrogate markers of survival benefit, such as response rate (RR) and progression free-survival (PFS) often show contradictory and highly variable correlations. These contradictions can be due to differences in 1) the studies analysed (sources), 2) the quality of clinical trials (intrinsic bias in the design, biased data analysis, heterogeneous PFS definitions) and 3) the second-line strategies between arms. PFS is a more vulnerable target than overall survival (OS), but the latter can also be affected by different biases and additional medical interventions such as secondary resection of metastases or second-line therapies. Therefore the correlation between PFS and survival must be clearly stated if PFS is to be considered as a primary endpoint. Of the differences between studies, only the quality of clinical trials can be improved by a deeper knowledge of both the area of study (i.e. colorectal cancer) and the methodology needed (i.e., clinical and translational trials). The aim of this manuscript is to offer the basic resources to develop experimental trials in ACRC. To this end, techniques for diagnosis and for response assessment are discussed, prognostic factors and treatment standards are critically exposed, and notes about how to design useful translational studies are provided.

  15. Pressure Injury Progression and Factors Associated With Different End-Points in a Home Palliative Care Setting: A Retrospective Chart Review Study.

    Science.gov (United States)

    Artico, Marco; D'Angelo, Daniela; Piredda, Michela; Petitti, Tommasangelo; Lamarca, Luciano; De Marinis, Maria Grazia; Dante, Angelo; Lusignani, Maura; Matarese, Maria

    2018-07-01

    Patients with advanced illnesses show the highest prevalence for pressure injuries. In the palliative care setting, the ultimate goal is injury healing, but equally important is wound maintenance, wound palliation (wound-related pain and symptom management), and primary and secondary wound prevention. To describe the course of healing for pressure injuries in a home palliative care setting according to different end-points, and to explore patient and caregiver characteristics and specific care activities associated with their achievement. Four-year retrospective chart review of 669 patients cared for in a home palliative care service, of those 124 patients (18.5%) had at least one pressure injury with a survival rate less than or equal to six months. The proportion of healed pressure injuries was 24.4%. Of the injuries not healed, 34.0% were in a maintenance phase, whereas 63.6% were in a process of deterioration. Body mass index (P = 0.0014), artificial nutrition (P = 0.002), and age pay attention to artificial nutrition, continuous deep sedation, and the caregiver's role and gender. Copyright © 2018 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.

  16. A simple and reliable in vitro test system for the analysis of induced aneuploidy as well as other cytogenetic end-points using Chinese hamster cells

    International Nuclear Information System (INIS)

    Dulout, F.N.; Natarajan, A.T.

    1987-01-01

    Although aneuploidy is a serious human health problem, the experimental methodology devised until now to study the mechanisms involved in the induction of aneuploidy and for the screening of aneuploidy-inducing agents has not been so much employed to have the necessary validation. A procedure using primary cell cultures of Chinese hamster embryo cells grown on cover glasses is described. To avoid the excessive scattering and subsequent loss of chromosomes, a hypotonic treatment with a 0.17% sodium chloride solution, at room temperature, followed by in situ fixation has been standardized. This procedure improves the method through the reduction of the spontaneous frequency of aneuploid cells. Experiments carried out with cells treated with X-rays, X-rays plus caffeine, and the synthetic estrogen diethylstilbestrol (DES) demonstrated the accuracy of the system since the average chromosome number remained constant in spite of the induction of high frequencies of aneuploid cells. Moreover, the method allows for the analysis of other cytogenetic endpoints such as anaphase-telophase alterations, structural chromosome aberrations or sister chromatid exchanges. (author)

  17. [Hypertension: once primary, always primary?

    NARCIS (Netherlands)

    Braam, R.L.; Pieters, G.F.F.M.; Thien, Th.

    2002-01-01

    Three patients diagnosed with primary hypertension suddenly developed hard-to-treat blood pressure after several years of stable blood pressure. One patient, a man aged 48 years, had developed a renal artery stenosis, which had not been present five years earlier. The other two patients, a man aged

  18. Hyperthyroidism (primary)

    OpenAIRE

    Nygaard, Birte

    2010-01-01

    Hyperthyroidism is characterised by high levels of serum thyroxine and triiodothyronine, and low levels of thyroid-stimulating hormone (TSH). Thyrotoxicosis is the clinical effect of high levels of thyroid hormones, whether or not the thyroid gland is the primary source.The main causes of hyperthyroidism are Graves' disease, toxic multinodular goitre, and toxic adenoma.About 20 times more women than men have hyperthyroidism.

  19. A randomized trial of obeticholic acid monotherapy in patients with primary biliary cholangitis.

    Science.gov (United States)

    Kowdley, Kris V; Luketic, Velimir; Chapman, Roger; Hirschfield, Gideon M; Poupon, Raoul; Schramm, Christoph; Vincent, Catherine; Rust, Christian; Parés, Albert; Mason, Andrew; Marschall, Hanns-Ulrich; Shapiro, David; Adorini, Luciano; Sciacca, Cathi; Beecher-Jones, Tessa; Böhm, Olaf; Pencek, Richard; Jones, David

    2018-05-01

    Obeticholic acid (OCA), a potent farnesoid X receptor agonist, was studied as monotherapy in an international, randomized, double-blind, placebo-controlled phase 2 study in patients with primary biliary cholangitis who were then followed for up to 6 years. The goals of the study were to assess the benefit of OCA in the absence of ursodeoxycholic acid, which is relevant for patients who are intolerant of ursodeoxycholic acid and at higher risk of disease progression. Patients were randomized and dosed with placebo (n = 23), OCA 10 mg (n = 20), or OCA 50 mg (n = 16) given as monotherapy once daily for 3 months (1 randomized patient withdrew prior to dosing). The primary endpoint was the percent change in alkaline phosphatase from baseline to the end of the double-blind phase of the study. Secondary and exploratory endpoints included change from baseline to month 3/early termination in markers of cholestasis, hepatocellular injury, and farnesoid X receptor activation. Efficacy and safety continue to be monitored through an ongoing 6-year open-label extension (N = 28). Alkaline phosphatase was reduced in both OCA groups (median% [Q1, Q3], OCA 10 mg -53.9% [-62.5, -29.3], OCA 50 mg -37.2% [-54.8, -24.6]) compared to placebo (-0.8% [-6.4, 8.7]; P OCA improved many secondary and exploratory endpoints (including γ-glutamyl transpeptidase, alanine aminotransferase, conjugated bilirubin, and immunoglobulin M). Pruritus was the most common adverse event; 15% (OCA 10 mg) and 38% (OCA 50 mg) discontinued due to pruritus. OCA monotherapy significantly improved alkaline phosphatase and other biochemical markers predictive of improved long-term clinical outcomes. Pruritus increased dose-dependently with OCA treatment. Biochemical improvements were observed through 6 years of open-label extension treatment. (Hepatology 2018;67:1890-1902). © 2017 The Authors. Hepatology published by Wiley Periodicals, Inc. on behalf of American Association for the Study of Liver Diseases.

  20. Primary balloon angioplasty for symptomatic, high-grade intracranial stenosis.

    Science.gov (United States)

    Tomycz, Luke; Bansal, Neil K; Lockney, Tim; Strothers, Megan; Connors, John J; Shay, Scott; Singer, Robert J

    2013-01-01

    In light of recent controversy about the safety and efficacy of intracranial stenting, we sought to evaluate our experience with primary balloon angioplasty for symptomatic, high-grade intracranial stenosis. All intracranial angioplasty cases performed at Vanderbilt University Medical Center from 2006 to 2011 were retrospectively reviewed for degree of stenosis pre- and post-procedure. Immediate peri-procedural complications were evaluated as well as one-month and long-term outcomes. A total of 26 patients were included in the study with a mean age of 63.0 years and a mean follow-up of 350.2 days. The average pre-procedure stenosis was 71.2%. The immediate, average post-procedure stenosis was 46.6%, and the average post-procedure stenosis at last angiographic follow-up was 44.5%. Retreatment was required in only 3.8% of patients. The primary end-point of major stroke or death at 30 days was observed in 11.5%, and the overall intra-procedural complication rate was 7.7%. The incidence of stroke or death at last follow-up was 15.4%, which is comparable to the one-year stroke or death rate in the medical arm of the SAMPRISS trial. In this retrospective series, primary balloon angioplasty was found to be effective as a treatment option for symptomatic intracranial stenosis with the risk of stroke or death at 30 days higher than the medical arm of SAMPRIS but lower than the stenting arm. The one-year risk of stroke was comparable to that reported for the one-year outcomes in the SAMPRISS medical arm.

  1. Extended Evaluation of Virological, Immunological and Pharmacokinetic Endpoints of CELADEN: A Randomized, Placebo-Controlled Trial of Celgosivir in Dengue Fever Patients.

    Science.gov (United States)

    Sung, Cynthia; Wei, Yuan; Watanabe, Satoru; Lee, How Sung; Khoo, Yok Moi; Fan, Lu; Rathore, Abhay P S; Chan, Kitti Wing-Ki; Choy, Milly M; Kamaraj, Uma S; Sessions, October M; Aw, Pauline; de Sessions, Paola F; Lee, Bernett; Connolly, John E; Hibberd, Martin L; Vijaykrishna, Dhanasekaran; Wijaya, Limin; Ooi, Eng Eong; Low, Jenny Guek-Hong; Vasudevan, Subhash G

    2016-08-01

    CELADEN was a randomized placebo-controlled trial of 50 patients with confirmed dengue fever to evaluate the efficacy and safety of celgosivir (A study registered at ClinicalTrials.gov, number NCT01619969). Celgosivir was given as a 400 mg loading dose and 200 mg bid (twice a day) over 5 days. Replication competent virus was measured by plaque assay and compared to reverse transcription quantitative PCR (qPCR) of viral RNA. Pharmacokinetics (PK) correlations with viremia, immunological profiling, next generation sequence (NGS) analysis and hematological data were evaluated as exploratory endpoints here to identify possible signals of pharmacological activity. Viremia by plaque assay strongly correlated with qPCR during the first four days. Immunological profiling demonstrated a qualitative shift in T helper cell profile during the course of infection. NGS analysis did not reveal any prominent signature that could be associated with drug treatment; however the phylogenetic spread of patients' isolates underlines the importance of strain variability that may potentially confound interpretation of dengue drug trials conducted during different outbreaks and in different countries. Celgosivir rapidly converted to castanospermine (Cast) with mean peak and trough concentrations of 5727 ng/mL (30.2 μM) and 430 ng/mL (2.3 μM), respectively and cleared with a half-life of 2.5 (± 0.6) hr. Mean viral log reduction between day 2 and 4 (VLR2-4) was significantly greater in secondary dengue than primary dengue (p = 0.002). VLR2-4 did not correlate with drug AUC but showed a trend of greater response with increasing Cmin. PK modeling identified dosing regimens predicted to achieve 2.4 to 4.5 times higher Cmin. than in the CELADEN trial for only 13% to 33% increase in overall dose. A small, non-statistical trend towards better outcome on platelet nadir and difference between maximum and minimum hematocrit was observed in celgosivir-treated patients with secondary dengue

  2. Modelling the long-term consequences of a hypothetical dispersal of radioactivity in an urban area including remediation alternatives

    International Nuclear Information System (INIS)

    Thiessen, K.M.; Andersson, K.G.; Batandjieva, B.; Cheng, J.-J.; Hwang, W.T.; Kaiser, J.C.; Kamboj, S.; Steiner, M.; Tomas, J.; Trifunovic, D.; Yu, C.

    2009-01-01

    The Urban Remediation Working Group of the International Atomic Energy Agency's EMRAS (Environmental Modelling for Radiation Safety) program was organized to address issues of remediation assessment modelling for urban areas contaminated with dispersed radionuclides. The present paper describes the second of two modelling exercises. This exercise was based on a hypothetical dispersal of radioactivity in an urban area from a radiological dispersal device, with reference surface contamination at selected sites used as the primary input information. Modelling endpoints for the exercise included radionuclide concentrations and external dose rates at specified locations, contributions to the dose rates from individual surfaces, and annual and cumulative external doses to specified reference individuals. Model predictions were performed for a 'no action' situation (with no remedial measures) and for selected countermeasures. The exercise provided an opportunity for comparison of three modelling approaches, as well as a comparison of the predicted effectiveness of various countermeasures in terms of their short-term and long-term effects on predicted doses to humans.

  3. Variation in pestivirus growth in testicle primary cell culture is more dependent on the individual cell donor than cattle breed.

    Science.gov (United States)

    Weber, Matheus N; Bauermann, Fernando V; Gómez-Romero, Ninnet; Herring, Andy D; Canal, Cláudio W; Neill, John D; Ridpath, Julia F

    2017-03-01

    The causes of bovine respiratory disease complex (BRDC) are multifactorial and include infection with both viral and bacterial pathogens. Host factors are also involved as different breeds of cattle appear to have different susceptibilities to BRDC. Infection with bovine pestiviruses, including bovine viral diarrhea virus 1 (BVDV1), BVDV2 and 'HoBi'-like viruses, is linked to the development of BRDC. The aim of the present study was to compare the growth of different bovine pestiviruses in primary testicle cell cultures obtained from taurine, indicine and mixed taurine and indicine cattle breeds. Primary cells strains, derived from testicular tissue, were generated from three animals from each breed. Bovine pestivirus strains used were from BVDV-1a, BVDV-1b, BVDV-2a and 'HoBi'-like virus. Growth was compared by determining virus titers after one passage in primary cells. All tests were run in triplicate. Virus titers were determined by endpoint dilution and RT-qPCR. Statistical analysis was performed using one way analysis of variance (ANOVA) followed by the Tukey's Multiple Comparison Test (P˂0.05). Significant differences in virus growth did not correlate with cattle breed. However, significant differences were observed between cells derived from different individuals regardless of breed. Variation in the replication of virus in primary cell strains may reflect a genetic predisposition that favors virus replication.

  4. Genetics of ovarian ageing : genetic association studies on natural menopause and primary ovarian insufficiency

    NARCIS (Netherlands)

    Voorhuis, M.

    2013-01-01

    Menopause is the endpoint of a process referred to as ovarian ageing. The mean age at menopause is approximately 51 years, but varies widely between 40 to 60 years of age. Approximately 1% of all women experience menopause before the age of 40, which is a condition known as primary ovarian

  5. DEPIVIH 2: Use of three HIV testing methods in French primary care settings - ELISA laboratory screening versus two rapid point-of-care HIV tests.

    Science.gov (United States)

    Papadima, D; Gauthier, R; Prévoteau du Clary, F; Bouée, S; Conort, G; Livrozet, J-M; Taulera, O; Wajsbrot, A; Majerholc, C; Peter, J-M; Aubert, J-P

    2018-03-01

    The primary endpoint was to evaluate the use of HIV testing methods by French primary care providers: Elisa laboratory screening, instant result HIV diagnostic test and rapid result HIV diagnostic test. The secondary endpoints were the population screening rate of unknown HIV status consulting during the study period, reasons for screening and for choosing the specific screening method, the investigators' satisfaction with the rapid diagnostic test (RDT) and problems encountered. National prospective interventional study with French family physicians (FP) from December 2013 to December 2014. FPs enrolled all consenting adults consulting for an HIV screening test during a 6-month period: the choice was an Elisa laboratory test or one of the two RDTs. During the study period, 43 FPs included 981 patients. HIV screening was performed for the first time for 31.6% of patients; 767 (78.2%) Elisa laboratory test prescriptions and 214 (21.8%) RDTs were performed, leading to a screening rate of 1.3%. For 120 (15.7%) of the Elisa laboratory tests, the result was not reported and six RDTs were not valid. Nine patients were diagnosed as HIV-infected (0.9%): five with Elisa laboratory test and four with RDT. Almost 90% of FPs were willing to keep on using RDTs in their daily practice. In general practice, RDTs may be an important additional tool to traditional HIV screening. They could account for one in five tests prescribed in this context. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  6. Contemporary Medical Management of Primary Hyperparathyroidism: A Systematic Review

    Directory of Open Access Journals (Sweden)

    Julius Simoni Leere

    2017-04-01

    Full Text Available IntroductionPrimary hyperparathyroidism is increasingly an asymptomatic disease at diagnosis, but the recognized guidelines for management are based on evidence obtained from studies on patients with symptomatic disease, and surgery is not always indicated. Other patients are unable to undergo surgery, and thus a medical treatment is warranted. This systematic review provides an overview of the existing literature on contemporary pharmaceutical options available for the medical management of primary hyperparathyroidism.MethodsDatabases of medical literature were searched for articles including terms for primary hyperparathyroidism and each of the included drugs. Data on s-calcium, s-parathyroid hormone, bone turnover markers, bone mineral density (BMD and hard endpoints were extracted and tabulated, and level of evidence was determined. Changes in s-calcium were estimated and a meta-regression analysis was performed.ResultsThe 1,999 articles were screened for eligibility and 54 were included in the review. Weighted mean changes calculated for each drug in s-total calcium (mean change from baseline ± SEM were pamidronate (0.31 ± 0.034 mmol/l; alendronate (0.07 ± 0.05 mmol/l; clodronate (0.20 ± 0.040 mmol/l; mixed bisphosphonates (0.16 ± 0.049 mmol/l; and cinacalcet (0.37 ± 0.013 mmol/l. The meta-analysis revealed a significant decrease of effect on s-calcium with time for the bisphosphonates (Coef. −0.049 ± 0.023, p = 0.035, while cinacalcet proved to maintain its effect on s-calcium over time. Bisphosphonates improved BMD while cinacalcet had no effect.DiscussionThe included studies demonstrate advantages and drawbacks of the available pharmaceutical options that can prove helpful in the clinical setting. The great variation in how primary hyperparathyroidism is manifested requires that management should rely on an individual evaluation when counseling patients. Combining resorptive agents with

  7. Quantitative interpretation of heavy ion effects: Comparison of different systems and endpoints

    Science.gov (United States)

    Kiefer, J.

