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Sample records for response secondary endpoints

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

    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.

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

    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.

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

    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

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

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

    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.

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

    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.

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

    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.

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

    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.

  9. B cell increases and ex vivo IL-2 production as secondary endpoints for the detection of sensitizers in non-radioisotopic local lymph node assay using flow cytometry.

    Jung, Kyoung-Mi; Jang, Won-Hee; Lee, Yong-Kyoung; Yum, Young Na; Sohn, Soojung; Kim, Bae-Hwan; Chung, Jin-Ho; Park, Young-Ho; Lim, Kyung-Min

    2012-03-25

    Non-radioisotopic local lymph node assay (LLNA) using 5-bromo-2'-deoxyuridine (BrdU) with flow cytometry (FCM) is gaining attention since it is free from the regulatory issues in traditional LLNA (tLLNA) accompanying in vivo uses of radioisotope, (3)H-thymidine. However, there is also concern over compromised performance of non-radioisotopic LLNA, raising needs for additional endpoints to improve the accuracy. With the full 22 reference substances enlisted in OECD Test Guideline No. 429, we evaluated the performance of LLNA:BrdU-FCM along with the concomitant measurements of B/T cell ratio and ex vivo cytokine production from isolated lymph node cells (LNCs) to examine the utility of these markers as secondary endpoints. Mice (Balb/c, female) were topically treated with substances on both ears for 3 days and then, BrdU was intraperitoneally injected on day 5. After a day, lymph nodes were isolated and undergone FCM to determine BrdU incorporation and B/T cell sub-typing with B220+ and CD3e+. Ex vivo cytokine production by LNCs was measured such as IL-2, IL-4, IL-6, IL-12, IFN-γ, MCP-1, GM-CSF and TNFα. Mice treated with sensitizers showed preferential increases in B cell population and the selective production of IL-2, which matched well with the increases in BrdU incorporation. When compared with guinea pig or human data, BrdU incorporation, B cell increase and IL-2 production ex vivo could successfully identify sensitizers with the accuracy comparable to tLLNA, suggesting that these markers may be useful for improving the accuracy of LLNA:BrdU-FCM or as stand-alone non-radioisotopic endpoints. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

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

    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

  11. QUANTITATION OF MOLECULAR ENDPOINTS FOR THE DOSE-RESPONSE COMPONENT OF CANCER RISK ASSESSMENT

    Cancer risk assessment involves the steps of hazard identification, dose-response assessment, exposure assessment and risk characterization. The rapid advances in the use of molecular biology approaches has had an impact on all four components, but the greatest overall current...

  12. Dose-response regressions for algal growth and similar continuous endpoints: Calculation of effective concentrations

    Christensen, Erik R.; Kusk, Kresten Ole; Nyholm, Niels

    2009-01-01

    We derive equations for the effective concentration giving 10% inhibition (EC10) with 95% confidence limits for probit (log-normal), Weibull, and logistic dose -responsemodels on the basis of experimentally derived median effective concentrations (EC50s) and the curve slope at the central point (50......% inhibition). For illustration, data from closed, freshwater algal assays are analyzed using the green alga Pseudokirchneriella subcapitata with growth rate as the response parameter. Dose-response regressions for four test chemicals (tetraethylammonium bromide, musculamine, benzonitrile, and 4...... regression program with variance weighting and proper inverse estimation. The Weibull model provides the best fit to the data for all four chemicals. Predicted EC10s (95% confidence limits) from our derived equations are quite accurate; for example, with 4-4-(trifluoromethyl)phenoxy-phenol and the probit...

  13. Improvement in latent variable indirect response modeling of multiple categorical clinical endpoints: application to modeling of guselkumab treatment effects in psoriatic patients.

    Hu, Chuanpu; Randazzo, Bruce; Sharma, Amarnath; Zhou, Honghui

    2017-10-01

    Exposure-response modeling plays an important role in optimizing dose and dosing regimens during clinical drug development. The modeling of multiple endpoints is made possible in part by recent progress in latent variable indirect response (IDR) modeling for ordered categorical endpoints. This manuscript aims to investigate the level of improvement achievable by jointly modeling two such endpoints in the latent variable IDR modeling framework through the sharing of model parameters. This is illustrated with an application to the exposure-response of guselkumab, a human IgG1 monoclonal antibody in clinical development that blocks IL-23. A Phase 2b study was conducted in 238 patients with psoriasis for which disease severity was assessed using Psoriasis Area and Severity Index (PASI) and Physician's Global Assessment (PGA) scores. A latent variable Type I IDR model was developed to evaluate the therapeutic effect of guselkumab dosing on 75, 90 and 100% improvement of PASI scores from baseline and PGA scores, with placebo effect empirically modeled. The results showed that the joint model is able to describe the observed data better with fewer parameters compared with the common approach of separately modeling the endpoints.

  14. The cytotoxicity of polycationic iron oxide nanoparticles: Common endpoint assays and alternative approaches for improved understanding of cellular response mechanism

    Hoskins Clare

    2012-04-01

    Our findings indicate that common in vitro cell endpoint assays do not give detailed and complete information on cellular state and it is essential to explore novel approaches and carry out more in-depth studies to elucidate cellular response mechanism to magnetic nanoparticles.

  15. Radiosensitivity of antibody responses and radioresistant secondary tetanus antitoxin responses

    Stoner, R.; Terres, G.; Cottier, H.; Hess, M.

    1976-01-01

    Primary tetanus antitoxin responses were increasingly repressed in mice when gamma radiation doses of 100 to 400 rads were delivered by whole-body exposure prior to immunization with fluid tetanus toxoid (FTT). Nearly normal secondary antitoxin responses were obtained in mice exposed to 600 rads of gamma radiation 4 days after secondary antigenic stimulation with FTT. A rapid transition from radiosensitivity of the antibody-forming system on days 1 to 3 was followed by relative radioresistance on day 4 after the booster injection of toxoid. Studies on lymphoid cellular kinetics in popliteal lymph nodes after injection of 3 H--thymidine ( 3 H--TdR) and incorporation of 3 H--L-histidine into circulating antitoxin were carried out. Analysis of tritium radioactivity in antigen--antibody precipitates of serums 2 hr after injection of the labeled amino acid revealed maximum incorporation into antibody around day 7 after the booster in nonirradiated controls and about day 12, i.e., 8 days after irradiation, in experimental mice. The shift from radiosensitivity to relative radioresistance was attributed to a marked peak of plasma-cell proliferation in the medulla of lymph nodes on day 3. Many medullary plasma cells survived and continued to proliferate after exposure to radiation. Germinal centers were destroyed by radiation within 1 day. Since antibody formation continued after exposure to radiation and after the loss of germinal centers, this supports the view that germinal-center cells were involved more in the generation of memory cells than in antibody synthesis