    For a quantitative interpretation of biological heavy ion action the following parameters have to be taken into account: variations of energy depositions in microscopical sites, the dependence of primary lesion formation on local energy density and changes in repairability. They can be studied in objects of different size and with different sensitivities. Results on survival and mutation induction in yeast and in mammalian cells will be compared with theoretical predictions. It is shown that shouldered survival curves of diploid yeast can be adequately described if the final slope is adjusted according to the varying production of primary lesions. This is not the case for mammalian cells where the experiments show a rapid loss of the shoulder with LET, contrary to theoretical expectations. This behaviour is interpreted to mean that the repairability of heavy ion lesions is different in the two systems. Mutation induction is theoretically expected to decrease with higher LET. This is found in yeast but not in mammalian cells where it actually increases. These results suggest a higher rate of misrepair in mammalian cells.

  8. Assessment of Correlation Between Early and Late Efficacy Endpoints to Identify Potential Surrogacy Relationships in Non-Hodgkin Lymphoma: a Literature-Based Meta-analysis of 108 Phase II and Phase III Studies.

    Science.gov (United States)

    Zhu, Rui; Lu, Dan; Chu, Yu-Waye; Chai, Akiko; Green, Michelle; Zhang, Nancy; Jin, Jin Yan

    2017-05-01

    Correlations between early and late efficacy endpoints were assessed to identify potential surrogate endpoints for overall survival (OS) or progression-free survival (PFS) with clinical trial-level data in three non-Hodgkin lymphoma (NHL) subtypes: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL). One hundred and eight phase II-III trials (129 trial arms) in DLBCL, FL, and MCL were identified and included in the database. Correlations between efficacy endpoints were analyzed using weighted linear regression and Pearson's coefficient of determination (R 2 ). In newly diagnosed DLBCL, 6-month PFS was strongly correlated with 2-year OS (R 2  = 0.81, 95% confidence interval [CI] 0.51-0.96). Six-month PFS was strongly correlated with 3-year PFS (R 2  = 0.89, 95% CI 0.62-0.96) in FL and was moderately correlated with 2-year OS (R 2  = 0.69, 95% CI 0.40-0.91) in MCL trials. Linear regression determined that a 10% increase in 6-month PFS would yield a 13% ± 1.2% increase in 2-year OS in DLBCL, a 23% ± 1.1% increase in 3-year PFS in FL, or a 6.7% ± 1.0% increase in 2-year OS in MCL. Both 6-month PFS and complete response (CR) rate were moderately correlated with median PFS in FL trials with R 2  = 0.66 (95% CI 0.52-0.98) and R 2  = 0.69 (95% CI 0.22-0.89), respectively. Six-month PFS is a potential surrogate endpoint for 2-year OS in newly diagnosed DLBCL and MCL and for 3-year PFS in FL. Both 6-month PFS and CR rate are potential surrogate endpoints for median PFS in FL patients. Confirmation and validation of these correlations may facilitate early interpretation of NHL trials.

  9. Validation of Progression‐Free Survival as a Surrogate Endpoint for Overall Survival in Malignant Mesothelioma: Analysis of Cancer and Leukemia Group B and North Central Cancer Treatment Group (Alliance) Trials

    Science.gov (United States)

    Wang, Xiaoyi; Hodgson, Lydia; George, Stephen L.; Sargent, Daniel J.; Foster, Nate R.; Ganti, Apar Kishor; Stinchcombe, Thomas E.; Crawford, Jeffrey; Kratzke, Robert; Adjei, Alex A.; Kindler, Hedy L.; Vokes, Everett E.; Pang, Herbert

    2017-01-01

    Abstract Purpose. The aim of this study was to investigate whether progression‐free survival (PFS) can be considered a surrogate endpoint for overall survival (OS) in malignant mesothelioma. Materials and Methods. Individual data were collected from 15 Cancer and Leukemia Group B (615 patients) and 2 North Central Cancer Treatment Group (101 patients) phase II trials. The effects of 5 risk factors for OS and PFS, including age, histology, performance status (PS), white blood cell count, and European Organisation for Research and Treatment of Cancer (EORTC) risk score, were used in the analysis. Individual‐level surrogacy was assessed by Kendall's tau through a Clayton bivariate Copula survival (CBCS) model. Summary‐level surrogacy was evaluated via the association between logarithms of the hazard ratio (log HR)—log HROS and log HRPFS—measured in R2 from a weighted least‐square (WLS) regression model and the CBCS model. Results. The median PFS for all patients was 3.0 months (95% confidence interval [CI], 2.8–3.5 months) and the median OS was 7.2 months (95% CI, 6.5–8.0 months). Moderate correlations between PFS and OS were observed across all risk factors at the individual level, with Kendall's tau ranging from 0.46 to 0.47. The summary‐level surrogacy varied among risk factors. The Copula R2 ranged from 0.51 for PS to 0.78 for histology. The WLS R2 ranged from 0.26 for EORTC and PS to 0.67 for age. Conclusions. The analyses demonstrated low to moderate individual‐level surrogacy between PFS and OS. At the summary level, the surrogacy between PFS and OS varied significantly across different risk factors. With a short postprogression survival and a moderate correlation between PFS and OS, there is no evidence that PFS is a valid surrogate endpoint for OS in malignant mesothelioma. Implications for Practice. For better disease management and for more efficient clinical trial designs, it is important to know if progression‐free survival (PFS) is

  10. (including travel dates) Proposed itinerary

    Indian Academy of Sciences (India)

    Ashok

    31 July to 22 August 2012 (including travel dates). Proposed itinerary: Arrival in Bangalore on 1 August. 1-5 August: Bangalore, Karnataka. Suggested institutions: Indian Institute of Science, Bangalore. St Johns Medical College & Hospital, Bangalore. Jawaharlal Nehru Centre, Bangalore. 6-8 August: Chennai, TN.

  11. The Factors Influencing Depression Endpoints Research (FINDER study: final results of Italian patients with depression

    Directory of Open Access Journals (Sweden)

    Quail Deborah

    2010-07-01

    Full Text Available Abstract Background Factors Influencing Depression Endpoints Research (FINDER is a 6-month, prospective, observational study carried out in 12 European countries aimed at investigating health-related quality of life (HRQoL in outpatients receiving treatment for a first or new depressive episode. The Italian HRQoL data at 6 months is described in this report, and the factors associated with HRQoL changes were determined. Methods Data were collected at baseline, 3 and 6 months of treatment. HRQoL was measured using components of the 36-item Short Form Health Survey (SF-36; mental component summary (MCS, physical component summary (PCS and the European Quality of Life-5 Dimensions (EQ-5D; visual analogue scale (VAS and health status index (HSI. The Hospital Anxiety and Depression Scale (HADS was adopted to evaluate depressive symptoms, while somatic and painful physical symptoms were assessed by using the 28-item Somatic Symptom Inventory (SSI-28 and a VAS. Results Of the initial 513 patients, 472 completed the 3-month observation and 466 the 6-month observation. The SF-36 and EQ-5D mean (± SD scores showed HRQoL improvements at 3 months and a further smaller improvement at 6 months, with the most positive effects for SF-36 MCS (baseline 22.0 ± 9.2, 3 months 34.6 ± 10.0; 6 months 39.3 ± 9.5 and EQ-5D HSI (baseline 0.4 ± 0.3; 3 months 0.7 ± 0.3; 6 months 0.7 ± 0.2. Depression and anxiety symptoms (HADS-D mean at baseline 13.3 ± 4.2; HADS-A mean at baseline 12.2 ± 3.9 consistently decreased during the first 3 months (8.7 ± 4.3; 7.5 ± 3.6 and showed a further positive change at 6 months (6.9 ± 4.3; 5.8 ± 3.4. Somatic and painful symptoms (SSI and VAS significantly decreased, with the most positive changes in the SSI-28 somatic item (mean at baseline 2.4 ± 0.7; mean change at 3 months: -0.5; 95% CI -0.6 to -0.5; mean change at 6 months: -0.7; 95% CI -0.8 to -0.7; in 'interference of overall pain with daily activities' (mean at baseline 45

  12. The effect of adherence to statin therapy on cardiovascular mortality: quantification of unmeasured bias using falsification end-points

    Directory of Open Access Journals (Sweden)

    Maarten J. Bijlsma

    2016-04-01

    Full Text Available Abstract Background To determine the clinical effectiveness of statins on cardiovascular mortality in practice, observational studies are needed. Control for confounding is essential in any observational study. Falsification end-points may be useful to determine if bias is present after adjustment has taken place. Methods We followed starters on statin therapy in the Netherlands aged 46 to 100 years over the period 1996 to 2012, from initiation of statin therapy until cardiovascular mortality or censoring. Within this group (n = 49,688, up to 16 years of follow-up, we estimated the effect of adherence to statin therapy (0 = completely non-adherent, 1 = fully adherent on ischemic heart diseases and cerebrovascular disease (ICD10-codes I20-I25 and I60-I69 as well as respiratory and endocrine disease mortality (ICD10-codes J00-J99 and E00-E90 as falsification end points, controlling for demographic factors, socio-economic factors, birth cohort, adherence to other cardiovascular medications, and diabetes using time-varying Cox regression models. Results Falsification end-points indicated that a simpler model was less biased than a model with more controls. Adherence to statins appeared to be protective against cardiovascular mortality (HR: 0.70, 95 % CI 0.61 to 0.81. Conclusions Falsification end-points helped detect overadjustment bias or bias due to competing risks, and thereby proved to be a useful technique in such a complex setting.

  13. A comparison of height and weight velocity as a part of the composite endpoint in pediatric HIV.

    Science.gov (United States)

    Benjamin, Daniel K; Miller, Wiliam C; Benjamin, Daniel K; Ryder, Robert W; Weber, David J; Walter, Emmanuel; McKinney, Ross E

    2003-11-07

    HIV adversely affects growth in children. Pediatric AIDS Clinical Trial Group (PACTG) protocols often use weight velocity [changes in weight z-score for age (WAZ)] as a part of the composite endpoint for phase II and III clinical trials. However, WAZ and height velocity (HAZ) have not been critically compared for their utility as part of the composite endpoint. HAZ and WAZ were compared to predict laboratory and clinical progression of HIV in a retrospective cohort study of HIV-infected children with data from PACTG Protocol 300. In both bivariable and multivariable analyses, changes in HAZ were more closely linked to subsequent progression than WAZ. Children with improved HAZ were somewhat less likely to exhibit virological failure [odds ratio (OR), 0.76; 95% confidence interval (CI) 0.51-1.14], than children with improved WAZ (OR, 1.45; 95% CI, 0.99,2.11). Children who had improved HAZ were less likely to exhibit immunological failure (OR, 0.7; 95% CI, 0.49-1.00), than children with improved WAZ (OR, 1.13; 95% CI, 0.82-1.57). Children who had improved HAZ were less likely to have other forms of clinical progression of HIV (OR, 0.55; 95% CI, 0.31-0.99), than children who had improved WAZ (OR, 1.0; 95% CI, 1.58-1.94). Increases in HAZ were associated with reduced risk of subsequent clinical progression and subsequent immune reconstitution and weakly associated with declines in HIV RNA. Changes in WAZ were not associated with laboratory outcomes relevant to pediatric HIV infection. Height velocity should be considered as a component of a composite clinical endpoint in future PACTG trials.

  14. An European inter-laboratory validation of alternative endpoints of the murine local lymph node assay: first round.

    Science.gov (United States)

    Ehling, G; Hecht, M; Heusener, A; Huesler, J; Gamer, A O; van Loveren, H; Maurer, Th; Riecke, K; Ullmann, L; Ulrich, P; Vandebriel, R; Vohr, H-W

    2005-08-15

    The new OECD guideline 429 (skin sensitization: local lymph node assay) is based upon a protocol, which utilises the incorporation of radioactivity into DNA as a measure for cell proliferation in vivo. The guideline also enables the use of alternative endpoints in order to assess draining lymph node (LN) cell proliferation. Here we describe the first round of an inter-laboratory validation of alternative endpoints in the LLNA conducted in seven laboratories. The validation study was managed and supervised by the Swiss Agency for Therapeutic Products, Swissmedic. Statistical analyses of all data were performed by an independent centre at the University of Bern, Department of Statistics. Ear-draining, LN weight and cell count were used to assess proliferation instead of radioactive labeling of lymph node cells. In addition, the acute inflammatory skin reaction was measured by ear swelling and weight of circular biopsies of the ears to identify skin irritating properties of the test items. Hexylcinnamaldehyde (HCA) and three blinded test items were applied to female, 8--10 weeks old NMRI and BALB/c mice. Results were sent via the independent study coordinator to the statistician. The results of this first round showed that the alternative endpoints of the LLNA are sensitive and robust parameters. The use of ear weights added an important parameter assessing the skin irritation potential, which supports the differentiation of pure irritative from contact allergenic potential. There were absolute no discrepancies between the categorisation of the three test substances A--C determined by each single participating laboratories. The results highlighted also that many parameters do have an impact on the strength of the responses. Therefore, such parameters have to be taken into consideration for the categorisation of compounds due to their relative sensitizing potencies.

  15. An European inter-laboratory validation of alternative endpoints of the murine local lymph node assay: First round

    International Nuclear Information System (INIS)

    Ehling, G.; Hecht, M.; Heusener, A.; Huesler, J.; Gamer, A.O.; Loveren, H. van; Maurer, Th.; Riecke, K.; Ullmann, L.; Ulrich, P.; Vandebriel, R.; Vohr, H.-W.

    2005-01-01

    The new OECD guideline 429 (skin sensitization: local lymph node assay) is based upon a protocol, which utilises the incorporation of radioactivity into DNA as a measure for cell proliferation in vivo. The guideline also enables the use of alternative endpoints in order to assess draining lymph node (LN) cell proliferation. Here we describe the first round of an inter-laboratory validation of alternative endpoints in the LLNA conducted in seven laboratories. The validation study was managed and supervised by the Swiss Agency for Therapeutic Products, Swissmedic. Statistical analyses of all data were performed by an independent centre at the University of Bern, Department of Statistics. Ear-draining, LN weight and cell count were used to assess proliferation instead of radioactive labeling of lymph node cells. In addition, the acute inflammatory skin reaction was measured by ear swelling and weight of circular biopsies of the ears to identify skin irritating properties of the test items. Hexylcinnamaldehyde (HCA) and three blinded test items were applied to female, 8-10 weeks old NMRI and BALB/c mice. Results were sent via the independent study coordinator to the statistician. The results of this first round showed that the alternative endpoints of the LLNA are sensitive and robust parameters. The use of ear weights added an important parameter assessing the skin irritation potential, which supports the differentiation of pure irritative from contact allergenic potential. There were absolute no discrepancies between the categorisation of the three test substances A-C determined by each single participating laboratories. The results highlighted also that many parameters do have an impact on the strength of the responses. Therefore, such parameters have to be taken into consideration for the categorisation of compounds due to their relative sensitizing potencies

  16. Primary ventriculoperitoneal shunting outcomes: a multicentre clinical audit for shunt infection and its risk factors.

    Science.gov (United States)

    Woo, P Ym; Wong, H T; Pu, J Ks; Wong, W K; Wong, L Yw; Lee, M Wy; Yam, K Y; Lui, W M; Poon, W S

    2016-10-01

    To determine the frequency of primary ventriculoperitoneal shunt infection among patients treated at neurosurgical centres of the Hospital Authority and to identify underlying risk factors. This multicentre historical cohort study included consecutive patients who underwent primary ventriculoperitoneal shunting at a Hospital Authority neurosurgery centre from 1 January 2009 to 31 December 2011. The primary endpoint was shunt infection, defined as: (1) the presence of cerebrospinal fluid or shunt hardware culture that yielded the pathogenic micro-organism with associated compatible symptoms and signs of central nervous system infection or shunt malfunction; or (2) surgical incision site infection requiring shunt reinsertion (even in the absence of positive culture); or (3) intraperitoneal pseudocyst formation (even in the absence of positive culture). Secondary endpoints were shunt malfunction, defined as unsatisfactory cerebrospinal fluid drainage that required shunt reinsertion, and 30-day mortality. A primary ventriculoperitoneal shunt was inserted in 538 patients during the study period. The mean age of patients was 48 years (range, 13-88 years) with a male-to-female ratio of 1:1. Aneurysmal subarachnoid haemorrhage was the most common aetiology (n=169, 31%) followed by intracranial tumour (n=164, 30%), central nervous system infection (n=42, 8%), and traumatic brain injury (n=27, 5%). The mean operating time was 75 (standard deviation, 29) minutes. Shunt reinsertion and infection rates were 16% (n=87) and 7% (n=36), respectively. The most common cause for shunt reinsertion was malfunction followed by shunt infection. Independent predictors for shunt infection were: traumatic brain injury (adjusted odds ratio=6.2; 95% confidence interval, 2.3-16.8), emergency shunting (2.3; 1.0-5.1), and prophylactic vancomycin as the sole antibiotic (3.4; 1.1-11.0). The 30-day all-cause mortality was 6% and none were directly procedure-related. This is the first Hong Kong

  17. Gemcitabine and irinotecan as first-line therapy for carcinoma of unknown primary: results of a multicenter phase II trial.