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

    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

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

    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

  18. Responsibility for Racism in the Everyday Talk of Secondary Students

    Halse, Christine

    2017-01-01

    This article examines the attributions of responsibility for racism in the everyday talk of secondary school students. It draws on focus groups with a cross section of students from different ethnic backgrounds in three, very different, secondary schools. In these focus groups, students deploy six different, sometimes contradictory, racialised…

  19. Jasmonate-responsive transcription factors regulating plant secondary metabolism.

    Zhou, Meiliang; Memelink, Johan

    2016-01-01

    Plants produce a large variety of secondary metabolites including alkaloids, glucosinolates, terpenoids and phenylpropanoids. These compounds play key roles in plant-environment interactions and many of them have pharmacological activity in humans. Jasmonates (JAs) are plant hormones which induce biosynthesis of many secondary metabolites. JAs-responsive transcription factors (TFs) that regulate the JAs-induced accumulation of secondary metabolites belong to different families including AP2/ERF, bHLH, MYB and WRKY. Here, we give an overview of the types and functions of TFs that have been identified in JAs-induced secondary metabolite biosynthesis, and highlight their similarities and differences in regulating various biosynthetic pathways. We review major recent developments regarding JAs-responsive TFs mediating secondary metabolite biosynthesis, and provide suggestions for further studies. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. A general theory of effect size, and its consequences for defining the benchmark response (BMR) for continuous endpoints.

    Slob, Wout

    2017-04-01

    A general theory on effect size for continuous data predicts a relationship between maximum response and within-group variation of biological parameters, which is empirically confirmed by results from dose-response analyses of 27 different biological parameters. The theory shows how effect sizes observed in distinct biological parameters can be compared and provides a basis for a generic definition of small, intermediate and large effects. While the theory is useful for experimental science in general, it has specific consequences for risk assessment: it solves the current debate on the appropriate metric for the Benchmark response in continuous data. The theory shows that scaling the BMR expressed as a percent change in means to the maximum response (in the way specified) automatically takes "natural variability" into account. Thus, the theory supports the underlying rationale of the BMR 1 SD. For various reasons, it is, however, recommended to use a BMR in terms of a percent change that is scaled to maximum response and/or within group variation (averaged over studies), as a single harmonized approach.

  1. Guidelines for secondary analysis in search of response shift

    Schwartz, Carolyn E.; Ahmed, Sara; Sawatzky, Richard; Sajobi, Tolulope; Mayo, Nancy; Finkelstein, Joel; Lix, Lisa; Verdam, Mathilde G. E.; Oort, Frans J.; Sprangers, Mirjam A. G.

    2013-01-01

    Response shift methods have developed substantially in the past decade, with a notable emphasis on model-based methods for response shift detection that are appropriate for the analysis of existing data sets. These secondary data analyses have yielded useful insights and motivated the continued

  2. Guidelines for secondary analysis in search of response shift

    Schwartz, C.E.; Ahmed, S.; Sawatzky, R.; Sajobi, T.; Mayo, N.; Finkelstein, J.; Verdam, M.G.E.; Oort, F.J.; Sprangers, M.A.G.

    2013-01-01

    Objective: Response shift methods have developed substantially in the past decade, with a notable emphasis on model-based methods for response shift detection that are appropriate for the analysis of existing data sets. These secondary data analyses have yielded useful insights and motivated the

  3. Barriers to Implementing the Response to Intervention Framework in Secondary Schools: Interviews with Secondary Principals

    Bartholomew, Mitch; De Jong, David

    2017-01-01

    Despite the successful implementation of the Response to Intervention (RtI) framework in many elementary schools, there is little evidence of successful implementation in high school settings. Several themes emerged from the interviews of nine secondary principals, including a lack of knowledge and training for successful implementation, the…

  4. TBI Endpoints Development

    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

  5. Secondary immune response of rainbow trout following repeated immersion vaccination

    Jaafar, R. M.; Al-Jubury, A.; Chettri, J. K.

    2017-01-01

    Teleosts are able to raise a protective immune response, comprising both innate and adaptive elements, against various pathogens. This is the basis for a widespread use of vaccines, administered as injection or immersion, in the aquaculture industry. It has been described that repeated injection...... vaccination of fish raises a secondary immune response, consisting of rapid, accelerated and increased antibody reaction. This study reports how rainbow trout responds to repeated immersion vaccination against yersiniosis (ERM) caused by the bacterial pathogen Yersinia ruckeri. It was found that rainbow trout...... does not raise a classical secondary response following repeated immersion vaccination. Serum antibody titres were merely slightly increased even after three immunizations, using 30-s immersion into a bacterin consisting of formalin-inactivated Y. ruckeri (serotype O1, biotypes 1 and 2), performed over...

  6. Secondary immune response of rainbow trout following repeated immersion vaccination

    Jaafar, R. M.; Al-Jubury, Azmi; Chettri, Jiwan Kumar

    2018-01-01

    Teleosts are able to raise a protective immune response, comprising both innate and adaptive elements, against various pathogens. This is the basis for a widespread use of vaccines, administered as injection or immersion, in the aquaculture industry. It has been described that repeated injection...... vaccination of fish raises a secondary immune response, consisting of rapid, accelerated and increased antibody reaction. This study reports how rainbow trout responds to repeated immersion vaccination against yersiniosis (ERM) caused by the bacterial pathogen Yersinia ruckeri. It was found that rainbow trout...... does not raise a classical secondary response following repeated immersion vaccination. Serum antibody titres were merely slightly increased even after three immunizations, using 30-s immersion into a bacterin consisting of formalin-inactivated Y. ruckeri (serotype O1, biotypes 1 and 2), performed over...

  7. Do changing levels of maternal exercise during pregnancy affect neonatal adiposity? Secondary analysis of the babies after SCOPE: evaluating the longitudinal impact using neurological and nutritional endpoints (BASELINE) birth cohort (Cork, Ireland).

    Norris, Tom; McCarthy, Fergus P; Khashan, Ali S; Murray, Deidre M; Kiely, Mairead; Hourihane, Jonathan O'B; Baker, Philip N; Kenny, Louise C

    2017-12-01

    To investigate whether changing levels of exercise during pregnancy are related to altered neonatal adiposity. Secondary analysis of data from a prospective cohort study. Cork, Ireland. 1200 mother - infant pairs recruited as part of a prospective birth cohort, Babies After SCOPE: Evaluating the Longitudinal Impact Using Neurological and Nutritional Endpoints (BASELINE). Neonatal adiposity was assessed within several days of birth using air displacement plethysmography (PEAPOD). Per cent body fat (BF%) as a continuous outcome and a pair of dichotomous variables; high or low adiposity, representing BF% >90th or <10th centile, respectively. Multivariable linear and logistic regression models were used to investigate the relationship between exercise and the respective outcomes. Crude analysis revealed no association between a changing level of exercise (since becoming pregnant) at 15 weeks' gestation and any of the outcomes (BF%, low adiposity and high adiposity). At 20 weeks' gestation, analyses revealed that relative to women who do not change their exercise level up to 20 weeks, those women who decreased their exercise level were more likely to give birth to a neonate with adiposity above the 90th centile (OR 1.62, 95% CI 1.07 to 2.46). This association was maintained after adjustment for putative confounders (OR 1.62, 95% CI 1.06 to 2.47). We observed a possible critical period for the association between changing exercise levels and neonatal adiposity, with no association observed with exercise recall for the first 15 weeks of gestation, but an association with a decreasing level of exercise between 15 and 20 weeks. These results should be interpreted in line with the limitations of the study and further studies utilising objectively measured estimates of exercise are required in order to replicate these findings. NCT01498965. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No

  8. Response to The Lost Thing: Notes from a Secondary Classroom

    Sandie Mourão

    2013-05-01

    Full Text Available This paper discusses students’ responses to the picturebook The Lost Thing (Tan, 2000 and its film (2010. It describes a small-scale project in a secondary school in Portugal, which involved 16-18 year-old students, learning English as a foreign language. Following a socio-constructivist approach to language learning and the basic tenets of reader response theory, discussion and an interpretative stance to meaning making were encouraged. The aim was to foster students’ appreciation of the visual during their interpretative discussions as well as developing their English language skills. This paper demonstrates how the picturebook in particular afforded the students with opportunities for language development through talk. It closes with notes on the implications of using picturebooks and their films in the classroom.

  9. Shared Contract-Obedient Endpoints

    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.

  10. Improved Endpoints for Cancer Immunotherapy Trials

    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

  11. Calorimetry end-point predictions

    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

  12. Biomarkers and correlative endpoints for immunotherapy trials.

    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.

  13. Coupled response spectrum analysis of secondary systems using uncoupled modal properties

    Gupta, A.K.; Jaw Jingwen

    1986-01-01

    A method of performing coupled response spectrum analysis of secondary systems is presented. The response spectrum specified at the base of the primary system is used as the input. The complex coupled mode shapes along with frequencies and damping values are calculated using an efficient and accurate perturbation scheme. The new method is applied to a 2 DOF secondary system coupled with a 6 DOF secondary system. The masses and the stiffness of the secondary system are varied to get nine different cases. The coupled system is subjected to El Centro (S00E, 1940) ground motion. It is shown that the response values from the present method are in good agreement with those from the coupled time history analysis. The conventional floor response spectrum method gives response values which are consistently much higher than the corresponding values from the time history analysis. It is concluded that the present method is sufficiently straightforward and efficient, and that it yields accurate response values. (orig.)

  14. Endpoints in pediatric pain studies

    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

  15. Shear and dielectric responses of propylene carbonate, tripropylene glycol, and a mixture of two secondary amides

    Gainaru, Catalin; Hecksher, Tina; Olsen, Niels Boye

    2012-01-01

    Propylene carbonate and a mixture of two secondary amides, N-ethylformamide and Nethylacetamide, are investigated by means of broadband dielectric and mechanical shear spectroscopy. The similarities between the rheological and the dielectric responses of these liquids and of the previously invest...... in the secondary amides. In addition, the predictions of the shoving model are confirmed for the investigated liquids...

  16. Helicopter EMS: Research Endpoints and Potential Benefits

    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.

  17. Impact of adaptation algorithm, timing, and stopping boundaries on the performance of Bayesian response adaptive randomization in confirmative trials with a binary endpoint.

    Jiang, Yunyun; Zhao, Wenle; Durkalski-Mauldin, Valerie

    2017-11-01

    Despite the concerns of time trend in subject profiles, the use of Bayesian response adaptive randomization (BRAR) in large multicenter phase 3 confirmative trials has been reported in recent years, motivated by the potential benefits in subject ethics and/or trial efficiency. However three issues remain unclear to investigators: 1) among several BRAR algorithms, how to choose one for the specific trial setting; 2) when to start and how frequently to update the allocation ratio; and 3) how to choose the interim analyses stopping boundaries to preserve the type 1 error. In this paper, three commonly used BRAR algorithms are evaluated based on type 1 error, power, sample size, the proportion of subjects assigned to the better performing arm, and the total number of failures, under two specific trial settings and different allocation ratio update timing and frequencies. Simulation studies show that for two-arm superiority trials, none of the three BRAR algorithms has predominant benefits in both patient ethics and trial efficiency when compared to fixed equal allocation design. For a specific trial aiming to identify the best or the worst among three treatments, a properly selected BRAR algorithm and its implementation parameters are able to gain ethical and efficiency benefits simultaneously. Although the simulation results come from a specific trial setting, the methods described in this paper are generally applicable to other trials. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Evaluation of the national secondary standard response of radiodiagnosis

    Peixoto, Jose Guilherme P.; Villalobos, Josefa P.; Carlos, Marcia T.

    1996-01-01

    Before calibration in Germany Primary Laboratory / PTB the Radcal diagnostic ionization chamber repeatability was tested in the Laboratorio Nacional de Metrologia das Radiacoes Ionizantes (LNMRI), Brazil. Response of the chamber during experiment for repeatability demonstrate a variance in the range of 0.1%

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

    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.

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

    Bonnetain Franck

    2010-06-01

    Full Text Available 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 opinion on surrogacy and quality of life (QoL. Methods In 2007 and 2008, self administered sequential questionnaires were sent to a panel of French clinicians and methodologists involved in the conduct of cancer clinical trials. In the first questionnaire, panellists were asked to choose the most important characteristics defining a surrogate among six proposals, to give advantages and drawbacks of the surrogates, and to answer questions about their validation and use. Then they had to suggest potential surrogate endpoints for OS in each of the following tumour sites: oesophagus, stomach, liver, pancreas, biliary tract, lymphoma, colon, rectum, and anus. They finally gave their opinion on QoL as surrogate endpoint. In the second questionnaire, they had to classify the previously proposed candidate surrogates from the most (position #1 to the least relevant in their opinion. Frequency at which the endpoints were chosen as first, second or third most relevant surrogates was calculated and served as final ranking. Results Response rate was 30% (24/80 in the first round and 20% (16/80 in the second one. Participants highlighted key points concerning surrogacy. In particular, they reminded that a surrogate endpoint is expected to predict clinical benefit in a well-defined therapeutic situation. Half of them thought it was not relevant to study QoL as surrogate for OS. DFS, in the neoadjuvant settings or early stages, and PFS, in the non operable or metastatic settings