    Directory of Open Access Journals (Sweden)

    Shernan G Holtan

    Full Text Available Metastatic carcinoma of unknown primary (CUP has a very poor prognosis, and no standard first-line therapy currently exists. Here, we report the results of a phase II study utilizing a combination of gemcitabine and irinotecan as first-line therapy. Treatment was with gemcitabine 1000 mg/m(2 and irinotecan 75 mg/m(2 weekly times four on a six week cycle (Cohort I. Due to excessive toxicity, the dose and schedule were modified as follows: gemcitabine 750 mg/m(2 and irinotecan 75 mg/m(2 given weekly times three on a four week cycle (Cohort II. The primary endpoint was the confirmed response rate (CR + PR. Secondary endpoints consisted of adverse events based upon the presence or absence of the UDP glucuronosyltransferase 1 family, polypeptide A1*28 (UGT1A1*28 polymorphism, time to progression, and overall survival. Thirty-one patients were enrolled with a median age of 63 (range: 38-94, and 26 patients were evaluable for efficacy. Significant toxicity was observed in Cohort 1, characterized by 50% (7/14 patients experiencing a grade 4+ adverse event, but not in cohort II. The confirmed response rate including patients from both cohorts was 12% (95% CI: 2-30%, which did not meet the criteria for continued enrollment. Overall median survival was 7.2 months (95% CI: 4.0 to 11.6 for the entire cohort but notably longer in cohort II than in cohort I (9.3 months (95% CI: 4.1 to 12.1 versus 4.0 months (95% CI: 2.2 to 15.6. Gemcitabine and irinotecan is not an active combination when used as first line therapy in patients with metastatic carcinoma of unknown primary. Efforts into developing novel diagnostic and therapeutic approaches remain important for improving the outlook for this heterogeneous group of patients.ClinicalTrials.gov NCT00066781.

  18. Theory including future not excluded

    DEFF Research Database (Denmark)

    Nagao, K.; Nielsen, H.B.

    2013-01-01

    We study a complex action theory (CAT) whose path runs over not only past but also future. We show that, if we regard a matrix element defined in terms of the future state at time T and the past state at time TA as an expectation value in the CAT, then we are allowed to have the Heisenberg equation......, Ehrenfest's theorem, and the conserved probability current density. In addition,we showthat the expectation value at the present time t of a future-included theory for large T - t and large t - T corresponds to that of a future-not-included theory with a proper inner product for large t - T. Hence, the CAT...

  19. Simulation from endpoint-conditioned, continuous-time Markov chains on a finite state space, with applications to molecular evolution

    DEFF Research Database (Denmark)

    Hobolth, Asger; Stone, Eric

    2009-01-01

    computational finance to human genetics and genomics. A common theme among these diverse applications is the need to simulate sample paths of a CTMC conditional on realized data that is discretely observed. Here we present a general solution to this sampling problem when the CTMC is defined on a discrete....... In doing so, we show that no method dominates the others across all model specifications, and we give explicit proof of which method prevails for any given Q, T, and endpoints. Finally, we introduce and compare three applications of CTMCs to demonstrate the pitfalls of choosing an inefficient sampler....

  20. Chloride and sulphate toxicity to Hydropsyche exocellata (Trichoptera, Hydropsychidae): Exploring intraspecific variation and sub-lethal endpoints

    International Nuclear Information System (INIS)

    Sala, Miquel; Faria, Melissa; Sarasúa, Ignacio; Barata, Carlos; Bonada, Núria; Brucet, Sandra; Llenas, Laia; Ponsá, Sergio; Prat, Narcís; Soares, Amadeu M.V.M.

    2016-01-01

    The rivers and streams of the world are becoming saltier due to human activities. In spite of the potential damage that salt pollution can cause on freshwater ecosystems, this is an issue that is currently poorly managed. Here we explored intraspecific differences in the sensitivity of freshwater fauna to two major ions (Cl"− and SO_4"2"−) using the net-spinning caddisfly Hydropsyche exocellata Dufour 1841 (Trichoptera, Hydropsychidae) as a model organism. We exposed H. exocellata to saline solutions (reaching a conductivity of 2.5 mS cm"−"1) with Cl"−:SO_4"2"− ratios similar to those occurring in effluents coming from the meat, mining and paper industries, which release dissolved salts to rivers and streams in Spain. We used two different populations, coming from low and high conductivity streams. To assess toxicity, we measured sub-lethal endpoints: locomotion, symmetry of the food-capturing nets and oxidative stress biomarkers. According to biomarkers and net building, the population historically exposed to lower conductivities (B10) showed higher levels of stress than the population historically exposed to higher conductivities (L102). However, the differences between populations were not strong. For example, net symmetry was lower in the B10 than in the L102 only 48 h after treatment was applied, and biomarkers showed a variety of responses, with no discernable pattern. Also, treatment effects were rather weak, i.e. only some endpoints, and in most cases only in the B10 population, showed a significant response to treatment. The lack of consistent differences between populations and treatments could be related to the high salt tolerance of H. exocellata, since both populations were collected from streams with relatively high conductivities. The sub-lethal effects tested in this study can offer an interesting and promising tool to monitor freshwater salinization by combining physiological and behavioural bioindicators. - Highlights: • We assessed Cl

  1. Chloride and sulphate toxicity to Hydropsyche exocellata (Trichoptera, Hydropsychidae): Exploring intraspecific variation and sub-lethal endpoints

    Energy Technology Data Exchange (ETDEWEB)

    Sala, Miquel [Centre Tecnològic Forestal de Catalunya - CTFC, Solsona, Catalunya (Spain); Faria, Melissa [CESAM, Departamento de Biologia, Universidade de Aveiro, 3810-193 Aveiro (Portugal); Sarasúa, Ignacio [Technische Universität München, Munich, Bayern (Germany); Barata, Carlos [Institute of Environmental Assessment and Water Research (IDAEA-CSIC), Barcelona (Spain); Bonada, Núria [Grup de Recerca Freshwater Ecology and Management (FEM), Departament d' Ecologia, Facultat de Biologia, Universitat de Barcelona (UB), Diagonal 643, 08028 Barcelona, Catalonia (Spain); Grup de Recerca Freshwater Ecology and Management (FEM), Departament d' Ecologia, Facultat de Biologia, Institut de Recerca de la Biodiversitat (IRBio), Universitat de Barcelona - UB, Diagonal 643, 08028 Barcelona, Catalonia (Spain); Brucet, Sandra [Aquatic Ecology Group, BETA Tecnio Centre, University of Vic - Central University of Catalonia, Vic, Catalonia (Spain); Catalan Institution for Research and Advanced Studies, ICREA, Barcelona 08010 (Spain); Llenas, Laia; Ponsá, Sergio [Aquatic Ecology Group, BETA Tecnio Centre, University of Vic - Central University of Catalonia, Vic, Catalonia (Spain); Prat, Narcís [Grup de Recerca Freshwater Ecology and Management (FEM), Departament d' Ecologia, Facultat de Biologia, Universitat de Barcelona (UB), Diagonal 643, 08028 Barcelona, Catalonia (Spain); Soares, Amadeu M.V.M. [CESAM, Departamento de Biologia, Universidade de Aveiro, 3810-193 Aveiro (Portugal); and others

    2016-10-01

    The rivers and streams of the world are becoming saltier due to human activities. In spite of the potential damage that salt pollution can cause on freshwater ecosystems, this is an issue that is currently poorly managed. Here we explored intraspecific differences in the sensitivity of freshwater fauna to two major ions (Cl{sup −} and SO{sub 4}{sup 2−}) using the net-spinning caddisfly Hydropsyche exocellata Dufour 1841 (Trichoptera, Hydropsychidae) as a model organism. We exposed H. exocellata to saline solutions (reaching a conductivity of 2.5 mS cm{sup −1}) with Cl{sup −}:SO{sub 4}{sup 2−} ratios similar to those occurring in effluents coming from the meat, mining and paper industries, which release dissolved salts to rivers and streams in Spain. We used two different populations, coming from low and high conductivity streams. To assess toxicity, we measured sub-lethal endpoints: locomotion, symmetry of the food-capturing nets and oxidative stress biomarkers. According to biomarkers and net building, the population historically exposed to lower conductivities (B10) showed higher levels of stress than the population historically exposed to higher conductivities (L102). However, the differences between populations were not strong. For example, net symmetry was lower in the B10 than in the L102 only 48 h after treatment was applied, and biomarkers showed a variety of responses, with no discernable pattern. Also, treatment effects were rather weak, i.e. only some endpoints, and in most cases only in the B10 population, showed a significant response to treatment. The lack of consistent differences between populations and treatments could be related to the high salt tolerance of H. exocellata, since both populations were collected from streams with relatively high conductivities. The sub-lethal effects tested in this study can offer an interesting and promising tool to monitor freshwater salinization by combining physiological and behavioural bioindicators

  2. A PHYSIOLOGICALLY BASED COMPUTATIONAL MODEL OF THE BPG AXIS IN FATHEAD MINNOWS: PREDICTING EFFECTS OF ENDOCRINE DISRUPTING CHEMICAL EXPOSURE ON REPRODUCTIVE ENDPOINTS

    Science.gov (United States)

    This presentation describes development and application of a physiologically-based computational model that simulates the brain-pituitary-gonadal (BPG) axis and other endpoints important in reproduction such as concentrations of sex steroid hormones, 17-estradiol, testosterone, a...

  3. Hazardous waste transportation risk assessment for the US Department of Energy Environmental Restoration and Waste Management Programmatic Environmental Impact Statement -- human health endpoints

    International Nuclear Information System (INIS)

    Hartmann, H.M.; Policastro, A.J.; Lazaro, M.A.

    1994-01-01

    In this presentation, a quantitative methodology for assessing the risk associated with the transportation of hazardous waste (HW) is proposed. The focus is on identifying air concentrations of HW that correspond to specific human health endpoints

  4. Predicting treatment effect from surrogate endpoints and historical trials: an extrapolation involving probabilities of a binary outcome or survival to a specific time.

    Science.gov (United States)

    Baker, Stuart G; Sargent, Daniel J; Buyse, Marc; Burzykowski, Tomasz

    2012-03-01

    Using multiple historical trials with surrogate and true endpoints, we consider various models to predict the effect of treatment on a true endpoint in a target trial in which only a surrogate endpoint is observed. This predicted result is computed using (1) a prediction model (mixture, linear, or principal stratification) estimated from historical trials and the surrogate endpoint of the target trial and (2) a random extrapolation error estimated from successively leaving out each trial among the historical trials. The method applies to either binary outcomes or survival to a particular time that is computed from censored survival data. We compute a 95% confidence interval for the predicted result and validate its coverage using simulation. To summarize the additional uncertainty from using a predicted instead of true result for the estimated treatment effect, we compute its multiplier of standard error. Software is available for download. © 2011, The International Biometric Society No claim to original US government works.

  5. Evaluation of Gene Expression Endpoints in the Context of a Xenopus laevis Metamorphosis-based Bioassay to Detect Thyroid Hormone Disruptors

    Science.gov (United States)

    This study accentuates the need to examine multiple tissues and provides critical information required for optimization of exposure regimens and endpoint assessments that focus on the detection of disruption in TH-regulatory systems.

  6. Primary amyloidosis

    Science.gov (United States)

    ... include: Abdominal fat pad aspiration Bone marrow biopsy Rectal mucosa biopsy Cardiac muscle biopsy Treatment Treatment may ... Copyright 1997-2018, A.D.A.M., Inc. Duplication for commercial use must be authorized in writing ...

  7. Cost-effectiveness of a mild compared with a standard strategy for IVF : a randomized comparison using cumulative term live birth as the primary endpoint

    NARCIS (Netherlands)

    Polinder, S.; Heijnen, E. M. E. W.; Macklon, N. S.; Habbema, J. D. F.; Fauser, B. J. C. M.; Eijkemans, M. J. C.

    Background: Conventional ovarian stimulation and the transfer of two embryos in IVF exhibits an inherent high probability of multiple pregnancies, resulting in high costs. We evaluated the cost-effectiveness of a mild compared with a conventional strategy for IVF. Methods: Four hundred and four

  8. Cost-effectiveness of a mild compared with a standard strategy for IVF: a randomized comparison using cumulative term live birth as the primary endpoint.

    Science.gov (United States)

    Polinder, S; Heijnen, E M E W; Macklon, N S; Habbema, J D F; Fauser, B J C M; Eijkemans, M J C

    2008-02-01

    BACKGROUND Conventional ovarian stimulation and the transfer of two embryos in IVF exhibits an inherent high probability of multiple pregnancies, resulting in high costs. We evaluated the cost-effectiveness of a mild compared with a conventional strategy for IVF. METHODS Four hundred and four patients were randomly assigned to undergo either mild ovarian stimulation/GnRH antagonist co-treatment combined with single embryo transfer, or standard stimulation/GnRH agonist long protocol and the transfer of two embryos. The main outcome measures are total costs of treatment within a 12 months period after randomization, and the relationship between total costs and proportion of cumulative pregnancies resulting in term live birth within 1 year of randomization. RESULTS Despite a significantly increased average number of IVF cycles (2.3 versus 1.7; P costs over a 12-month period (8333 versus euro10 745; P = 0.006) were observed using the mild strategy. This was mainly due to higher costs of the obstetric and post-natal period for the standard strategy, related to multiple pregnancies. The costs per pregnancy leading to term live birth were euro19 156 in the mild strategy and euro24 038 in the standard. The incremental cost-effectiveness ratio of the standard strategy compared with the mild strategy was euro185 000 per extra pregnancy leading to term live birth. CONCLUSIONS Despite an increased mean number of IVF cycles within 1 year, from an economic perspective, the mild treatment strategy is more advantageous per term live birth. It is unlikely, over a wide range of society's willingness-to-pay, that the standard treatment strategy is cost-effective, compared with the mild strategy.

  9. Device including a contact detector

    DEFF Research Database (Denmark)

    2011-01-01

    arms (12) may extend from the supporting body in co-planar relationship with the first surface. The plurality of cantilever arms (12) may extend substantially parallel to each other and each of the plurality of cantilever arms (12) may include an electrical conductive tip for contacting the area......The present invention relates to a probe for determining an electrical property of an area of a surface of a test sample, the probe is intended to be in a specific orientation relative to the test sample. The probe may comprise a supporting body defining a first surface. A plurality of cantilever...... of the test sample by movement of the probe relative to the surface of the test sample into the specific orientation.; The probe may further comprise a contact detector (14) extending from the supporting body arranged so as to contact the surface of the test sample prior to any one of the plurality...

  10. Neoclassical transport including collisional nonlinearity.

    Science.gov (United States)

    Candy, J; Belli, E A

    2011-06-10

    In the standard δf theory of neoclassical transport, the zeroth-order (Maxwellian) solution is obtained analytically via the solution of a nonlinear equation. The first-order correction δf is subsequently computed as the solution of a linear, inhomogeneous equation that includes the linearized Fokker-Planck collision operator. This equation admits analytic solutions only in extreme asymptotic limits (banana, plateau, Pfirsch-Schlüter), and so must be solved numerically for realistic plasma parameters. Recently, numerical codes have appeared which attempt to compute the total distribution f more accurately than in the standard ordering by retaining some nonlinear terms related to finite-orbit width, while simultaneously reusing some form of the linearized collision operator. In this work we show that higher-order corrections to the distribution function may be unphysical if collisional nonlinearities are ignored.

  11. Neutralization Assay for Zika and Dengue Viruses by Use of Real-Time-PCR-Based Endpoint Assessment.

    Science.gov (United States)

    Wilson, Heather L; Tran, Thomas; Druce, Julian; Dupont-Rouzeyrol, Myrielle; Catton, Michael

    2017-10-01

    The global spread and infective complications of Zika virus (ZKV) and dengue virus (DENV) have made them flaviviruses of public health concern. Serological diagnosis can be challenging due to antibody cross-reactivity, particularly in secondary flavivirus infections or when there is a history of flavivirus vaccination. The virus neutralization assay is considered to be the most specific assay for measurement of anti-flavivirus antibodies. This study describes an assay where the neutralization endpoint is measured by real-time PCR, providing results within 72 h. It demonstrated 100% sensitivity (24/24 ZKV and 15/15 DENV) and 100% specificity (11/11 specimens) when testing well-characterized sera. In addition, the assay was able to determine the correct DENV serotype in 91.7% of cases. The high sensitivity and specificity of the real-time PCR neutralization assay makes it suitable to use as a confirmatory test for sera that are reactive in commercial IgM/IgG enzyme immunoassays. Results are objective and the PCR-based measurement of the neutralization endpoint lends itself to automation so that throughput may be increased in times of high demand. Copyright © 2017 American Society for Microbiology.

  12. A Portable Automatic Endpoint Detection System for Amplicons of Loop Mediated Isothermal Amplification on Microfluidic Compact Disk Platform

    Directory of Open Access Journals (Sweden)

    Shah Mukim Uddin

    2015-03-01

    Full Text Available In recent years, many improvements have been made in foodborne pathogen detection methods to reduce the impact of food contamination. Several rapid methods have been developed with biosensor devices to improve the way of performing pathogen detection. This paper presents an automated endpoint detection system for amplicons generated by loop mediated isothermal amplification (LAMP on a microfluidic compact disk platform. The developed detection system utilizes a monochromatic ultraviolet (UV emitter for excitation of fluorescent labeled LAMP amplicons and a color sensor to detect the emitted florescence from target. Then it processes the sensor output and displays the detection results on liquid crystal display (LCD. The sensitivity test has been performed with detection limit up to 2.5 × 10−3 ng/µL with different DNA concentrations of Salmonella bacteria. This system allows a rapid and automatic endpoint detection which could lead to the development of a point-of-care diagnosis device for foodborne pathogens detection in a resource-limited environment.