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

    Methy, Nicolas; Bedenne, Laurent; Bonnetain, Franck

    2010-01-01

    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 opinion on surrogacy and quality of life (QoL). In 2007 and 2008, self administered sequential questionnaires were sent to a panel of French clinicians and methodologists involved in the conduct of cancer clinical trials. In the first questionnaire, panellists were asked to choose the most important characteristics defining a surrogate among six proposals, to give advantages and drawbacks of the surrogates, and to answer questions about their validation and use. Then they had to suggest potential surrogate endpoints for OS in each of the following tumour sites: oesophagus, stomach, liver, pancreas, biliary tract, lymphoma, colon, rectum, and anus. They finally gave their opinion on QoL as surrogate endpoint. In the second questionnaire, they had to classify the previously proposed candidate surrogates from the most (position N1) to the least relevant in their opinion. Frequency at which the endpoints were chosen as first, second or third most relevant surrogates was calculated and served as final ranking. Response rate was 30% (24/80) in the first round and 20% (16/80) in the second one. Participants highlighted key points concerning surrogacy. In particular, they reminded that a surrogate endpoint is expected to predict clinical benefit in a well-defined therapeutic situation. Half of them thought it was not relevant to study QoL as surrogate for OS. DFS, in the neoadjuvant settings or early stages, and PFS, in the non operable or metastatic settings, were ranked first, with a frequency of more than

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

    Methy, Nicolas; Bedenne, Laurent; Bonnetain, Franck

    2010-06-10

    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 opinion on surrogacy and quality of life (QoL). In 2007 and 2008, self administered sequential questionnaires were sent to a panel of French clinicians and methodologists involved in the conduct of cancer clinical trials. In the first questionnaire, panellists were asked to choose the most important characteristics defining a surrogate among six proposals, to give advantages and drawbacks of the surrogates, and to answer questions about their validation and use. Then they had to suggest potential surrogate endpoints for OS in each of the following tumour sites: oesophagus, stomach, liver, pancreas, biliary tract, lymphoma, colon, rectum, and anus. They finally gave their opinion on QoL as surrogate endpoint. In the second questionnaire, they had to classify the previously proposed candidate surrogates from the most (position #1) to the least relevant in their opinion.Frequency at which the endpoints were chosen as first, second or third most relevant surrogates was calculated and served as final ranking. Response rate was 30% (24/80) in the first round and 20% (16/80) in the second one. Participants highlighted key points concerning surrogacy. In particular, they reminded that a surrogate endpoint is expected to predict clinical benefit in a well-defined therapeutic situation. Half of them thought it was not relevant to study QoL as surrogate for OS.DFS, in the neoadjuvant settings or early stages, and PFS, in the non operable or metastatic settings, were ranked first, with a frequency of more than 69

  3. Estimation of induced secondary metabolites in chickpea tissues in response to elicitor preparation of seaweeds

    Bi, F.; Iqbal, S.

    2000-01-01

    Disease response of plants in terms of induced browning and phytoalexin (induced secondary metabolites) production were recorded in the tissues of Cicer arietinum (Chick pea) treated with the High Molecular Crude Elicitor Preparations, HMWCEP 'Polysaccharides' of Hypnea musciformis (red algae), Padina tetrastromatica (brown algae) and Ulva lactulus (green algae). A UV-visible spectrophotometric method has been developed for the quantification of induced secondary metabolites with time. (author)

  4. Estimation method for first excursion probability of secondary system with impact and friction using maximum response

    Shigeru Aoki

    2005-01-01

    The secondary system such as pipings, tanks and other mechanical equipment is installed in the primary system such as building. The important secondary systems should be designed to maintain their function even if they are subjected to destructive earthquake excitations. The secondary system has many nonlinear characteristics. Impact and friction characteristic, which are observed in mechanical supports and joints, are common nonlinear characteristics. As impact damper and friction damper, impact and friction characteristic are used for reduction of seismic response. In this paper, analytical methods of the first excursion probability of the secondary system with impact and friction, subjected to earthquake excitation are proposed. By using the methods, the effects of impact force, gap size and friction force on the first excursion probability are examined. When the tolerance level is normalized by the maximum response of the secondary system without impact or friction characteristics, variation of the first excursion probability is very small for various values of the natural period. In order to examine the effectiveness of the proposed method, the obtained results are compared with those obtained by the simulation method. Some estimation methods for the maximum response of the secondary system with nonlinear characteristics have been developed. (author)

  5. Radiological endpoints relevant to ecological risk assessment

    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)

  6. Investigation of the conservatism associated with different combinations between primary and secondary piping responses

    Wang, Y.K.; Subudhi, M.; Bezler, P.

    1983-01-01

    This report includes the findings of an investigation of the conservatism associated with different combinations between the primary and secondary stress components for piping systems under dynamic loading, such as in an earthquake event. The primary stresses are induced by piping response to its mass inertia effects. The secondary stresses are induced by relative displacements of piping supports. The study involves an independnent time history analysis of several typical piping models to predict a best estimate of the actual dynamic and pseudo-static pipe responses to an earthquake. These piping systems are also analyzed using the response spectrum method to obtain the maximum primary stress components. Secondary stresses are next calculated by performing a set of static analyses which provide the worst stress condition. The two components are then combined by both SRSS and absolute sum methods as the results are compared with time history solutions. It is found that the SRSS combination of the primary and secondary stress components yield acceptable results provided the secondary stress component is calculated in the most unfavorable phasing relationship among displacements of piping supports

  7. The Host Response in Patients with Sepsis Developing Intensive Care Unit-acquired Secondary Infections.

    van Vught, Lonneke A; Wiewel, Maryse A; Hoogendijk, Arie J; Frencken, Jos F; Scicluna, Brendon P; Klein Klouwenberg, Peter M C; Zwinderman, Aeilko H; Lutter, Rene; Horn, Janneke; Schultz, Marcus J; Bonten, Marc M J; Cremer, Olaf L; van der Poll, Tom

    2017-08-15

    Sepsis can be complicated by secondary infections. We explored the possibility that patients with sepsis developing a secondary infection while in the intensive care unit (ICU) display sustained inflammatory, vascular, and procoagulant responses. To compare systemic proinflammatory host responses in patients with sepsis who acquire a new infection with those who do not. Consecutive patients with sepsis with a length of ICU stay greater than 48 hours were prospectively analyzed for the development of ICU-acquired infections. Twenty host response biomarkers reflective of key pathways implicated in sepsis pathogenesis were measured during the first 4 days after ICU admission and at the day of an ICU-acquired infection or noninfectious complication. Of 1,237 admissions for sepsis (1,089 patients), 178 (14.4%) admissions were complicated by ICU-acquired infections (at Day 10 [6-13], median with interquartile range). Patients who developed a secondary infection showed higher disease severity scores and higher mortality up to 1 year than those who did not. Analyses of biomarkers in patients who later went on to develop secondary infections revealed a more dysregulated host response during the first 4 days after admission, as reflected by enhanced inflammation, stronger endothelial cell activation, a more disturbed vascular integrity, and evidence for enhanced coagulation activation. Host response reactions were similar at the time of ICU-acquired infectious or noninfectious complications. Patients with sepsis who developed an ICU-acquired infection showed a more dysregulated proinflammatory and vascular host response during the first 4 days of ICU admission than those who did not develop a secondary infection.

  8. Developing Culturally Responsive Mathematics Teachers: Secondary Teachers' Evolving Conceptions of Knowing Students

    Parker, Frieda; Bartell, Tonya Gau; Novak, Jodie D.

    2017-01-01

    Research advances in teaching, learning, curriculum, and assessment have not changed the continued underperformance of marginalized students in mathematics education. Culturally responsive teaching is a means of addressing the needs of these students. It is sometimes challenging, however, to convince secondary mathematics teachers about the…

  9. School Responsiveness to Quality Rankings. An Empirical Analysis of Secondary Education in the Netherlands

    Koning, P.W.C.; van der Wiel, K.

    2012-01-01

    This paper assesses the response of Dutch secondary schools to the publication of relative quality ratings in a national newspaper (Trouw). Our research design exploits the discontinuities in the ranking formula that was used to generate five consecutive levels for the overall quality of schools. We

  10. A Case Study on Primary, Secondary and University Students' Environmentally Responsible Behaviors in Turkey

    Kahyaoglu, Mustafa

    2013-01-01

    The purpose of the study is to prove the environmentally responsible behaviors of primary, secondary and university students in Turkey. The students', who attended the study as participants, environmentally political behaviors, consumer/economical behaviors, direct behaviors toward protecting the environment and individual and public persuasion…

  11. Tool for generation of seismic floor response spectra for secondary system design

    Cardoso, Tarcisio F.; Almeida, Andreia A. Diniz de

    2009-01-01

    The spectral analysis is still a valuable method to the seismic structure design, especially when one focalizes the topics of secondary systems in large industrial installations, as nuclear power plants. Two aspects of this situation add their arguments to recommend the use of this kind of analysis: the random character of the excitation and the multiplicity and the variability of the secondary systems. The first aspect can be managed if one assumes the site seismicity represented by a power spectrum density function of the ground acceleration, and then, by the systematic resolution of a first passage problem, to develop a uniformly probable response spectrum. The second one suggests also a probabilistic approach to the response spectrum in order to be representative all over the extensive group of systems with different characteristics, which can be enrolled in a plant. The present paper proposes a computational tool to achieve in-structure floor response spectra for secondary system design, which includes a probabilistic approach and considers coupling effects between primary and inelastic secondary systems. The analysis is performed in the frequency domain, with SASSI2000 system. A set of auxiliary programs are developed to consider three-dimensional models and their responses to a generic base excitation, acting in 3 orthogonal directions. The ground excitation is transferred to a secondary system SDOF model conveniently attached to the primary system. Then, a uniformly probable coupled response spectrum is obtained using a first passage analysis. In this work, the ExeSASSI program is created to manage SASSI2000 several modules and a set of auxiliary programs created to perform the probabilistic analyses. (author)

  12. 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.

    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.

  13. Delaware Technical & Community College's response to the critical shortage of Delaware secondary science teachers

    Campbell, Nancy S.

    This executive position paper examines the critical shortage of Delaware high school science teachers and Delaware Technical & Community College's possible role in addressing this shortage. A concise analysis of economic and political implications of the science teacher shortage is presented. The following topics were researched and evaluated: the specific science teacher needs for Delaware school districts; the science teacher education program offerings at Delaware universities and colleges; the Alternative Route to Teacher Certification (ARTC); and the state of Delaware's scholarship response to the need. Recommendations for Delaware Tech's role include the development and implementation of two new Associate of Arts of Teaching programs in physics secondary science education and chemistry secondary science education.

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

    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.

  15. Cytokines in tears during the secondary keratoconjunctival responses induced by allergic reaction in the nasal mucosa.

    Pelikan, Zdenek

    2014-01-01

    Allergic keratoconjunctivitis (KC) can occur in a primary form due to an allergic reaction taking place in the conjunctivae or in a secondary form induced by nasal allergy. To search for the cytokine changes in tears accompanying the secondary keratoconjunctival response types (SKCR), caused by the nasal allergy. In 43 KC patients developing 15 immediate (SIKCR), 16 late (SLKCR) and 12 delayed (SDYKCR) responses to nasal provocation tests with allergens (NPT), the NPTs were repeated with subsequent recording of cytokine concentrations in tears up to 72 h. The SIKCRs (ptears, suggesting involvement of different hypersensitivity mechanisms. These results also stress the diagnostic usefulness of NPTs combined with monitoring of ocular features in KC patients who did not respond satisfactorily to the topical ophthalmological treatment. © 2014 S. Karger AG, Basel.

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

    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...

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

    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

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

    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

  19. Program to Promote Personal and Social Responsibility in the Secondary Classroom

    Miguel A. Carbonero

    2017-05-01

    Full Text Available The performance of school children has been studied by considering partial relationships between several personal variables such as the link between cognition and motivation. However, contextual variables, such as a child’s willingness to accept social responsibility, also influence students’ social and academic performance. Thus, students with greater responsibility have a better attitude toward their studies, resulting in higher academic achievement. This 2-year study aims to reveal to what extent an intervention program affects student performance and is based on the Theory of Positive Action among young people proposed by Don Hellison and the Theory of Reasoned Action by Fishbein and Ajzen. The program focuses on positive influences on social and personal responsibility, taking into consideration parental styles, gender, and academic performance. The program was a part of the educational curricula in participating schools and it targeted four main areas: (a teaching units using academic texts about social responsibility, (b student training in mediation processes, (c teacher training, and (d family training and involvement. A total of 271 students took part from first and second year of Secondary Education (12–14 years old. The experimental group was made up of 132 students while the remaining 139 formed the control group. All participants completed the Assessment Scale of Social Responsibility Attitudes in Secondary Education and the Parent–Adolescent Communication Scale. Results show that students in the experimental group performed significantly better than those in the control group. Additionally, the issue of social responsibility seems to be related to commitment, self-discipline and perseverance. Regarding gender, males appear to score higher in the factor for well-mannered, friendly and tidy. Finally, a positive relationship has been identified between social responsibility attitudes and parenting with an open communicational

  20. Program to Promote Personal and Social Responsibility in the Secondary Classroom.

    Carbonero, Miguel A; Martín-Antón, Luis J; Otero, Lourdes; Monsalvo, Eugenio

    2017-01-01

    The performance of school children has been studied by considering partial relationships between several personal variables such as the link between cognition and motivation. However, contextual variables, such as a child's willingness to accept social responsibility, also influence students' social and academic performance. Thus, students with greater responsibility have a better attitude toward their studies, resulting in higher academic achievement. This 2-year study aims to reveal to what extent an intervention program affects student performance and is based on the Theory of Positive Action among young people proposed by Don Hellison and the Theory of Reasoned Action by Fishbein and Ajzen. The program focuses on positive influences on social and personal responsibility, taking into consideration parental styles, gender, and academic performance. The program was a part of the educational curricula in participating schools and it targeted four main areas: (a) teaching units using academic texts about social responsibility, (b) student training in mediation processes, (c) teacher training, and (d) family training and involvement. A total of 271 students took part from first and second year of Secondary Education (12-14 years old). The experimental group was made up of 132 students while the remaining 139 formed the control group. All participants completed the Assessment Scale of Social Responsibility Attitudes in Secondary Education and the Parent-Adolescent Communication Scale. Results show that students in the experimental group performed significantly better than those in the control group. Additionally, the issue of social responsibility seems to be related to commitment, self-discipline and perseverance. Regarding gender, males appear to score higher in the factor for well-mannered, friendly and tidy. Finally, a positive relationship has been identified between social responsibility attitudes and parenting with an open communicational style. This paper