  13. Allergenicity evaluation of fragrance mix and its ingredients by using ex vivo local lymph node assay-BrdU endpoints.

    Science.gov (United States)

    Ulker, Ozge Cemiloglu; Kaymak, Yesim; Karakaya, Asuman

    2014-03-01

    The present studies were performed to compare the differences between sensitization potency of fragrance mix and its ingredients (oak moss absolute, isoeugenol, eugenol, cinnamal, hydroxycitronellal, geraniol, cinnamic alcohol, alpha amyl cinnamal), by using ex vivo LLNA-BrdU ELISA. The SI and EC3 values were calculated and potency classification was found for the mixture and for each ingredients. TH1 cytokines (IL-2, IFN-γ) and TH2 cytokines (IL-4, IL-5) releases from lymph node cell culture were also investigated as contact sensitization endpoints. The EC3 values were calculated and the potency of contact sensitization were classified for fragrance mix, oak moss absolute, isoeugenol, eugenol, cinnamal, hydroxycitronellal, geraniol, cinnamic alcohol, alpha amyl cinnamal respectively: 4.4% (moderate), 3.4% (moderate), 0.88% (strong), 16.6% (weak), 1.91% (moderate), 9.77% (moderate), 13.1% (weak), 17.93% (weak), 7.74% (moderate). According to our results it should be concluded that exposure to fragrance mix does not constitute an evidently increased hazard compared to exposure to each of the eight fragrance ingredients separately. Cytokine analyses results indicate that both TH1 and TH2 cytokines are involved in the regulation of murine contact allergy and can be considered as useful endpoints. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. How Can Viral Dynamics Models Inform Endpoint Measures in Clinical Trials of Therapies for Acute Viral Infections?

    Directory of Open Access Journals (Sweden)

    Carolin Vegvari

    Full Text Available Acute viral infections pose many practical challenges for the accurate assessment of the impact of novel therapies on viral growth and decay. Using the example of influenza A, we illustrate how the measurement of infection-related quantities that determine the dynamics of viral load within the human host, can inform investigators on the course and severity of infection and the efficacy of a novel treatment. We estimated the values of key infection-related quantities that determine the course of natural infection from viral load data, using Markov Chain Monte Carlo methods. The data were placebo group viral load measurements collected during volunteer challenge studies, conducted by Roche, as part of the oseltamivir trials. We calculated the values of the quantities for each patient and the correlations between the quantities, symptom severity and body temperature. The greatest variation among individuals occurred in the viral load peak and area under the viral load curve. Total symptom severity correlated positively with the basic reproductive number. The most sensitive endpoint for therapeutic trials with the goal to cure patients is the duration of infection. We suggest laboratory experiments to obtain more precise estimates of virological quantities that can supplement clinical endpoint measurements.

  15. Testing of an End-Point Control Unit Designed to Enable Precision Control of Manipulator-Coupled Spacecraft

    Science.gov (United States)

    Montgomery, Raymond C.; Ghosh, Dave; Tobbe, Patrick A.; Weathers, John M.; Manouchehri, Davoud; Lindsay, Thomas S.

    1994-01-01

    This paper presents an end-point control concept designed to enable precision telerobotic control of manipulator-coupled spacecraft. The concept employs a hardware unit (end-point control unit EPCU) that is positioned between the end-effector of the Space Shuttle Remote Manipulator System and the payload. Features of the unit are active compliance (control of the displacement between the end-effector and the payload), to allow precision control of payload motions, and inertial load relief, to prevent the transmission of loads between the end-effector and the payload. This paper presents the concept and studies the active compliance feature using a simulation and hardware. Results of the simulation show the effectiveness of the EPCU in smoothing the motion of the payload. Results are presented from initial, limited tests of a laboratory hardware unit on a robotic arm testbed at the l Space Flight Center. Tracking performance of the arm in a constant speed automated retraction and extension maneuver of a heavy payload with and without the unit active is compared for the design speed and higher speeds. Simultaneous load reduction and tracking performance are demonstrated using the EPCU.

  16. Primary headaches in children

    Directory of Open Access Journals (Sweden)

    Ajay Kumar Pan

    2015-01-01

    Full Text Available Headache is a widespread clinical problem; the prevalence is high in all age groups, from which children and teenagers are not spared. It has been reported that, as many as 75% of school-age children may experience headache infrequently, among them 10% have recurrent headaches. [1],[2] The vast majority of headaches are primary and classified as migraine, tension-type headache (TTH, cluster headache, and other trigeminal autonomic cephalgias. The type of primary headaches could usually be diagnosed by a thorough and careful history taking, and physical examination. Once the diagnosis of migraine is established and appropriate reassurance provided, a balanced and individually tailored treatment plan can be instituted. The goal of treatment includes abortive or acute pain treatment, preventive long-term treatment, and biobehavioral therapy. Knowledge of precise impact of primary headaches on child′s quality of life helps to design a proper comprehensive treatment plan.

  17. Surrogate endpoints for overall survival in chemotherapy and radiotherapy trials in operable and locally advanced lung cancer: a re-analysis of meta-analyses of individual patients' data

    NARCIS (Netherlands)

    Mauguen, Audrey; Pignon, Jean-Pierre; Burdett, Sarah; Domerg, Caroline; Fisher, David; Paulus, Rebecca; Mandrekar, Samithra J.; Belani, Chandra P.; Shepherd, Frances A.; Eisen, Tim; Pang, Herbert; Collette, Laurence; Sause, William T.; Dahlberg, Suzanne E.; Crawford, Jeffrey; O'Brien, Mary; Schild, Steven E.; Parmar, Mahesh; Tierney, Jayne F.; Le Pechoux, Cécile; Michiels, Stefan; Burdett, S.; Fisher, D.; Le Péchoux, C.; Mauguen, A.; Michiels, S.; Pignon, J. P.; Tierney, J. F.; Belani, C. P.; Collette, L.; Dahlberg, S.; Eisen, T.; Mandrekar, S.; O'Brien, M.; Parmar, M.; Pang, H.; Paulus, R.; Crawford, J.; Sause, W.; Schild, S. E.; Shepherd, F.; Arriagada, R.; Atagi, S.; Auperin, A.; Ball, D.; Baumann, M.; Behrendt, K.; Belderbos, J.; Koning, C. C. E.; Uitterhoeve, A.

    2013-01-01

    The gold standard endpoint in clinical trials of chemotherapy and radiotherapy for lung cancer is overall survival. Although reliable and simple to measure, this endpoint takes years to observe. Surrogate endpoints that would enable earlier assessments of treatment effects would be useful. We

  18. Other primary headaches

    Directory of Open Access Journals (Sweden)

    Anish Bahra

    2012-01-01

    Full Text Available The ′Other Primary Headaches′ include eight recognised benign headache disorders. Primary stabbing headache is a generally benign disorder which often co-exists with other primary headache disorders such as migraine and cluster headache. Primary cough headache is headache precipitated by valsalva; secondary cough has been reported particularly in association with posterior fossa pathology. Primary exertional headache can occur with sudden or gradual onset during, or immediately after, exercise. Similarly headache associated with sexual activity can occur with gradual evolution or sudden onset. Secondary headache is more likely with both exertional and sexual headache of sudden onset. Sudden onset headache, with maximum intensity reached within a minute, is termed thunderclap headache. A benign form of thunderclap headache exists. However, isolated primary and secondary thunderclap headache cannot be clinically differentiated. Therefore all headache of thunderclap onset should be investigated. The primary forms of the aforementioned paroxysmal headaches appear to be Indomethacin sensitive disorders. Hypnic headache is a rare disorder which is termed ′alarm clock headache′, exclusively waking patients from sleep. The disorder can be Indomethacin responsive, but can also respond to Lithium and caffeine. New daily persistent headache is a rare and often intractable headache which starts one day and persists daily thereafter for at least 3 months. The clinical syndrome more often has migrainous features or is otherwise has a chronic tension-type headache phenotype. Management is that of the clinical syndrome. Hemicrania continua straddles the disorders of migraine and the trigeminal autonomic cephalalgias and is not dealt with in this review.

  19. The impact of surgical resection of the primary tumor on the development of synchronous colorectal liver metastasis: a systematic review.

    Science.gov (United States)

    Pinson, H; Cosyns, S; Ceelen, Wim P

    2018-05-22

    In recent years different therapeutic strategies for synchronously liver metastasized colorectal cancer were described. Apart from the classical staged surgical approach, simultaneous and liver-first strategies are now commonly used. One theoretical drawback of the classical approach is, however, the stimulatory effect on liver metastases growth that may result from resection of the primary tumour. This systematic review, therefore, aims to investigate the current insights on the stimulatory effects of colorectal surgery on the growth of synchronous colorectal liver metastases in humans. The systematic review was conducted according to the PRISMA statement. A literature search was performed using PubMed and Embase. Articles investigating the effects of colorectal surgery on synchronous colorectal liver metastases were included. Primary endpoints were metastatic tumor volume, metabolic and proliferative activity and tumour vascularization. Four articles meeting the selection criteria were found involving 200 patients. These studies investigate the effects of resection of the primary tumour on synchronous liver metastases using histological and radiological techniques. These papers support a possible stimulatory effect of resection of the primary tumor. Some limited evidence supports the hypothesis that colorectal surgery might stimulate the growth and development of synchronous colorectal liver metastases.

  20. Statins for the primary prevention of cardiovascular disease

    Science.gov (United States)

    Taylor, Fiona; Ward, Kirsten; Moore, Theresa HM; Burke, Margaret; Smith, George Davey; Casas, Juan P; Ebrahim, Shah

    2014-01-01

    Background Reducing high blood cholesterol, a risk factor for cardiovascular disease (CVD) events in people with and without a past history of coronary heart disease (CHD) is an important goal of pharmacotherapy. Statins are the first-choice agents. Previous reviews of the effects of statins have highlighted their benefits in people with coronary artery disease. The case for primary prevention, however, is less clear. Objectives To assess the effects, both harms and benefits, of statins in people with no history of CVD. Search methods To avoid duplication of effort, we checked reference lists of previous systematic reviews. We searched the Cochrane Central Register of Controlled Trials (Issue 1, 2007), MEDLINE (2001 to March 2007) and EMBASE (2003 to March 2007). There were no language restrictions. Selection criteria Randomised controlled trials of statins with minimum duration of one year and follow-up of six months, in adults with no restrictions on their total low density lipoprotein (LDL) or high density lipoprotein (HDL) cholesterol levels, and where 10% or less had a history of CVD, were included. Data collection and analysis Two authors independently selected studies for inclusion and extracted data. Outcomes included all cause mortality, fatal and non-fatal CHD, CVD and stroke events, combined endpoints (fatal and non-fatal CHD, CVD and stroke events), change in blood total cholesterol concentration, revascularisation, adverse events, quality of life and costs. Relative risk (RR) was calculated for dichotomous data, and for continuous data pooled weighted mean differences (with 95% confidence intervals) were calculated. Main results Fourteen randomised control trials (16 trial arms; 34,272 participants) were included. Eleven trials recruited patients with specific conditions (raised lipids, diabetes, hypertension, microalbuminuria). All-cause mortality was reduced by statins (RR 0.84, 95% CI 0.73 to 0.96) as was combined fatal and non-fatal CVD endpoints

  1. The Comparison of the Outcomes between Primary PCI, Fibrinolysis, and No Reperfusion in Patients ≥ 75 Years Old with ST-Segment Elevation Myocardial Infarction: Results from the Chinese Acute Myocardial Infarction (CAMI) Registry.

    Science.gov (United States)

    Peiyuan, He; Jingang, Yang; Haiyan, Xu; Xiaojin, Gao; Ying, Xian; Yuan, Wu; Wei, Li; Yang, Wang; Xinran, Tang; Ruohua, Yan; Chen, Jin; Lei, Song; Xuan, Zhang; Rui, Fu; Yunqing, Ye; Qiuting, Dong; Hui, Sun; Xinxin, Yan; Runlin, Gao; Yuejin, Yang

    2016-01-01

    Only a few randomized trials have analyzed the clinical outcomes of elderly ST-segment elevation myocardial infarction (STEMI) patients (≥ 75 years old). Therefore, the best reperfusion strategy has not been well established. An observational study focused on clinical outcomes was performed in this population. Based on the national registry on STEMI patients, the in-hospital outcomes of elderly patients with different reperfusion strategies were compared. The primary endpoint was defined as death. Secondary endpoints included recurrent myocardial infarction, ischemia driven revascularization, myocardial infarction related complications, and major bleeding. Multivariable regression analysis was performed to adjust for the baseline disparities between the groups. Patients who had primary percutaneous coronary intervention (PCI) or fibrinolysis were relatively younger. They came to hospital earlier, and had lower risk of death compared with patients who had no reperfusion. The guideline recommended medications were more frequently used in patients with primary PCI during the hospitalization and at discharge. The rates of death were 7.7%, 15.0%, and 19.9% respectively, with primary PCI, fibrinolysis, and no reperfusion (P PCI also had lower rates of heart failure, mechanical complications, and cardiac arrest compared with fibrinolysis and no reperfusion (P PCI, fibrinolysis, and no reperfusion group (P > 0.05). In the multivariable regression analysis, primary PCI outweighs no reperfusion in predicting the in-hospital death in patients ≥ 75 years old. However, fibrinolysis does not. Early reperfusion, especially primary PCI was safe and effective with absolute reduction of mortality compared with no reperfusion. However, certain randomized trials were encouraged to support the conclusion.

  2. Is there a role for hyperbaric oxygen as primary treatment for grade IV radiation-induced haemorrhagic cystitis? a prospective pilot-feasibility study and review of literature

    International Nuclear Information System (INIS)

    Dellis, Athanasios; Deliveliotis, Charalambos; Kalentzos, Vasileios; Vavasis, Pavlos; Skolarikos, Andreas

    2014-01-01

    Purpose: To examine the safety and efficacy of hyperbaric oxygen as the primary treatment for Grade IV radiation-induced haemorrhagic cystitis. Materials and Methods: Hyperbaric oxygen was prospectively applied as a primary treatment option in 11 patients with Grade IV radiation cystitis. Primary endpoint was the incidence of complete and partial response to treatment. Secondary endpoints included the duration of response, the correlation of treatment success-rate to the interval between the onset of haematuria and initiation of therapy, blood transfusion need and total radiation dose, the number of sessions to success, the avoidance of surgery and the overall survival. Results: All patients completed therapy without complications for a mean follow-up of 17.82 months (range 3 to 34). Mean number of sessions needed was 32.8 (range 27 to 44). Complete and partial response rate was 81.8% and 18.2%, respectively. However, in three patients the first treatment session was not either sufficient or durable giving a 72.7% rate of durable effect. Interestingly, all 9 patients with complete response received therapy within 6 months of the haematuria onset compared to the two patients with partial response who received therapy at 8 and 10 months from the haematuria onset, respectively (p = 0.018). The need for blood transfusion (p = 0.491) and the total radiation dose (p = 0.259) were not correlated to success-rate. One patient needed cystectomy, while all patients were alive at the end of follow-up. Conclusions: Early primary use of hyperbaric oxygen to treat radiation-induced grade IV cystitis is an effective and safe treatment option. (author)

  3. Is there a role for hyperbaric oxygen as primary treatment for grade IV radiation-induced haemorrhagic cystitis? a prospective pilot-feasibility study and review of literature

    Energy Technology Data Exchange (ETDEWEB)

    Dellis, Athanasios [Surgical Department, University of Athens, Aretaieion Hospital (Greece); Deliveliotis, Charalambos [Urologic Department, University of Athens, Sismanoglio General Hospital (Greece); Kalentzos, Vasileios; Vavasis, Pavlos; Skolarikos, Andreas [Diving and Hyperbaric Oxygen Department, Naval and Veterans Hospital, Athens (Greece)

    2014-05-15

    Purpose: To examine the safety and efficacy of hyperbaric oxygen as the primary treatment for Grade IV radiation-induced haemorrhagic cystitis. Materials and Methods: Hyperbaric oxygen was prospectively applied as a primary treatment option in 11 patients with Grade IV radiation cystitis. Primary endpoint was the incidence of complete and partial response to treatment. Secondary endpoints included the duration of response, the correlation of treatment success-rate to the interval between the onset of haematuria and initiation of therapy, blood transfusion need and total radiation dose, the number of sessions to success, the avoidance of surgery and the overall survival. Results: All patients completed therapy without complications for a mean follow-up of 17.82 months (range 3 to 34). Mean number of sessions needed was 32.8 (range 27 to 44). Complete and partial response rate was 81.8% and 18.2%, respectively. However, in three patients the first treatment session was not either sufficient or durable giving a 72.7% rate of durable effect. Interestingly, all 9 patients with complete response received therapy within 6 months of the haematuria onset compared to the two patients with partial response who received therapy at 8 and 10 months from the haematuria onset, respectively (p = 0.018). The need for blood transfusion (p = 0.491) and the total radiation dose (p = 0.259) were not correlated to success-rate. One patient needed cystectomy, while all patients were alive at the end of follow-up. Conclusions: Early primary use of hyperbaric oxygen to treat radiation-induced grade IV cystitis is an effective and safe treatment option. (author)

  4. Impact of Primary Tumor Location on First-line Bevacizumab or Cetuximab in Metastatic Colorectal Cancer.

    Science.gov (United States)