  1. Exploring the Use of Audience Response Systems in Secondary School Science Classrooms

    Kay, Robin; Knaack, Liesel

    2009-10-01

    An audience response systems (ARS) allows students to respond to multiple choice questions using remote control devices. Once the feedback is collected and displayed, the teacher and students discuss misconceptions and difficulties experienced. ARSs have been extremely popular and effective in higher education science classrooms, although almost no research has been done at the secondary school level. The purpose of this study was to conduct a detailed formative analysis of the benefits, challenges, and use of ARSs from the perspective of 213 secondary school science students. Perceived benefits were increased student involvement (engagement, participation, and attention) and effective formative assessment of student understanding. Perceived challenges included decreased student involvement and learning when ARSs were used for summative assessment, occasional technological malfunctions, resistance to using a new method of learning, and increased stress due to time constraints when responding to questions. Finally, students rated the use of ARSs significantly higher when it was used for formative as opposed to summative assessment.

  2. The Interplay between Adolescent Needs and Secondary School Structures: Fostering Developmentally Responsive Middle and High School Environments across the Transition

    Ellerbrock, Cheryl R.; Kiefer, Sarah M.

    2013-01-01

    Understanding the developmental responsiveness of secondary school environments may be an important factor in supporting students as they make the transition from one school to the next. Students' needs may or may not be met depending on the nature of the fit between their basic and developmental needs and secondary school structures at the middle…

  3. Cytokine profiles in tears accompanying the secondary conjunctival responses induced by nasal allergy.

    Pelikan, Zdenek

    2014-02-01

    Allergic conjunctivitis (AC) occurs either in a primary form, due to the allergic reaction localized in the conjunctivae or in a secondary form, induced by an allergic reaction initiated primarily in the nasal mucosa. The purpose of this study was to investigate the cytokine profiles in tears associated with the secondary conjunctival response (SCR) types. In 47 AC patients developing 16 immediate (SICR; p tears. The SCRs were associated with significant concentration changes of particular cytokines in tears (p tears during the phosphate-buffered saline controls or negative SCRs. Different cytokine profiles in the tears accompanying the immediate, late and delayed types of SCR, induced by nasal allergy, would indicate involvement of different hypersensitivity mechanisms in the particular SCR types. The low cytokine concentrations in tears recorded during the SCRs may suggest their origin from the nasal mucosa. These results emphasize the diagnostic value of NPTs with allergens combined with monitoring of various ocular features in patients suffering from the secondary form of AC. These results may also have an impact on the therapeutical approach to this clinical entity.

  4. Microbial Composition in Decomposing Pine Litter Shifts in Response to Common Soil Secondary Minerals

    Welty-Bernard, A. T.; Heckman, K.; Vazquez, A.; Rasmussen, C.; Chorover, J.; Schwartz, E.

    2011-12-01

    A range of environmental and biotic factors have been identified that drive microbial community structure in soils - carbon substrates, redox conditions, mineral nutrients, salinity, pH, and species interactions. However, soil mineralogy has been largely ignored as a candidate in spite of recent studies that indicate that minerals have a substantial impact on soil organic matter stores and subsequent fluxes from soils. Given that secondary minerals and organic colloids govern a soil's biogeochemical activity due to surface area and electromagnetic charge, we propose that secondary minerals are a strong determinant of the communities that are responsible for process rates. To test this, we created three microcosms to study communities during decomposition using pine forest litter mixed with two common secondary minerals in soils (goethite and gibbsite) and with quartz as a control. Changes in bacterial and fungal communities were tracked over the 154-day incubation by pyrosequencing fragments of the bacterial 16S and fungal 18S rRNA genes. Ordination using nonmetric multidimensional scaling showed that bacterial communities separated on the basis of minerals. Overall, a single generalist - identified as an Acidobacteriaceae isolate - dominated all treatments over the course of the experiment, representing roughly 25% of all communities. Fungal communities discriminated between the quartz control alone and mineral treatments as a whole. Again, several generalists dominated the community. Coniochaeta ligniaria dominated communities with abundances ranging from 29 to 40%. The general stability of generalist populations may explain the similarities between treatment respiration rates. Variation between molecular fingerprints, then, were largely a function of unique minor members with abundances ranging from 0.01 to 8%. Carbon availability did not surface as a possible mechanism responsible for shifts in fingerprints due to the relatively large mass of needles in the

  5. Establishing a group of endpoints in a parallel computer

    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.

  6. Proteomic Characterization of Armillaria mellea Reveals Oxidative Stress Response Mechanisms and Altered Secondary Metabolism Profiles

    Cassandra Collins

    2017-09-01

    Full Text Available Armillaria mellea is a major plant pathogen. Yet, the strategies the organism uses to infect susceptible species, degrade lignocellulose and other plant material and protect itself against plant defences and its own glycodegradative arsenal are largely unknown. Here, we use a combination of gel and MS-based proteomics to profile A. mellea under conditions of oxidative stress and changes in growth matrix. 2-DE and LC-MS/MS were used to investigate the response of A. mellea to H2O2 and menadione/FeCl3 exposure, respectively. Several proteins were detected with altered abundance in response to H2O2, but not menadione/FeCl3 (i.e., valosin-containing protein, indicating distinct responses to these different forms of oxidative stress. One protein, cobalamin-independent methionine synthase, demonstrated a common response in both conditions, which may be a marker for a more general stress response mechanism. Further changes to the A. mellea proteome were investigated using MS-based proteomics, which identified changes to putative secondary metabolism (SM enzymes upon growth in agar compared to liquid cultures. Metabolomic analyses revealed distinct profiles, highlighting the effect of growth matrix on SM production. This establishes robust methods by which to utilize comparative proteomics to characterize this important phytopathogen.

  7. A summation free β+-endpoint spectrometer

    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.)

  8. End-point sharpness in thermometric titrimetry.

    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.

  9. Forecasting interest rates with shifting endpoints

    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....

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

    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.

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

    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.

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

    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

  13. The mediating role of secondary beliefs: enhancing the understanding of emotional responses and illness perceptions in arthritis.