    Snyder, Matthew; Bottiglieri, Sal; Almhanna, Khaldoun

    2018-01-01

    Colorectal cancer is one of the most common malignancies in the United States, with a large proportion of patients presenting with metastatic disease or developing a recurrence. Systemic chemotherapy is the mainstay of therapy in this setting. There is a clear benefit in the addition of bevacizumab or cetuximab (for rat sarcoma [RAS] wild type tumors) to oxaliplatin- and irinotecan-based regimens which can be considered for first-line therapy. However, many significant questions remain as to which agent reflects best practice. Our review aimed to elucidate the benefit of adding bevacizumab and cetuximab to initial therapy for metastatic colorectal cancer based on primary tumor location and a variety of other disease- and patient-related factors, addressing the paucity of evidence that currently exists in this area and contributing to current literature and clinical practices. The primary endpoints of the study were first Progression-Free Survival (PFS) and Overall Survival (OS). Secondary endpoints included best response to first- and second-line therapies, Treatment- Related Adverse Events (TRAEs), second PFS, cost of therapy, and an assessment of other patient- and disease-related factors affecting PFS and OS. While there were trends towards improved OS in patients with left-sided primary tumors (n=57) compared to those with right-sided disease (n=23), there were no significant differences between the two groups in either primary endpoint. While no differences were found for patients with left- or right- sided tumors stratified by add-on agent, these analyses were limited by the small number of patients receiving cetuximab with first-line therapy (n=4). However, the bevacizumab cohort (n=76) was sizable enough to provide ample data and produce clinically relevant results. Add-on therapy with bevacizumab in our study achieved impressive survival outcomes in both left-sided (median first PFS = 13 months, 95% CI 11-15 months; median OS = 37 months, 95% CI 21

  5. Biomonitoring: Guide for the Use of Biological Endpoints in Monitoring Species, Habitats, and Projects

    Science.gov (United States)

    2007-11-01

    et al ., 1991; Welsh and Ollivier 1998), behavior (Daly et al ., 1995; Maltby et al ., 2002 ...include changes in species diversity and community structure (Karr 1981; Bramblett and Fausch 1991; Barbour et al ., 1999; Zweig and Rabeni 2001; Martin et ...programs in aquatic habitats; these programs typically employ benthic invertebrates such as molluscs (Maltby et al ., 2002 ; Applied Biomonitoring

  6. Effects of Structured Versus Usual Care on Renal Endpoint in Type 2 Diabetes: The SURE Study

    Science.gov (United States)

    Chan, Juliana C.; So, Wing-Yee; Yeung, Chun-Yip; Ko, Gary T.; Lau, Ip-Tim; Tsang, Man-Wo; Lau, Kam-Piu; Siu, Sing-Chung; Li, June K.; Yeung, Vincent T.; Leung, Wilson Y.; Tong, Peter C.

    2009-01-01

    OBJECTIVE Multifaceted care has been shown to reduce mortality and complications in type 2 diabetes. We hypothesized that structured care would reduce renal complications in type 2 diabetes. RESEARCH DESIGN AND METHODS A total of 205 Chinese type 2 diabetic patients from nine public hospitals who had plasma creatinine levels of 150–350 μmol/l were randomly assigned to receive structured care (n = 104) or usual care (n = 101) for 2 years. The structured care group was managed according to a prespecified protocol with the following treatment goals: blood pressure triglyceride 500 μmol/l or dialysis). RESULTS Of these 205 patients (mean ± SD age 65 ± 7.2 years; disease duration 14 ± 7.9 years), the structured care group achieved better control than the usual care group (diastolic blood pressure 68 ± 12 vs. 71 ± 12 mmHg, respectively, P = 0.02; A1C 7.3 ± 1.3 vs. 8.0 ± 1.6%, P structured care (23.1%, n = 24) and usual care (23.8%, n = 24; NS) groups had similar end points, but more patients in the structured care group attained ≥3 treatment goals (61%, n = 63, vs. 28%, n = 28; P < 0.001). Patients who attained ≥3 treatment targets (n = 91) had reduced risk of the primary end point (14 vs. 34; relative risk 0.43 [95% CI 0.21–0.86] compared with that of those who attained ≤2 targets (n = 114). CONCLUSIONS Attainment of multiple treatment targets reduced the renal end point and death in type 2 diabetes. In addition to protocol, audits and feedback are needed to improve outcomes. PMID:19460913

  7. Reaction paths and equilibrium end-points in solid-solution aqueous-solution systems

    Science.gov (United States)

    Glynn, P.D.; Reardon, E.J.; Plummer, Niel; Busenberg, E.

    1990-01-01

    Equations are presented describing equilibrium in binary solid-solution aqueous-solution (SSAS) systems after a dissolution, precipitation, or recrystallization process, as a function of the composition and relative proportion of the initial phases. Equilibrium phase diagrams incorporating the concept of stoichiometric saturation are used to interpret possible reaction paths and to demonstrate relations between stoichiometric saturation, primary saturation, and thermodynamic equilibrium states. The concept of stoichiometric saturation is found useful in interpreting and putting limits on dissolution pathways, but there currently is no basis for possible application of this concept to the prediction and/ or understanding of precipitation processes. Previously published dissolution experiments for (Ba, Sr)SO4 and (Sr, Ca)C??O3orth. solids are interpreted using equilibrium phase diagrams. These studies show that stoichiometric saturation can control, or at least influence, initial congruent dissolution pathways. The results for (Sr, Ca)CO3orth. solids reveal that stoichiometric saturation can also control the initial stages of incongruent dissolution, despite the intrinsic instability of some of the initial solids. In contrast, recrystallisation experiments in the highly soluble KCl-KBr-H2O system demonstrate equilibrium. The excess free energy of mixing calculated for K(Cl, Br) solids is closely modeled by the relation GE = ??KBr??KClRT[a0 + a1(2??KBr-1)], where a0 is 1.40 ?? 0.02, a1, is -0.08 ?? 0.03 at 25??C, and ??KBr and ??KCl are the mole fractions of KBr and KCl in the solids. The phase diagram constructed using this fit reveals an alyotropic maximum located at ??KBr = 0.676 and at a total solubility product, ???? = [K+]([Cl-] + [Br-]) = 15.35. ?? 1990.

  8. The surgery of peripheral nerves (including tumors)

    DEFF Research Database (Denmark)

    Fugleholm, Kåre

    2013-01-01

    Surgical pathology of the peripheral nervous system includes traumatic injury, entrapment syndromes, and tumors. The recent significant advances in the understanding of the pathophysiology and cellular biology of peripheral nerve degeneration and regeneration has yet to be translated into improved...... surgical techniques and better outcome after peripheral nerve injury. Decision making in peripheral nerve surgery continues to be a complex challenge, where the mechanism of injury, repeated clinical evaluation, neuroradiological and neurophysiological examination, and detailed knowledge of the peripheral...... nervous system response to injury are prerequisite to obtain the best possible outcome. Surgery continues to be the primary treatment modality for peripheral nerve tumors and advances in adjuvant oncological treatment has improved outcome after malignant peripheral nerve tumors. The present chapter...

  9. A multiple endpoint analysis of the effects of chronic exposure to sediment contaminated with Deepwater Horizon oil on juvenile Southern flounder and their associated microbiomes

    International Nuclear Information System (INIS)

    Brown-Peterson, Nancy J.; Krasnec, Michelle; Takeshita, Ryan; Ryan, Caitlin N.; Griffitt, Kimberly J.; Lay, Claire; Mayer, Gregory D.; Bayha, Keith M.; Hawkins, William E.; Lipton, Ian; Morris, Jeffrey

    2015-01-01

    Highlights: • Juvenile southern flounder were exposed to sediment mixed with different amount of oil from the Deepwater Horizon spill. • The exposure was performed for 32 days, with growth and survival assessed throughout. • After the termination of the experiment, the survivors were examined at multiple endpoints, including histopathology and microbiome analysis. • The results indicated that the flounder were adversely affected at each endpoint examined. • Growth and survival were significantly reduced. • Histopathology found effects on gills and livers of exposed fish. • The microbiomes of the exposed fish were significantly altered by the exposure to sediment-associated oil in both gills and intestines. - Abstract: Exposure to oiled sediments can negatively impact the health of fish species. Here, we examine the effects of chronic exposure of juvenile southern flounder, Paralichthys lethostigma, to a sediment-oil mixture. Oil:sediment mixtures are persistent over time and can become bioavailable following sediment perturbation or resuspension. Juvenile flounder were exposed for 32 days under controlled laboratory conditions to five concentrations of naturally weathered Macondo MC252 oil mixed into uncontaminated, field-collected sediments. The percent composition of individual polycyclic aromatic hydrocarbons (PAHs) of the weathered oil did not change after mixing with the sediment. Spiked exposure sediments contained 0.04–395 mg/kg tPAH50 (sum of 50 individual PAH concentration measurements). Mortality increased with both exposure duration and concentration of sediment-associated PAHs, and flounder exposed to concentrations above 8 mg/kg tPAH50 showed significantly reduced growth over the course of the experiment. Evident histopathologic changes were observed in liver and gill tissues of fish exposed to more than 8 mg/kg tPAH50. All fish at these concentrations showed hepatic intravascular congestion, macrovesicular hepatic vacoulation

  10. A multiple endpoint analysis of the effects of chronic exposure to sediment contaminated with Deepwater Horizon oil on juvenile Southern flounder and their associated microbiomes

    Energy Technology Data Exchange (ETDEWEB)

    Brown-Peterson, Nancy J., E-mail: nancy.brown-peterson@usm.edu [Department of Coastal Sciences, The University of Southern Mississippi, 703 East Beach Dr., Ocean Springs, MS 39564 (United States); Krasnec, Michelle, E-mail: MKrasnec@stratusconsulting.com [Abt Associates, 1881 Ninth Street, Suite 201, Boulder, Colorado 80302 (United States); Takeshita, Ryan, E-mail: RTakeshita@stratusconsulting.com [Abt Associates, 1881 Ninth Street, Suite 201, Boulder, Colorado 80302 (United States); Ryan, Caitlin N., E-mail: Caitlin.ryan@ttu.edu [The Institute of Environmental and Human Health, Department of Environmental Toxicology, Texas Tech University, Box 41163, Lubbock, TX 79409 (United States); Griffitt, Kimberly J., E-mail: kim.griffitt@gmail.com [Department of Coastal Sciences, The University of Southern Mississippi, 703 East Beach Dr., Ocean Springs, MS 39564 (United States); Lay, Claire, E-mail: claymsc@stratusconsulting.com [Abt Associates, 1881 Ninth Street, Suite 201, Boulder, Colorado 80302 (United States); Mayer, Gregory D., E-mail: greg.mayer@ttu.edu [The Institute of Environmental and Human Health, Department of Environmental Toxicology, Texas Tech University, Box 41163, Lubbock, TX 79409 (United States); Bayha, Keith M., E-mail: kmbayha@gmail.com [Department of Coastal Sciences, The University of Southern Mississippi, 703 East Beach Dr., Ocean Springs, MS 39564 (United States); Hawkins, William E., E-mail: william.hawkins@usm.edu [Department of Coastal Sciences, The University of Southern Mississippi, 703 East Beach Dr., Ocean Springs, MS 39564 (United States); Lipton, Ian, E-mail: ianlipton@stratusconsulting.com [Abt Associates, 1881 Ninth Street, Suite 201, Boulder, Colorado 80302 (United States); Morris, Jeffrey, E-mail: JMorrisMSCanyon252@stratusconsulting.com [Abt Associates, 1881 Ninth Street, Suite 201, Boulder, Colorado 80302 (United States); and others

    2015-08-15

    Highlights: • Juvenile southern flounder were exposed to sediment mixed with different amount of oil from the Deepwater Horizon spill. • The exposure was performed for 32 days, with growth and survival assessed throughout. • After the termination of the experiment, the survivors were examined at multiple endpoints, including histopathology and microbiome analysis. • The results indicated that the flounder were adversely affected at each endpoint examined. • Growth and survival were significantly reduced. • Histopathology found effects on gills and livers of exposed fish. • The microbiomes of the exposed fish were significantly altered by the exposure to sediment-associated oil in both gills and intestines. - Abstract: Exposure to oiled sediments can negatively impact the health of fish species. Here, we examine the effects of chronic exposure of juvenile southern flounder, Paralichthys lethostigma, to a sediment-oil mixture. Oil:sediment mixtures are persistent over time and can become bioavailable following sediment perturbation or resuspension. Juvenile flounder were exposed for 32 days under controlled laboratory conditions to five concentrations of naturally weathered Macondo MC252 oil mixed into uncontaminated, field-collected sediments. The percent composition of individual polycyclic aromatic hydrocarbons (PAHs) of the weathered oil did not change after mixing with the sediment. Spiked exposure sediments contained 0.04–395 mg/kg tPAH50 (sum of 50 individual PAH concentration measurements). Mortality increased with both exposure duration and concentration of sediment-associated PAHs, and flounder exposed to concentrations above 8 mg/kg tPAH50 showed significantly reduced growth over the course of the experiment. Evident histopathologic changes were observed in liver and gill tissues of fish exposed to more than 8 mg/kg tPAH50. All fish at these concentrations showed hepatic intravascular congestion, macrovesicular hepatic vacoulation

  11. Methotrexate for primary biliary cirrhosis

    DEFF Research Database (Denmark)

    Giljaca, Vanja; Poropat, Goran; Stimac, Davor

    2010-01-01

    Methotrexate has been used to treat patients with primary biliary cirrhosis as it possesses immunosuppressive properties. The previously prepared version of this review from 2005 showed that methotrexate seemed to significantly increase mortality in patients with primary biliary cirrhosis. Since...... that last review version, follow-up data of the included trials have been published....

  12. Abdominal pain endpoints currently recommended by the FDA and EMA for adult patients with irritable bowel syndrome may not be reliable in children.

    Science.gov (United States)

    Saps, M; Lavigne, J V

    2015-06-01

    The Food and Drug Administration (FDA) recommended ≥30% decrease on patient-reported outcomes for pain be considered clinically significant in clinical trials for adults with irritable bowel syndrome. This percent change approach may not be appropriate for children. We compared three alternate approaches to determining clinically significant reductions in pain among children. 80 children with functional abdominal pain participated in a study of the efficacy of amitriptyline. Endpoints included patient-reported estimates of feeling better, and pain Visual Analog Scale (VAS). The minimum clinically important difference in pain report was calculated as (i) mean change in VAS score for children reporting being 'better'; (ii) percent changes in pain (≥30% and ≥50%) on the VAS; and (iii) statistically reliable changes on the VAS for 68% and 95% confidence intervals. There was poor agreement between the three approaches. 43.6% of the children who met the FDA ≥30% criterion for clinically significant change did not achieve a reliable level of improvement (95% confidence interval). Children's self-reported ratings of being better may not be statistically reliable. A combined approach in which children must report improvement as better and achieve a statistically significant change may be more appropriate for outcomes in clinical trials. © 2015 John Wiley & Sons Ltd.

  13. An application of the 'end-point' method to the minimum critical mass problem in two group transport theory

    International Nuclear Information System (INIS)

    Williams, M.M.R.

    2003-01-01

    A two group integral equation derived using transport theory, which describes the fuel distribution necessary for a flat thermal flux and minimum critical mass, is solved by the classical end-point method. This method has a number of advantages and in particular highlights the changing behaviour of the fissile mass distribution function in the neighbourhood of the core-reflector interface. We also show how the reflector thermal flux behaves and explain the origin of the maximum which arises when the critical size is less than that corresponding to minimum critical mass. A comparison is made with diffusion theory and the necessary and somewhat artificial presence of surface delta functions in the fuel distribution is shown to be analogous to the edge transients that arise naturally in transport theory

  14. Prediction of the relative toxicity of environmental toxins as a function of behavioral and non-behavioral endpoints

    International Nuclear Information System (INIS)

    Young, R.W.

    1979-01-01

    This study was conducted in order to examine the differential effects of behavioral and non-behavioral endpoints on the prediction of the relative toxicity of an environmental toxin. The effects of ionizing radiation were taken as the model for this evaluation. Forty rhesus monkeys were irradiated in groups of four at five different dose levels of high energy neuton and Bremsstrahlung radiations. Measures of behavioral performance, emesis and mortality were taken for each subject in order to test the hypotheses that behavioral indices would be more sensitive to gamma radiation than would physiological indices and that the physiological indices would be more sensitive to neutron radiations than would behavioral indices. The results supported these hypotheses

  15. Some thoughts on the nature of chromosomal aberrations and their use as a quantitative end-point for radiobiological studies

    International Nuclear Information System (INIS)

    Savage, J.R.K.

    1978-01-01

    A vital condition when chromosomal aberrations are to be used as a quantitative end-point (e.g. for constructing a dose response curve) is that a specific dose must produce a specific yield of aberrations under a given set of experimental conditions. In practice, there are very few cell systems where this condition is met. The majority show significant variations in observed yield with time between irradiation and sampling, indicative of variable radiosensitivity within the cell population. The profile of this yield time curve is determined by the cell-cycle kinetics and therefore is itself subject to modification by radiation through mitotic delay and perturbation. Thus in such heterogeneous populations, each increment of dose not only induces more aberrations, but at the same time modifies the recovered yield per cell. This has an obvious bearing upon the interpretation of the shape of any dose-response curve obtained

  16. Comparison between the radiosensitivity of human, mouse and chicken fibroblast-like cells using short-term endpoints

    International Nuclear Information System (INIS)

    Diatloff-Zito, C.; Loria, E.; Maciera-Coelho, A.; Deschavanne, P.J.; Malaise, E.P.