    McCracken, James; Lindner, Helen; Sciacchitano, Laura

    2008-01-01

    Chronic illnesses are a significant issue across many health professional domains, becoming an increasing burden on limited and costly resources. The current study investigated the relationship between secondary beliefs and emotional responses, beyond the relationship accounted for by illness perceptions, using the framework of Rational Emotive Behavior Therapy. Sixty-five adults with arthritis participated in the questionnaire-based study. Multivariate analysis found that different emotional representations of the illness were significantly predicted by the individual's secondary belief, above and beyond that predicted by the cognitive representation of their illness alone. The study found that individuals who utilized an achievement secondary belief experienced feelings of worry, whereas individuals who used an approval orientation to understand their arthritis experienced emotions such as depression, being upset, anger, anxiety, and fear. No significant pattern emerged for individuals who used a comfort secondary belief to understand their arthritis. These findings are in line with the theory of secondary beliefs, as articulated by Rational Emotive Behavior Therapy.

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

    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. Measuring general and specific stress causes and stress responses among beginning secondary school teachers in the Netherlands

    Harmsen, R; Helms-Lorenz, M.; Maulana, R; van Veen, K; van Veldhoven, M.J.P.M.

    2018-01-01

    The main aim of this study was to adjust the Questionnaire on the Experience and Evaluation of Work (QEEW) in order to measure stress causes and stress responses of beginning secondary school teachers in the Netherlands. First, the suitability of the original QEEW stress scales for use in the beginning teachers (BTs) context was investigated using a sample of 356 beginning teachers from 52 different secondary school locations in the Netherlands. Confirmatory Factor Analyses, Principal Compone...

  16. Measuring general and specific stress causes and stress responses among beginning secondary school teachers in the Netherlands.

    Harmsen, Ruth; Helms-Lorenz, Michelle; Maulana, Ridwan; van Veen, Klaas; van Veldhoven, M.J.P.M.

    2018-01-01

    The main aim of this study was to adjust the Questionnaire on the Experience and Evaluation of Work (QEEW) in order to measure stress causes and stress responses of beginning secondary school teachers in the Netherlands. First, the suitability of the original QEEW stress scales for use in the beginning teachers (BTs) context was investigated using a sample of 356 beginning teachers from 52 different secondary school locations in the Netherlands. Confirmatory Factor Analyses, Principal Compone...

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

    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

  18. Space radiation-induced bystander effect: kinetics of biologic responses, mechanisms, and significance of secondary radiations

    Gonon, Geraldine

    2011-01-01

    more cells than expected based on the fraction of cells traversed through the nucleus by an iron or silicon ion. The effect was expressed as early as 15 min after exposure, peaked at 1 h and decreased by 24 h. A similar tendency occurred after exposure to a mean absorbed dose of 0.2 cGy of 3.7 MeV a particles, but not after 0.2 cGy of 290 MeV/u carbon ions.Analyses in dishes that incorporate a CR-39 solid state nuclear track detector bottom identified the cells irradiated with iron or silicon ions and further supported the participation of bystander cells in the stress response. Mechanistic studies indicated that gap junction intercellular communication, DNA repair, and oxidative metabolism participate in the propagation of the induced effects. We also considered the possible contribution of secondary particles produced along the primary particle tracks to the biological responses. Simulations with the FLUKA multi-particle transport code revealed that fragmentation products, other than electrons, in cells cultures exposed to HZE particles comprise ≤1 % of the absorbed dose. Further, the radial spread of dose due to secondary heavy ion fragments is confined to approximately 10-20 μm. Thus, the latter are unlikely to significantly contribute to the stressful effects in cells not targeted by primary HZE particles. (author)

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

    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.

  20. Inflammatory responses to secondary organic aerosols (SOA generated from biogenic and anthropogenic precursors

    W. Y. Tuet

    2017-09-01

    Full Text Available Cardiopulmonary health implications resulting from exposure to secondary organic aerosols (SOA, which comprise a significant fraction of ambient particulate matter (PM, have received increasing interest in recent years. In this study, alveolar macrophages were exposed to SOA generated from the photooxidation of biogenic and anthropogenic precursors (isoprene, α-pinene, β-caryophyllene, pentadecane, m-xylene, and naphthalene under different formation conditions (RO2 + HO2 vs. RO2 + NO dominant, dry vs. humid. Various cellular responses were measured, including reactive oxygen and nitrogen species (ROS/RNS production and secreted levels of cytokines, tumor necrosis factor-α (TNF-α and interleukin-6 (IL-6. SOA precursor identity and formation condition affected all measured responses in a hydrocarbon-specific manner. With the exception of naphthalene SOA, cellular responses followed a trend where TNF-α levels reached a plateau with increasing IL-6 levels. ROS/RNS levels were consistent with relative levels of TNF-α and IL-6, due to their respective inflammatory and anti-inflammatory effects. Exposure to naphthalene SOA, whose aromatic-ring-containing products may trigger different cellular pathways, induced higher levels of TNF-α and ROS/RNS than suggested by the trend. Distinct cellular response patterns were identified for hydrocarbons whose photooxidation products shared similar chemical functionalities and structures, which suggests that the chemical structure (carbon chain length and functionalities of photooxidation products may be important for determining cellular effects. A positive nonlinear correlation was also detected between ROS/RNS levels and previously measured DTT (dithiothreitol activities for SOA samples. In the context of ambient samples collected during summer and winter in the greater Atlanta area, all laboratory-generated SOA produced similar or higher levels of ROS/RNS and DTT activities. These results

  1. Decreased hedonic responsiveness following chronic mild stress is not secondary to loss of body weight.

    Willner, P; Moreau, J L; Nielsen, C K; Papp, M; Sluzewska, A

    1996-07-01

    Chronic exposure to mild unpredictable stress (CMS) has previously been found to decrease hedonic responsiveness, as measured by the consumption of palatable sweet solutions or sensitivity to brain stimulation reward. These effects are reversed by chronic treatment with antidepressant drugs, and the CMS procedure has been proposed as a relatively valid animal model of depression. It has recently been suggested that the behavioural effects of CMS may be secondary to loss of body weight. This article collates data from five laboratories using the CMS procedure. Data are presented from seven studies using five different rat strains, as well as CD1 mice. Three-week exposure to CMS significantly decreased sucrose consumption by Lister hooded, PVG hooded, Wistar, and Wistar WU rats, and by CD1 mice, and sensitivity to brain stimulation reward in Ibm:Ro Ro rats. Weight loss in different experiments varied between 0 and 10%. Hedonic sensitivity relative to body weight (e.g., mg sucrose/g body weight) decreased significantly in all experiments. Animals maintained on a restricted feeding regime lost weight but did not show decreases in sucrose intake. It is concluded that decreased hedonic sensitivity following chronic mild stress cannot be attributed to loss of body weight.