    1981-01-01

    A comparative study has been made of the radiosensitivity of fibroblastic cell lines from three different animal species: human, mouse and chicken. Endpoints reflecting short term responses were utilized: colony forming ability (CFA), DNA single strand break (SSB) repair and repair of potentially lethal damage (PLD). Regardless of the criterion employed, the response to radiation varies from one species to another. According to survival curves, chicken cells appear to be more radioresistant than those of human and mouse. SSB repair is apparently absent in murine cells, partial in chicken cells and complete in human cells. This lack of correlation between survival curves and SSB repair demonstrates that survival of irradiated cells does not depend only (or at all) on the repair of SSB. The repair of PLD is much more efficient in human and chicken cells than in murine cells. (author)

  17. The Medical Imaging & Technology Alliance conference on research endpoints appropriate for Medicare coverage of new PET radiopharmaceuticals.

    Science.gov (United States)

    Hillman, Bruce J; Frank, Richard A; Abraham, Brian C

    2013-09-01

    The outcomes of a 2011 Medical Imaging & Technology Alliance (MITA) conference helped shape considerations about what might be the most appropriate pathways for the regulatory and payment considerations of new PET radiopharmaceuticals. As follow-up to that conference, MITA convened a second conference of stakeholders to advise payers on what might be acceptable endpoints for clinical trials to support the coverage of novel PET agents. The conference involved experts on imaging and clinical research, providers of PET services, as well as representatives of interested medical societies, the PET industry, and the regulatory and payer communities. The principal outcome of their deliberations was that it was unrealistic to expect trials of new PET radiopharmaceuticals to directly demonstrate a health benefit. Rather, intermediate outcomes, such as a positive change in patient management, would be more efficient and appropriate.

  18. Primary Productivity (PP_Master)

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — This data set included primary production for each subregion in the study (Georges Bank, Gulf of Maine, Southern New England, Middle Atlantic Bight) . The data came...

  19. Allegheny County Primary Care Access

    Data.gov (United States)

    Allegheny County / City of Pittsburgh / Western PA Regional Data Center — The data on health care facilities includes the name and location of all the hospitals and primary care facilities in Allegheny County. The current listing of...

  20. Chloride and sulphate toxicity to Hydropsyche exocellata (Trichoptera, Hydropsychidae): Exploring intraspecific variation and sub-lethal endpoints.

    Science.gov (United States)

    Sala, Miquel; Faria, Melissa; Sarasúa, Ignacio; Barata, Carlos; Bonada, Núria; Brucet, Sandra; Llenas, Laia; Ponsá, Sergio; Prat, Narcís; Soares, Amadeu M V M; Cañedo-Arguelles, Miguel

    2016-10-01

    The rivers and streams of the world are becoming saltier due to human activities. In spite of the potential damage that salt pollution can cause on freshwater ecosystems, this is an issue that is currently poorly managed. Here we explored intraspecific differences in the sensitivity of freshwater fauna to two major ions (Cl(-) and SO4(2-)) using the net-spinning caddisfly Hydropsyche exocellata Dufour 1841 (Trichoptera, Hydropsychidae) as a model organism. We exposed H. exocellata to saline solutions (reaching a conductivity of 2.5mScm(-1)) with Cl(-):SO4(2-) ratios similar to those occurring in effluents coming from the meat, mining and paper industries, which release dissolved salts to rivers and streams in Spain. We used two different populations, coming from low and high conductivity streams. To assess toxicity, we measured sub-lethal endpoints: locomotion, symmetry of the food-capturing nets and oxidative stress biomarkers. According to biomarkers and net building, the population historically exposed to lower conductivities (B10) showed higher levels of stress than the population historically exposed to higher conductivities (L102). However, the differences between populations were not strong. For example, net symmetry was lower in the B10 than in the L102 only 48h after treatment was applied, and biomarkers showed a variety of responses, with no discernable pattern. Also, treatment effects were rather weak, i.e. only some endpoints, and in most cases only in the B10 population, showed a significant response to treatment. The lack of consistent differences between populations and treatments could be related to the high salt tolerance of H. exocellata, since both populations were collected from streams with relatively high conductivities. The sub-lethal effects tested in this study can offer an interesting and promising tool to monitor freshwater salinization by combining physiological and behavioural bioindicators. Copyright © 2016 Elsevier B.V. All rights

  1. Predicting the outcome of oral food challenges with hen's egg through skin test end-point titration.

    Science.gov (United States)

    Tripodi, S; Businco, A Di Rienzo; Alessandri, C; Panetta, V; Restani, P; Matricardi, P M

    2009-08-01

    Oral food challenge (OFC) is the diagnostic 'gold standard' of food allergies but it is laborious and time consuming. Attempts to predict a positive OFC through specific IgE assays or conventional skin tests so far gave suboptimal results. To test whether skin test with titration curves predict with enough confidence the outcome of an oral food challenge. Children (n=47; mean age 6.2 +/- 4.2 years) with suspected and diagnosed allergic reactions to hen's egg (HE) were examined through clinical history, physical examination, oral food challenge, conventional and end-point titrated skin tests with HE white extract and determination of serum specific IgE against HE white. Predictive decision points for a positive outcome of food challenges were calculated through receiver operating characteristic (ROC) analysis for HE white using IgE concentration, weal size and end-point titration (EPT). OFC was positive (Sampson's score >or=3) in 20/47 children (42.5%). The area under the ROC curve obtained with the EPT method was significantly bigger than the one obtained by measuring IgE-specific antibodies (0.99 vs. 0.83, P<0.05) and weal size (0.99 vs. 0.88, P<0.05). The extract's dilution that successfully discriminated a positive from a negative OFC (sensitivity 95%, specificity 100%) was 1 : 256, corresponding to a concentration of 5.9 microg/mL of ovotransferrin, 22.2 microg/mL of ovalbumin, and 1.4 microg/mL of lysozyme. EPT is a promising approach to optimize the use of skin prick tests and to predict the outcome of OFC with HE in children. Further studies are needed to test whether this encouraging finding can be extended to other populations and food allergens.

  2. Characterization and evaluation of a modified local lymph node assay using ATP content as a non-radio isotopic endpoint.

    Science.gov (United States)

    Idehara, Kenji; Yamagishi, Gaku; Yamashita, Kunihiko; Ito, Michio

    2008-01-01

    The murine local lymph node assay (LLNA) is an accepted and widely used method for assessing the skin-sensitizing potential of chemicals. Here, we describe a non-radio isotopic modified LLNA in which adenosine triphosphate (ATP) content is used as an endpoint instead of radioisotope (RI); the method is termed LLNA modified by Daicel based on ATP content (LLNA-DA). Groups of female CBA/JNCrlj mice were treated topically on the dorsum of both ears with test chemicals or a vehicle control on days 1, 2, and 3; an additional fourth application was conducted on day 7. Pretreatment with 1% sodium lauryl sulfate solution was performed 1 h before each application. On day 8, the amount of ATP in the draining auricular lymph nodes was measured as an alternative endpoint by the luciferin-luciferase assay in terms of bioluminescence (relative light units, RLU). A stimulation index (SI) relative to the concurrent vehicle control was derived based on the RLU value, and an SI of 3 was set as the cut-off value. Using the LLNA-DA method, 31 chemicals were tested and the results were compared with those of other test methods. The accuracy of LLNA-DA vs LLNA, guinea pig tests, and human tests was 93% (28/30), 80% (20/25), and 79% (15/19), respectively. The estimated concentration (EC) 3 value was calculated and compared with that of the original LLNA. It was found that the EC3 values obtained by LLNA-DA were almost equal to those obtained by the original LLNA. The SI value based on ATP content is similar to that of the original LLNA as a result of the modifications in the chemical treatment procedure, which contribute to improving the SI value. It is concluded that LLNA-DA is a promising non-RI alternative method for evaluating the skin-sensitizing potential of chemicals.

  3. Review of titanium dioxide nanoparticle phototoxicity: Developing a phototoxicity ratio to correct the endpoint values of toxicity tests

    Science.gov (United States)

    2015-01-01

    Abstract Titanium dioxide nanoparticles are photoactive and produce reactive oxygen species under natural sunlight. Reactive oxygen species can be detrimental to many organisms, causing oxidative damage, cell injury, and death. Most studies investigating TiO2 nanoparticle toxicity did not consider photoactivation and performed tests either in dark conditions or under artificial lighting that did not simulate natural irradiation. The present study summarizes the literature and derives a phototoxicity ratio between the results of nano‐titanium dioxide (nano‐TiO2) experiments conducted in the absence of sunlight and those conducted under solar or simulated solar radiation (SSR) for aquatic species. Therefore, the phototoxicity ratio can be used to correct endpoints of the toxicity tests with nano‐TiO2 that were performed in absence of sunlight. Such corrections also may be important for regulators and risk assessors when reviewing previously published data. A significant difference was observed between the phototoxicity ratios of 2 distinct groups: aquatic species belonging to order Cladocera, and all other aquatic species. Order Cladocera appeared very sensitive and prone to nano‐TiO2 phototoxicity. On average nano‐TiO2 was 20 times more toxic to non‐Cladocera and 1867 times more toxic to Cladocera (median values 3.3 and 24.7, respectively) after illumination. Both median value and 75% quartile of the phototoxicity ratio are chosen as the most practical values for the correction of endpoints of nano‐TiO2 toxicity tests that were performed in dark conditions, or in the absence of sunlight. Environ Toxicol Chem 2015;34:1070–1077. © 2015 The Author. Published by SETAC. PMID:25640001

  4. Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE): rationale and study design

    DEFF Research Database (Denmark)

    Parving, Hans-Henrik; Brenner, Barry M; McMurray, John J V

    2009-01-01

    BACKGROUND: Patients with type 2 diabetes are at increased risk of macro- and microvascular disease, and the presence of albuminuria and/or reduced kidney function further enhances macrovascular risk. Angiotensin-converting-enzyme inhibitors reduce both macro- and microvascular events, yet......, which will include three categories of high-risk patients with type 2 diabetes (aged > or =35 years): those with either urinary albumin/creatinine ratio (UACR) > or =200 mg/g; microalbuminuria (UACR) > or =20 or =30 ... whether dual RAAS blockade with the direct renin inhibitor aliskiren in combination with an ACEi or ARB will reduce major morbidity and mortality in a broad range of high-risk patients with type 2 diabetes....

  5. Summary statistics for end-point conditioned continuous-time Markov chains

    DEFF Research Database (Denmark)

    Hobolth, Asger; Jensen, Jens Ledet

    Continuous-time Markov chains are a widely used modelling tool. Applications include DNA sequence evolution, ion channel gating behavior and mathematical finance. We consider the problem of calculating properties of summary statistics (e.g. mean time spent in a state, mean number of jumps between...... two states and the distribution of the total number of jumps) for discretely observed continuous time Markov chains. Three alternative methods for calculating properties of summary statistics are described and the pros and cons of the methods are discussed. The methods are based on (i) an eigenvalue...... decomposition of the rate matrix, (ii) the uniformization method, and (iii) integrals of matrix exponentials. In particular we develop a framework that allows for analyses of rather general summary statistics using the uniformization method....

  6. Quality control for electron beam processing of polymeric materials by end-point analysis

    International Nuclear Information System (INIS)

    DeGraff, E.; McLaughlin, W.L.

    1981-01-01

    Properties of certain plastics, e.g. polytetrafluoroethylene, polyethylene, ethylene vinyl acetate copolymer, can be modified selectively by ionizing radiation. One of the advantages of this treatment over chemical methods is better control of the process and the end-product properties. The most convenient method of dosimetry for monitoring quality control is post-irradiation evaluation of the plastic itself, e.g., melt index and melt point determination. It is shown that by proper calibration in terms of total dose and sufficiently reproducible radiation effects, such product test methods provide convenient and meaningful analyses. Other appropriate standardized analytical methods include stress-crack resistance, stress-strain-to-fracture testing and solubility determination. Standard routine dosimetry over the dose and dose rate ranges of interest confirm that measured product end points can be correlated with calibrated values of absorbed dose in the product within uncertainty limits of the measurements. (author)

  7. Lack of Bystander Effects From High LET Radiation For Early Cytogenetic Endpoints.

    Energy Technology Data Exchange (ETDEWEB)

    Groesser, Torsten; Cooper, Brian; Rydberg, Bjorn

    2008-05-07

    The aim of this work was to study radiation-induced bystander effects for early cytogenetic end points in various cell lines using the medium transfer technique after exposure to high- and low-LET radiation. Cells were exposed to 20 MeV/ nucleon nitrogen ions, 968 MeV/nucleon iron ions, or 575 MeV/nucleon iron ions followed by transfer of the conditioned medium from the irradiated cells to unirradiated test cells. The effects studied included DNA double-strand break induction, {gamma}-H2AX focus formation, induction of chromatid breaks in prematurely condensed chromosomes, and micronucleus formation using DNA repair-proficient and -deficient hamster and human cell lines (xrs6, V79, SW48, MO59K and MO59J). Cell survival was also measured in SW48 bystander cells using X rays. Although it was occasionally possible to detect an increase in chromatid break levels using nitrogen ions and to see a higher number of {gamma}-H2AX foci using nitrogen and iron ions in xrs6 bystander cells in single experiments, the results were not reproducible. After we pooled all the data, we could not verify a significant bystander effect for any of these end points. Also, we did not detect a significant bystander effect for DSB induction or micronucleus formation in these cell lines or for clonogenic survival in SW48 cells. The data suggest that DNA damage and cytogenetic changes are not induced in bystander cells. In contrast, data in the literature show pronounced bystander effects in a variety of cell lines, including clonogenic survival in SW48 cells and induction of chromatid breaks and micronuclei in hamster cells. To reconcile these conflicting data, it is possible that the epigenetic status of the specific cell line or the precise culture conditions and medium supplements, such as serum, may be critical for inducing bystander effects.

  8. Measuring titratable alkalinity by single versus double endpoint titration: An evaluation in two cyprinodont species and implications for characterizing net H+ flux in aquatic organisms.

    Science.gov (United States)

    Brix, Kevin V; Wood, Chris M; Grosell, Martin

    2013-01-01

    In this study, Na(+) uptake and acid-base balance in the euryhaline pupfish Cyprinodon variegatus variegatus were characterized when fish were exposed to pH 4.5 freshwater (7mM Na(+)). Similar to the related cyprinodont, Fundulus heteroclitus, Na(+) uptake was significantly inhibited when exposed to low pH water. However, it initially appeared that C. v. variegatus increased apparent net acid excretion at low pH relative to circumneutral pH. This result is opposite to previous observations for F. heteroclitus under similar conditions where fish were observed to switch from apparent net H(+) excretion at circumneutral pH to apparent net H(+) uptake at low pH. Further investigation revealed disparate observations between these studies were the result of using double endpoint titrations to measure titratable alkalinity fluxes in the current study, while the earlier study utilized single endpoint titrations to measure these fluxes (i.e.,. Cyprinodon acid-base transport is qualitatively similar to Fundulus when characterized using single endpoint titrations). This led to a comparative investigation of these two methods. We hypothesized that either the single endpoint methodology was being influenced by a change in the buffer capacity of the water (e.g., mucus being released by the fish) at low pH, or the double endpoint methodology was not properly accounting for ammonia flux by the fish. A series of follow-up experiments indicated that buffer capacity of the water did not change significantly, that excretion of protein (a surrogate for mucus) was actually reduced at low pH, and that the double endpoint methodology does not properly account for NH(3) excretion by fish under low pH conditions. As a result, it overestimates net H(+) excretion during low pH exposure. After applying the maximum possible correction for this error (i.e., assuming that all ammonia is excreted as NH(3)), the double endpoint methodology indicates that net H(+) transport was reduced to

  9. Efficacy and Toxicity of Chemoradiotherapy Using Intensity-Modulated Radiotherapy for Unknown Primary of Head and Neck

    International Nuclear Information System (INIS)

    Sher, David J.; Balboni, Tracy A.; Haddad, Robert I.; Norris, Charles M.; Posner, Marshall R.; Wirth, Lori J.; Goguen, Laura A.; Annino, Donald; Tishler, Roy B.

    2011-01-01

    Purpose: No single standard treatment paradigm is available for head-and-neck squamous cell carcinoma of an unknown primary (HNCUP). Bilateral neck radiotherapy with mucosal axis irradiation is widely used, with or without chemotherapy and/or surgical resection. Intensity-modulated radiotherapy (IMRT) is a highly conformal method for delivering radiation that is becoming the standard of care and might reduce the long-term treatment-related sequelae. We report the Dana-Farber Cancer Institute experience with IMRT-based treatment for HNCUP. Patients and Materials: A retrospective study of all patients treated at the Dana-Farber Cancer Institute for HNCUP with IMRT between August 2004 and January 2009. The primary endpoint was overall survival; the secondary endpoints were locoregional and distant control, and acute and chronic toxicity. Results: A total of 24 patients with HNCUP were included. Of these patients, 22 had Stage N2 disease or greater. All patients underwent neck computed tomography, positron emission tomography-computed tomography, and examination under anesthesia with directed biopsies. Of the 24 patients, 22 received concurrent chemotherapy, and 7 (29%) also underwent induction chemotherapy. The median involved nodal dose was 70 Gy, and the median mucosal dose was 60 Gy. With a median follow-up of 2.1 years, the 2-year actuarial overall survival and locoregional control rate was 92% and 100%, respectively. Only 25% of the patients had Grade 2 xerostomia, although 11 patients (46%) required esophageal dilation for stricture. Conclusion: In a single-institution series, IMRT-based chemoradiotherapy for HNCUP was associated with superb overall survival and locoregional control. The xerostomia rates were promising, but the aggressive therapy was associated with significant rates of esophageal stenosis.

  10. Intensive speech and language therapy in patients with chronic aphasia after stroke: a randomised, open-label, blinded-endpoint, controlled trial in a health-care setting.

    Science.gov (United States)

    Breitenstein, Caterina; Grewe, Tanja; Flöel, Agnes; Ziegler, Wolfram; Springer, Luise; Martus, Peter; Huber, Walter; Willmes, Klaus; Ringelstein, E Bernd; Haeusler, Karl Georg; Abel, Stefanie; Glindemann, Ralf; Domahs, Frank; Regenbrecht, Frank; Schlenck, Klaus-Jürgen; Thomas, Marion; Obrig, Hellmuth; de Langen, Ernst; Rocker, Roman; Wigbers, Franziska; Rühmkorf, Christina; Hempen, Indra; List, Jonathan; Baumgaertner, Annette

    2017-04-15

    Treatment guidelines for aphasia recommend intensive speech and language therapy for chronic (≥6 months) aphasia after stroke, but large-scale, class 1 randomised controlled trials on treatment effectiveness are scarce. We aimed to examine whether 3 weeks of intensive speech and language therapy under routine clinical conditions improved verbal communication in daily-life situations in people with chronic aphasia after stroke. In this multicentre, parallel group, superiority, open-label, blinded-endpoint, randomised controlled trial, patients aged 70 years or younger with aphasia after stroke lasting for 6 months or more were recruited from 19 inpatient or outpatient rehabilitation centres in Germany. An external biostatistician used a computer-generated permuted block randomisation method, stratified by treatment centre, to randomly assign participants to either 3 weeks or more of intensive speech and language therapy (≥10 h per week) or 3 weeks deferral of intensive speech and language therapy. The primary endpoint was between-group difference in the change in verbal communication effectiveness in everyday life scenarios (Amsterdam-Nijmegen Everyday Language Test A-scale) from baseline to immediately after 3 weeks of treatment or treatment deferral. All analyses were done using the modified intention-to-treat population (those who received 1 day or more of intensive treatment or treatment deferral). This study is registered with ClinicalTrials.gov, number NCT01540383. We randomly assigned 158 patients between April 1, 2012, and May 31, 2014. The modified intention-to-treat population comprised 156 patients (78 per group). Verbal communication was significantly improved from baseline to after intensive speech and language treatment (mean difference 2·61 points [SD 4·94]; 95% CI 1·49 to 3·72), but not from baseline to after treatment deferral (-0·03 points [4·04]; -0·94 to 0·88; between-group difference Cohen's d 0·58; p=0·0004). Eight patients had

  11. Evaluation of Marijuana Compounds on Neuroimmune Endpoints in Experimental Autoimmune Encephalomyelitis.

    Science.gov (United States)

    Kaplan, Barbara L F

    2018-02-21

    Cannabinoid compounds refer to a group of more than 60 plant-derived compounds in Cannabis sativa, more commonly known as marijuana. Exposure to marijuana and cannabinoid compounds has been increasing due to increased societal acceptance for both recreational and possible medical use. Cannabinoid compounds suppress immune function, and while this could compromise one's ability to fight infections, immune suppression is the desired effect for therapies for autoimmune diseases. It is critical, therefore, to understand the effects and mechanisms by which cannabinoid compounds alter immune function, especially immune responses induced in autoimmune disease. Therefore, this unit will describe induction and assessment of the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS), and its potential alteration by cannabinoid compounds. The unit includes three approaches to induce EAE, two of which provide correlations to two forms of MS, and the third specifically addresses the role of autoreactive T cells in EAE. © 2018 by John Wiley & Sons, Inc. Copyright © 2018 John Wiley & Sons, Inc.

  12. Worldwide associations between air quality and health end-points: Are they meaningful?

    Directory of Open Access Journals (Sweden)

    Peter Wallner

    2014-10-01

    Full Text Available Objectives: The World Health Organization (WHO provides data on national indices of health, environment and economy. When we were asked, why air pollution is negatively correlated with cancer mortality, our first response (presumably the mortality data are not age-adjusted was not sufficient to explain the paradox. Material and Methods: A table including all-cause, cancer and childhood mortality, life expectancy, gross national product per person, smoking prevalence, physician density and particulate matter (PM10 per country (N = 193 was developed. For explorative purposes weighted cross-sectional multiple linear regressions models were built. Results: Air pollution is positively correlated with infant and overall mortality and negatively with life expectancy. This might not only depict a true causal effect of PM10 because air quality is also an indicator of a country’s prosperity and general state of environment. Cancer mortality is negatively correlated with PM10. However, this association turns positive when economic or health system indicators are controlled. Conclusions: The World Health Organization’s world-wide data sets demonstrate the large disparity of our world. A careful and professional approach is needed as interpretation is difficult, especially for lay persons. Therefore, with publicly available data WHO should also provide interpretation and guidance.

  13. Primary amenorrhea: diagnosis and management.

    Science.gov (United States)

    Marsh, Courtney A; Grimstad, Frances W

    2014-10-01

    Puberty is a defining time of many adolescents' lives. It is a series of events that includes thelarche, pubarche, and menarche. Primary amenorrhea is the absence of menarche. There are numerous etiologies including outflow tract obstructions, gonadal dysgenesis, and anomalies of the hypothalamic axis. This review's aims are to define primary amenorrhea and describe the various causes, their workups, associated comorbidities, and treatment options. At the end, a generalist should be able to perform an assessment of an adolescent who presents with primary amenorrhea and, if warranted, begin initial treatment.

  14. THROMBOLYSIS OR PRIMARY PCI FOR MYOCARDIAL INFARCTION WITH ST-SEGMENT ELEVATION? THE STREAM TRIAL (STRATEGIC REPERFUSION EARLY AFTER MYOCARDIAL INFARCTION

    Directory of Open Access Journals (Sweden)

    V. A. Sulimov

    2013-01-01

    Full Text Available Ambiguous data about comparability regarding clinical outcomes for prehospital thrombolysis, coupled with timely coronary angiography, and primary percutaneous coronary intervention (PCI in the early after acute ST-segment elevation myocardial infarction (STEMI, there are now.In the STREAM trial 1892 patients with STEMI diagnosed within 3 hours after onset of symptoms, and whom it was impossible to perform primary PCI within 1 h after the first medical contact, were randomly assigned into two treatment groups: a primary PCI b prehospital thrombolytic therapy with bolus tenecteplase (dose decreased by half in patients aged ≥75 years in combination with clopidogrel and enoxaparin followed by admission to the hospital, where it was possible to perform PCI. Emergency coronary angiography performed if thrombolysis failed. Coronary angiography and PCI of the infarct-related artery were performed in the period from 6 to 24 hours after randomization and thrombolytic therapy in the case of an effective thrombolysis. Primary endpoints include a composite of death, shock, congestive heart failure, or reinfarction up to 30 days.The primary endpoint occurred in 116 of 939 patients (12.4 % of the thrombolysis group and in 135 of 943 patients (14.3% of the primary PCI group (relative risk in the group thrombolysis 0.86, 95% confidence interval 0.68-1.09, p=0.21. Emergency angiography was required in 36.3% of patients in the thrombolysis, and the remaining patients, coronary angiography and PCI were performed at a mean of 17 hours after randomization and thrombolytic therapy. Thrombolysis group had more intracranial hemorrhages than primary PCI group (1.0% vs 0.2%, p=0.04; after correction protocol and dose reduction by half of tenecteplase in patients ≥75 years: 0.5% vs. 0.3%, p=0.45. The rate of non- intracranial bleeding in two treatment groups did not differ.Prehospital thrombolysis followed by coronary angiography and timely PCI provide effective

  15. A phase II trial with bevacizumab and irinotecan for patients with primary brain tumors and progression after standard therapy

    DEFF Research Database (Denmark)

    Møller, Søren; Grunnet, Kirsten; Hansen, Steinbjørn

    2012-01-01

    The combination of irinotecan and bevacizumab has shown efficacy in the treatment of recurrent glioblastoma multiforme (GBM). A prospective, phase II study of 85 patients with various recurrent brain tumors was carried out. Primary endpoints were progression free survival (PFS) and response rate....

  16. Actin dynamics at focal adhesions: a common endpoint and putative therapeutic target for proteinuric kidney diseases.

    Science.gov (United States)

    Sever, Sanja; Schiffer, Mario

    2018-06-01

    Proteinuria encompasses diverse causes including both genetic diseases and acquired forms such as diabetic and hypertensive nephropathy. The basis of proteinuria is a disturbance in size selectivity of the glomerular filtration barrier, which largely depends on the podocyte: a terminally differentiated epithelial cell type covering the outer surface of the glomerulus. Compromised podocyte structure is one of the earliest signs of glomerular injury. The phenotype of diverse animal models and podocyte cell culture firmly established the essential role of the actin cytoskeleton in maintaining functional podocyte structure. Podocyte foot processes, actin-based membrane extensions, contain 2 molecularly distinct "hubs" that control actin dynamics: a slit diaphragm and focal adhesions. Although loss of foot processes encompasses disassembly of slit diaphragm multiprotein complexes, as long as cells are attached to the glomerular basement membrane, focal adhesions will be the sites in which stress due to filtration flow is counteracted by forces generated by the actin network in foot processes. Numerous studies within last 20 years have identified actin binding and regulatory proteins as well as integrins as essential components of signaling and actin dynamics at focal adhesions in podocytes, suggesting that some of them may become novel, druggable targets for proteinuric kidney diseases. Here we review evidence supporting the idea that current treatments for chronic kidney diseases beneficially and directly target the podocyte actin cytoskeleton associated with focal adhesions and suggest that therapeutic reagents that target the focal adhesion-regulated actin cytoskeleton in foot processes have potential to modernize treatments for chronic kidney diseases. Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

  17. Quantitative Evidence for Revising the Definition of Primary Graft Dysfunction after Lung Transplant.

    Science.gov (United States)

    Cantu, Edward; Diamond, Joshua M; Suzuki, Yoshikazu; Lasky, Jared; Schaufler, Christian; Lim, Brian; Shah, Rupal; Porteous, Mary; Lederer, David J; Kawut, Steven M; Palmer, Scott M; Snyder, Laurie D; Hartwig, Matthew G; Lama, Vibha N; Bhorade, Sangeeta; Bermudez, Christian; Crespo, Maria; McDyer, John; Wille, Keith; Orens, Jonathan; Shah, Pali D; Weinacker, Ann; Weill, David; Wilkes, David; Roe, David; Hage, Chadi; Ware, Lorraine B; Bellamy, Scarlett L; Christie, Jason D

    2018-01-15

    Primary graft dysfunction (PGD) is a form of acute lung injury that occurs after lung transplantation. The definition of PGD was standardized in 2005. Since that time, clinical practice has evolved, and this definition is increasingly used as a primary endpoint for clinical trials; therefore, validation is warranted. We sought to determine whether refinements to the 2005 consensus definition could further improve construct validity. Data from the Lung Transplant Outcomes Group multicenter cohort were used to compare variations on the PGD definition, including alternate oxygenation thresholds, inclusion of additional severity groups, and effects of procedure type and mechanical ventilation. Convergent and divergent validity were compared for mortality prediction and concurrent lung injury biomarker discrimination. A total of 1,179 subjects from 10 centers were enrolled from 2007 to 2012. Median length of follow-up was 4 years (interquartile range = 2.4-5.9). No mortality differences were noted between no PGD (grade 0) and mild PGD (grade 1). Significantly better mortality discrimination was evident for all definitions using later time points (48, 72, or 48-72 hours; P definition can be simplified by combining lower PGD grades. Construct validity of grading was present regardless of transplant procedure type or use of mechanical ventilation. Additional severity categories had minimal impact on mortality or biomarker discrimination.

  18. Cancer of unknown primary

    DEFF Research Database (Denmark)

    Dyrvig, Anne-Kirstine; Yderstræde, Knud Bonnet; Gerke, Oke

    2017-01-01

    210 (38.7%) had a CUP diagnosis confirmed. Within the cohort, 347 patients (64.0%) had a registration in CR matching with the NPR registration. Exposure to diagnostic procedures included biopsy (n = 439, 81.0%) and image modalities (n = 532, 98.2%). Survival was poor with 67 (12.4%) individuals alive...... after 4 years.The validity of a CUP diagnosis in NPR was low when using data from CR as reference. More than half the suspected CUP patients had a previous cancer diagnosis with CUP being the most frequent. Patients were diagnosed in compliance with guidelines indicating high external validity, but less...... than 1 quarter had their primary identified and the 1-year survival was approximately 20%. Research is needed to develop efficacious methods for primary detection....

  19. Basics of primary immunodeficiencies

    Directory of Open Access Journals (Sweden)

    Claudia Hernández-Martínez

    2016-05-01

    Full Text Available Primary immunodeficiencies (PID are a heterogeneous group of inherited disorders, the etiology are the defects in the development or function of the immune system. The principal PID manifestations are the infections in early age, malignancy and diseases of immune dysregulation as autoimmunity and allergy. PIDs are genetics disorders and most of them are inherited as autosomal recessive, also this group of diseases is more prevalent in males and in childhood. The antibody immunodeficiency is the PID more common in adults. The more frequent disorders are the infections in the respiratory tract, abscesses, candidiasis, diarrhea, BCGosis etc. Initial approach included a complete blood count and quantification of immunoglobulins. The delay in diagnosis could be explained due to a perception that the recurrent infections are normal process or think that they are exclusively of childhood. The early diagnosis of PID by primary care physicians is important to opportune treatment and better prognosis.

  20. Investigation of Rheological Impacts on Sludge Batch 3 as Insoluble Solids and Wash Endpoints are Adjusted

    International Nuclear Information System (INIS)

    Fellinger, T. L.

    2005-01-01

    approximately a factor of 1.6 to 4 times higher for yield stress and 2.6 to 4 times hi gher for the plastic viscosity over a similar range of insoluble solids loadings. The difference noted between the radioactive and simulant samples could be due to several factors including particle size, thermal treatment (i.e. aging of the sludge), shear history, etc

  1. Significant prognosticators after primary radiotherapy in 903 nondisseminated nasopharyngeal carcinoma evaluated by computer tomography

    International Nuclear Information System (INIS)

    Teo, P.; Yu, P.; Lee, W.Y.; Leung, S.F.; Kwan, W.H.; Yu, K.H.; Choi, P.; Johnson, P.J.

    1996-01-01

    Purpose: To evaluate the significant prognosticators in nasopharyngeal carcinoma (NPC). Methods and Materials: From 1984 to 1989, 903 treatment-naive nondisseminated (MO) NPC were given primary radical radiotherapy to 60-62.5 Gy in 6 weeks. All patients had computed tomographic (CT) and endoscopic evaluation of the primary tumor. Potentially significant parameters (the patient's age and sex, the anatomical structures infiltrated by the primary lesion, the cervical nodal characteristics, the tumor histological subtypes, and various treatment variables were analyzed by both monovariate and multivariate methods for each of the five clinical endpoints: actuarial survival, disease-free survival, free from distant metastasis, free from local failure, and free from regional failure. Results: The significant prognosticators predicting for an increased risk of distant metastases and poorer survival included male sex, skull base and cranial nerve(s) involvement, advanced Ho's N level, and presence of fixed or partially fixed nodes or nodes contralateral to the side of the bulk of the nasopharyngeal primary. Advanced patient age led to significantly worse survival and poorer local tumor control. Local and regional failures were both increased by tumor infiltrating the skull base and/or the cranial nerves. In addition, regional failure was increased significantly by advancing Ho's N level. Parapharyngeal tumor involvement was the strongest independent prognosticator that determined distant metastasis and survival rates in the absence of the overriding prognosticators of skull base infiltration, cranial nerve(s) palsy, and cervical nodal metastasis. Conclusions: The significant prognosticators are delineated after the advent of CT and these should form the foundation of the modern stage classification for NPC

  2. Environmental risk assessment of triclosan and ibuprofen in marine sediments using individual and sub-individual endpoints.

    Science.gov (United States)

    Pusceddu, F H; Choueri, R B; Pereira, C D S; Cortez, F S; Santos, D R A; Moreno, B B; Santos, A R; Rogero, J R; Cesar, A

    2018-01-01

    The guidelines for the Environmental Risk Assessment (ERA) of pharmaceuticals and personal care products (PPCP) recommend the use of standard ecotoxicity assays and the assessment of endpoints at the individual level to evaluate potential effects of PPCP on biota. However, effects at the sub-individual level can also affect the ecological fitness of marine organisms chronically exposed to PPCP. The aim of the current study was to evaluate the environmental risk of two PPCP in marine sediments: triclosan (TCS) and ibuprofen (IBU), using sub-individual and developmental endpoints. The environmental levels of TCS and IBU were quantified in marine sediments from the vicinities of the Santos submarine sewage outfall (Santos Bay, São Paulo, Brazil) at 15.14 and 49.0 ng g -1 , respectively. A battery (n = 3) of chronic bioassays (embryo-larval development) with a sea urchin (Lytechinus variegatus) and a bivalve (Perna perna) were performed using two exposure conditions: sediment-water interface and elutriates. Moreover, physiological stress through the Neutral Red Retention Time Assay (NRRT) was assessed in the estuarine bivalve Mytella charruana exposed to TCS and IBU spiked sediments. These compounds affected the development of L. variegatus and P. perna (75 ng g -1 for TCS and 15 ng g -1 for IBU), and caused a significant decrease in M. charruana lysosomal membrane stability at environmentally relevant concentrations (0.08 ng g -1 for TCS and 0.15 ng g -1 for IBU). Chemical and ecotoxicological data were integrated and the risk quotient estimated for TCS and IBU were higher than 1.0, indicating a high environmental risk of these compounds in sediments. These are the first data of sediment risk assessment of pharmaceuticals and personal care products of Latin America. In addition, the results suggest that the ERA based only on individual-level and standard toxicity tests may overlook other biological effects that can affect the health of marine organisms

  3. Cardiac neuronal imaging with 123I-meta-iodobenzylguanidine in heart failure: implications of endpoint selection and quantitative analysis on clinical decisions

    International Nuclear Information System (INIS)

    Petretta, Mario; Pellegrino, Teresa; Cuocolo, Alberto

    2014-01-01

    There are a number of radiopharmaceuticals that can be used to investigate autonomic neuronal functions. Among these, the norepinephrine analogue meta-iodobenzylguanidine (MIBG) labelled with 123 I has been widely used and validated as a marker of adrenergic neuron function. The first study addressing the prognostic value of 123 I-MIBG imaging in heart failure (HF) was that of Merlet et al. in 90 patients suffering from either ischaemic or idiopathic cardiomyopathy. After publication of this study, more recent studies have indicated that patients with HF and decreased late heart-to-mediastinum (H/M) ratio or increased myocardial MIBG washout have a worse prognosis than those with normal quantitative myocardial MIBG parameters. However, MIBG scintigraphy has still to reach widespread clinical application mainly because of the value of other cheaper variables such as left ventricular (LV) ejection fraction and brain natriuretic peptide (BNP) plasma levels. The possibility that the detection of mechanical dyssynchrony by innervation imaging might identify patients who would benefit from resynchronization pacing is another area of research interest. In 2010, the landmark AdreView Myocardial Imaging for Risk Evaluation in Heart Failure (ADMIRE-HF) study was published. This trial consisted of two identical open-label phase III studies enrolling patients in 96 sites in North America and Europe to provide prospective validation of the prognostic role of quantitation of sympathetic cardiac innervation using MIBG. The primary endpoint was the relationship between late HIM ratio and time-to-occurrence of the first event among a combination of HF progression, potentially life-threatening arrhythmic event, and cardiac death. The authors found that a HIM ratio <1.6 provided prognostic information beyond LV ejection fraction, BNP, and New York Heart Association (NYHA) functional class at the time of enrolment. In a recent article in this journal, Parker et al. present the results

  4. Cardiac neuronal imaging with {sup 123}I-meta-iodobenzylguanidine in heart failure: implications of endpoint selection and quantitative analysis on clinical decisions

    Energy Technology Data Exchange (ETDEWEB)

    Petretta, Mario [University Federico II, Department of Translational Medicine, Naples (Italy); Pellegrino, Teresa [National Council of Research, Institute of Biostructure and Bioimaging, Naples (Italy); Cuocolo, Alberto [University Federico II, Department of Advanced Biomedical Sciences, Naples (Italy)

    2014-09-15

    There are a number of radiopharmaceuticals that can be used to investigate autonomic neuronal functions. Among these, the norepinephrine analogue meta-iodobenzylguanidine (MIBG) labelled with {sup 123}I has been widely used and validated as a marker of adrenergic neuron function. The first study addressing the prognostic value of {sup 123}I-MIBG imaging in heart failure (HF) was that of Merlet et al. in 90 patients suffering from either ischaemic or idiopathic cardiomyopathy. After publication of this study, more recent studies have indicated that patients with HF and decreased late heart-to-mediastinum (H/M) ratio or increased myocardial MIBG washout have a worse prognosis than those with normal quantitative myocardial MIBG parameters. However, MIBG scintigraphy has still to reach widespread clinical application mainly because of the value of other cheaper variables such as left ventricular (LV) ejection fraction and brain natriuretic peptide (BNP) plasma levels. The possibility that the detection of mechanical dyssynchrony by innervation imaging might identify patients who would benefit from resynchronization pacing is another area of research interest. In 2010, the landmark AdreView Myocardial Imaging for Risk Evaluation in Heart Failure (ADMIRE-HF) study was published. This trial consisted of two identical open-label phase III studies enrolling patients in 96 sites in North America and Europe to provide prospective validation of the prognostic role of quantitation of sympathetic cardiac innervation using MIBG. The primary endpoint was the relationship between late HIM ratio and time-to-occurrence of the first event among a combination of HF progression, potentially life-threatening arrhythmic event, and cardiac death. The authors found that a HIM ratio <1.6 provided prognostic information beyond LV ejection fraction, BNP, and New York Heart Association (NYHA) functional class at the time of enrolment. In a recent article in this journal, Parker et al. present

  5. Efficacy of interventions to increase the uptake of chlamydia screening in primary care: a systematic review

    Directory of Open Access Journals (Sweden)

    Donovan Basil

    2011-08-01

    Full Text Available Abstract Background As most genital chlamydia infections are asymptomatic, screening is the main way to detect and cases for treatment. We undertook a systematic review of studies assessing the efficacy of interventions for increasing the uptake of chlamydia screening in primary care. Methods We reviewed studies which compared chlamydia screening in the presence and the absence of an intervention. The primary endpoints were screening rate or total tests. Results We identified 16 intervention strategies; 11 were randomised controlled trials and five observational studies, 10 targeted females only, five both males and females, and one males only. Of the 15 interventions among females, six were associated with significant increases in screening rates at the 0.05 level including a multifaceted quality improvement program that involved provision of a urine jar to patients at registration (44% in intervention clinics vs. 16% in the control clinic; linking screening to routine Pap smears (6.9% vs. 4.5%, computer alerts for doctors (12.2% vs. 10.6%; education workshops for clinic staff; internet-based continuing medical education (15.5% vs. 12.4%; and free sexual health consultations (16.8% vs. 13.2%. Of the six interventions targeting males, two found significant increases including the multifaceted quality improvement program in which urine jars were provided to patients at registration (45% vs. 15%; and the offering by doctors of a test to all presenting young male clients, prior to consultation (29 vs. 4%. Conclusions Interventions that promoted the universal offer of a chlamydia test in young people had the greatest impact on increasing screening in primary care.

  6. Ranking of patient and surgeons' perspectives for endpoints in randomized controlled trials--lessons learned from the POVATI trial [ISRCTN 60734227].

    Science.gov (United States)

    Fischer, Lars; Deckert, Andreas; Diener, Markus K; Zimmermann, Johannes B; Büchler, Markus W; Seiler, Christoph M

    2011-10-01

    Surgical trials focus mainly on mortality and morbidity rates, which may be not the most important endpoints from the patient's perspective. Evaluation of expectations and needs of patients enrolled in clinical trials can be analyzed using a procedure called ranking. Within the Postsurgical Pain Outcome of Vertical and Transverse Abdominal Incision randomized trial (POVATI), the perspectives of participating patients and surgeons were assessed as well as the influence of the surgical intervention on patients' needs. All included patients of the POVATI trial were asked preoperatively and postoperatively to rank predetermined outcome variables concerning the upcoming surgical procedure (e.g., pain, complication, cosmetic result) hierarchically according to their importance. Preoperatively, the surgeons were asked to do the same. One hundred eighty two out of 200 randomized patients (71 females, 111 males; mean age 59 years) returned the ranking questionnaire preoperatively and 152 patients (67 females, 85 males; mean age 60 years) on the day of discharge. There were no differences between the two groups with respect to the distribution of ranking variables (p > 0.05). Thirty-five surgeons (7 residents, 6 fellows, and 22 consultants) completed the same ranking questionnaire. The order of the four most important ranking variables for both patients and surgeons were death, avoiding of postoperative complications, avoiding of intraoperative complications, and pain. Surgeons ranked the variable "cosmetic result" significantly as more important compared to patients (p = 0.034, Fisher's exact test). Patients and surgeons did not differ in ranking predetermined outcomes in the POVATI trial. Only the variable "cosmetic result" is significantly more important from the surgeon's than from the patient's perspective. Ranking of outcomes might be a beneficial tool and can be a proper addition to RCTs.

  7. Toxicity of the main electronic cigarette components, propylene glycol, glycerin, and nicotine, in Sprague-Dawley rats in a 90-day OECD inhalation study complemented by molecular endpoints.

    Science.gov (United States)

    Phillips, Blaine; Titz, Bjoern; Kogel, Ulrike; Sharma, Danilal; Leroy, Patrice; Xiang, Yang; Vuillaume, Grégory; Lebrun, Stefan; Sciuscio, Davide; Ho, Jenny; Nury, Catherine; Guedj, Emmanuel; Elamin, Ashraf; Esposito, Marco; Krishnan, Subash; Schlage, Walter K; Veljkovic, Emilija; Ivanov, Nikolai V; Martin, Florian; Peitsch, Manuel C; Hoeng, Julia; Vanscheeuwijck, Patrick

    2017-11-01

    While the toxicity of the main constituents of electronic cigarette (ECIG) liquids, nicotine, propylene glycol (PG), and vegetable glycerin (VG), has been assessed individually in separate studies, limited data on the inhalation toxicity of them is available when in mixtures. In this 90-day subchronic inhalation study, Sprague-Dawley rats were nose-only exposed to filtered air, nebulized vehicle (saline), or three concentrations of PG/VG mixtures, with and without nicotine. Standard toxicological endpoints were complemented by molecular analyses using transcriptomics, proteomics, and lipidomics. Compared with vehicle exposure, the PG/VG aerosols showed only very limited biological effects with no signs of toxicity. Addition of nicotine to the PG/VG aerosols resulted in effects in line with nicotine effects observed in previous studies, including up-regulation of xenobiotic enzymes (Cyp1a1/Fmo3) in the lung and metabolic effects, such as reduced serum lipid concentrations and expression changes of hepatic metabolic enzymes. No toxicologically relevant effects of PG/VG aerosols (up to 1.520  mg PG/L + 1.890 mg VG/L) were observed, and no adverse effects for PG/VG/nicotine were observed up to 438/544/6.6 mg/kg/day. This study demonstrates how complementary systems toxicology analyses can reveal, even in the absence of observable adverse effects, subtoxic and adaptive responses to pharmacologically active compounds such as nicotine. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  8. The Traumatic Brain Injury Endpoints Development (TED) Initiative: Progress on a Public-Private Regulatory Collaboration to Accelerate Diagnosis and Treatment of Traumatic Brain Injury.

    Science.gov (United States)

    Manley, Geoffrey T; MacDonald, Christine L; Markowitz, Amy; Stephenson, Diane; Robbins, Ann; Gardner, Raquel C; Winkler, Ethan A; Bodien, Yelena; Taylor, Sabrina; Yue, John K; Kannan, Lakshmi; Kumar, Allison; McCrea, Michael; Wang, Kevin K W

    2017-03-31

    The Traumatic Brain Injury Endpoints Development (TED) Initiative is a 5-year, Department of Defense (DoD) funded project that is working toward the ultimate goal of developing better designed clinical trials, leading to more precise diagnosis, and effective treatments for traumatic brain injury (TBI). TED is comprised of leading academic clinician-scientists, along with innovative industry leaders in biotechnology and imaging technology, patient advocacy organizations, and philanthropists, working collaboratively with regulatory authorities, specifically the US Food and Drug Administration (FDA). The goals of the TED Initiative are to gain consensus and validation of TBI clinical outcome assessment measures and biomarkers for endorsement by global regulatory agencies for use in drug and device development processes. This manuscript summarizes the Initiative's Stage 1 progress over the first 18 months, including intensive engagement with a number of FDA divisions responsible for review and validation of biomarkers and clinical outcome assessments, progression into the prequalification phase of FDA's Medical Device Development Tool program for a candidate set of neuroimaging biomarkers, and receipt of FDA's Recognition of Research Importance Letter regarding TBI. Other signal achievements relate to the creation of the TED Metadataset, harmonizing study measures across eight major TBI studies, and the leadership role played by TED investigators in the conversion of the NINDS TBI Common Data Elements (CDEs) to Clinical Data Interchange Standards Consortium (CDISC) standards. This paper frames both the near-term expectations and the Initiative's long-term vision to accelerate approval of treatments for patients affected by TBI in urgent need of effective therapies.

  9. The toxicity of chlorpyrifos on the early life stage of zebrafish: a survey on the endpoints at development, locomotor behavior, oxidative stress and immunotoxicity.

    Science.gov (United States)

    Jin, Yuanxiang; Liu, Zhenzhen; Peng, Tao; Fu, Zhengwei

    2015-04-01

    Chlorpyrifos (CPF) is one of the most toxic pesticides in aquatic ecosystem, but its toxicity mechanisms to fish are still not fully understood. This study examined the toxicity targets of CPF in early life stage of zebrafish on the endpoints at developmental toxicity, neurotoxicity, oxidative stress and immunotoxicity. Firstly, CPF exposure decreased the body length, inhibited the hatchability and heart rate, and resulted in a number of morphological abnormalities, primarily spinal deformities (SD) and pericardial edema (PE), in larval zebrafish. Secondly, the free swimming activities and the swimming behaviors of the larvae in response to the stimulation of light-to-dark photoperiod transition were significantly influenced by the exposure to 100 and 300 μg/L CPF. In addition, the activity of acetylcholinesterase (AChE) and the transcription of some genes related to neurotoxicity were also influenced by CPF exposure. Thirdly, CPF exposure induced oxidative stress in the larval zebrafish. The malondialdehyde (MDA) levels increased and the glutathione (GSH) contents decreased significantly in a concentration-dependent manner after the exposure to CPF for 96 hours post fertilization (hpf). CPF affected not only the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX) and glutathione S-transferase (GST), but also the transcriptional levels of their respective genes. Finally, the mRNA levels of the main cytokines including tumor necrosis factor α (Tnfα), interferon (Ifn), interleukin-1 beta (Il-1β), interleukin 6 (Il6), complement factor 4 (C4) in the larvae increased significantly after the exposure to 100 or 300 μg/L CPF for 96 hpf, suggesting that the innate immune system disturbed by CPF in larvae. Taken together, our results suggested that CPF had the potential to cause developmental toxicity, behavior alterations, oxidative stress and immunotoxicity in the larval zebrafish. Copyright © 2015 Elsevier Ltd. All rights

  10. Towards free 3D end-point control for robotic-assisted human reaching using binocular eye tracking.

    Science.gov (United States)

    Maimon-Dror, Roni O; Fernandez-Quesada, Jorge; Zito, Giuseppe A; Konnaris, Charalambos; Dziemian, Sabine; Faisal, A Aldo

    2017-07-01

    Eye-movements are the only directly observable behavioural signals that are highly correlated with actions at the task level, and proactive of body movements and thus reflect action intentions. Moreover, eye movements are preserved in many movement disorders leading to paralysis (or amputees) from stroke, spinal cord injury, Parkinson's disease, multiple sclerosis, and muscular dystrophy among others. Despite this benefit, eye tracking is not widely used as control interface for robotic interfaces in movement impaired patients due to poor human-robot interfaces. We demonstrate here how combining 3D gaze tracking using our GT3D binocular eye tracker with custom designed 3D head tracking system and calibration method enables continuous 3D end-point control of a robotic arm support system. The users can move their own hand to any location of the workspace by simple looking at the target and winking once. This purely eye tracking based system enables the end-user to retain free head movement and yet achieves high spatial end point accuracy in the order of 6 cm RMSE error in each dimension and standard deviation of 4 cm. 3D calibration is achieved by moving the robot along a 3 dimensional space filling Peano curve while the user is tracking it with their eyes. This results in a fully automated calibration procedure that yields several thousand calibration points versus standard approaches using a dozen points, resulting in beyond state-of-the-art 3D accuracy and precision.

  11. End-point effector stress mediators in neuroimmune interactions: their role in immune system homeostasis and autoimmune pathology.

    Science.gov (United States)

    Dimitrijevic, Mirjana; Stanojevic, Stanislava; Kustrimovic, Natasa; Leposavic, Gordana

    2012-04-01

    Much evidence has identified a direct anatomical and functional link between the brain and the immune system, with glucocorticoids (GCs), catecholamines (CAs), and neuropeptide Y (NPY) as its end-point mediators. This suggests the important role of these mediators in immune system homeostasis and the pathogenesis of inflammatory autoimmune diseases. However, although it is clear that these mediators can modulate lymphocyte maturation and the activity of distinct immune cell types, their putative role in the pathogenesis of autoimmune disease is not yet completely understood. We have contributed to this field by discovering the influence of CAs and GCs on fine-tuning thymocyte negative selection and, in particular, by pointing to the putative CA-mediated mechanisms underlying this influence. Furthermore, we have shown that CAs are implicated in the regulation of regulatory T-cell development in the thymus. Moreover, our investigations related to macrophage biology emphasize the complex interaction between GCs, CAs and NPY in the modulation of macrophage functions and their putative significance for the pathogenesis of autoimmune inflammatory diseases.

  12. A structured approach to Exposure Based Waiving of human health endpoints under REACH developed in the OSIRIS project.

    Science.gov (United States)

    Marquart, Hans; Meijster, Tim; Van de Bovenkamp, Marja; Ter Burg, Wouter; Spaan, Suzanne; Van Engelen, Jacqueline

    2012-03-01

    Exposure Based Waiving (EBW) is one of the options in REACH when there is insufficient hazard data on a specific endpoint. Rules for adaptation of test requirements are specified and a general option for EBW is given via Appen