  2. Incapacity of the Mind Secondary to Medication Misuse as a Not Criminally Responsible Defense.

    Prat, Sebastien S; Losier, Bruno J; Moulden, Heather M; Chaimowitz, Gary A

    2017-01-01

    The manifestations of disorders of the mind may play a role in the occurrence of criminal behavior. In the majority of the cases, the presence of a psychiatric disorder is cited as the reason that an individual was not fully aware of his behavior. However, other conditions, such as seizure disorders or hypoglycemia, have also been linked to an inability to understand the nature and consequences of one's actions. On occasion, these situations can be explained by a state of automatism that may be described as insane or noninsane. In this article, we describe the case of a 77-year-old man, suffering from Parkinson's disease, where the issue of criminal responsibility associated with incapacity of the mind secondary to medication misuse was raised. We elaborate on the thinking behind this opinion and the implications according to Canadian law. Although the legal outcome of this case is specific to our jurisdiction, the clinical implication may be common to any patient suffering from a similar condition and may inform physicians, families, and lawyers. © 2016 American Academy of Forensic Sciences.

  3. RTI and the Adolescent Reader: Responsive Literacy Instruction in Secondary Schools (Middle and High School). Language & Literacy Series Practitioners Bookshelf

    Brozo, William G.

    2011-01-01

    "RTI and the Adolescent Reader" focuses exclusively on Response to Intervention (RTI) for literacy at the secondary level. In this accessible guide, William Brozo defines RTI and explains why and how it is considered a viable intervention model for adolescent readers. He analyzes the authentic structural, political, cultural, and teacher…

  4. Affordances of the Cultural Inquiry Process in Building Secondary Mathematics Teachers' Capacity for Cultural Responsiveness

    Parker, Frieda; Bartell, Tonya; Novak, Jodie D.

    2017-01-01

    Over the last couple of decades, there has been a growing call for teachers to become more responsive to the increasing cultural diversity of students as a means of improving students' experiences in school and their learning outcomes. Challenges exist in working with secondary mathematics teachers due to the common belief that math is…

  5. Measuring general and specific stress causes and stress responses among beginning secondary school teachers in the Netherlands

    Harmsen, R; Helms-Lorenz, M.; Maulana, R; van Veen, K; van Veldhoven, M.J.P.M.

    2018-01-01

    The main aim of this study was to adjust the Questionnaire on the Experience and Evaluation of Work (QEEW) in order to measure stress causes and stress responses of beginning secondary school teachers in the Netherlands. First, the suitability of the original QEEW stress scales for use in the

  6. Piriformospora indica root colonization triggers local and systemic root responses and inhibits secondary colonization of distal roots.

    Pedrotti, Lorenzo; Mueller, Martin J; Waller, Frank

    2013-01-01

    Piriformosporaindica is a basidiomycete fungus colonizing roots of a wide range of higher plants, including crop plants and the model plant Arabidopsis thaliana. Previous studies have shown that P. indica improves growth, and enhances systemic pathogen resistance in leaves of host plants. To investigate systemic effects within the root system, we established a hydroponic split-root cultivation system for Arabidopsis. Using quantitative real-time PCR, we show that initial P. indica colonization triggers a local, transient response of several defense-related transcripts, of which some were also induced in shoots and in distal, non-colonized roots of the same plant. Systemic effects on distal roots included the inhibition of secondary P. indica colonization. Faster and stronger induction of defense-related transcripts during secondary inoculation revealed that a P. indica pretreatment triggers root-wide priming of defense responses, which could cause the observed reduction of secondary colonization levels. Secondary P. indica colonization also induced defense responses in distant, already colonized parts of the root. Endophytic fungi therefore trigger a spatially specific response in directly colonized and in systemic root tissues of host plants.

  7. Secondary school learners' perceptions of responsible citizenship as taught in the life orientation learning area: a case study

    2008-01-01

    In this study, secondary school learners perceptions of Responsible Citizenship as taught in the Life Orientation learning area are explored. Citizen Education, which is set out in Learning Outcome Two of the Life Orientation Curriculum, forms the basis of the programme used to conduct this study. An international as well as a national perspective of Responsible Citizenship and the teaching thereof is explicated with special reference being made to the Further Education and Training Band. The...

  8. Endpoint singularities in unintegrated parton distributions

    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.

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

    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.

  10. Manifestations of Heterosexism in Icelandic Upper Secondary Schools and the Responses of LGBT Students

    Kjaran, Jón Ingvar; Jóhannesson, Ingólfur Ásgeir

    2013-01-01

    How does institutionalized heterosexism manifest itself in Icelandic upper secondary schools and how do lesbian, gay, bisexual, and transgender (LGBT) students respond to these manifestations? In addressing these questions, interviews were conducted with six current and former LGBT upper secondary school students, using queer theory and thematic…

  11. Vaccination Enhances Early Immune Responses in White Shrimp Litopenaeus vannamei after Secondary Exposure to Vibrio alginolyticus

    Lin, Yong-Chin; Chen, Jiann-Chu; Morni, Wan Zabidii W.; Putra, Dedi Fazriansyah; Huang, Chien-Lun; Li, Chang-Che; Hsieh, Jen-Fang

    2013-01-01

    Background Recent work suggested that the presence of specific memory or some form of adaptive immunity occurs in insects and shrimp. Hypervariable pattern recognition molecules, known as Down syndrome cell adhesion molecules, are able to mount specific recognition, and immune priming in invertebrates. In the present study, we attempted to understand the immune response pattern of white shrimp Litopenaeus vannamei which received primary (PE) and secondary exposure (SE) to Vibrio alginolyticus. Methodology Immune parameters and proliferation of haematopoietic tissues (HPTs) of shrimp which had received PE and SE to V. alginolyticus were measured. In the PE trial, the immune parameters and proliferation of HPTs of shrimp that received heat-killed V. alginolyticus (HVa) and formalin-inactivated V. alginolyticus (FVa) were measured. Mortality, immune parameters and proliferation of HPTs of 7-day-HVa-PE shrimp (shrimp that received primary exposure to HVa after 7 days) and 7-day-FVa-PE shrimp (shrimp that received primary exposure to FVa after 7 days) following SE to live V. alginolyticus (LVa) were measured. Phagocytic activity and clearance efficiency were examined for the 7∼35-day-HVa-PE and FVa-PE shrimp. Results HVa-receiving shrimp showed an earlier increase in the immune response on day 1, whereas FVa-receiving shrimp showed a late increase in the immune response on day 5. The 7-day-FVa-PE shrimp showed enhancement of immunity when encountering SE to LVa, whereas 7-day-HVa-PE shrimp showed a minor enhancement in immunity. 7-day-FVa-PE shrimp showed higher proliferation and an HPT mitotic index. Both phagocytic activity and clearance maintained higher for both HVa-PE and FVa-PE shrimp after 28 days. Conclusions HVa- and FVa-receiving shrimp showed the bacteria agglutinated prior to being phagocytised. FVa functions as a vaccine, whereas HVa functions as an inducer and can be used as an immune adjuvant. A combined mixture of FVa and HVa can serve as a

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

    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.

  13. Response of secondary production and its components to multiple stressors in nematode field populations.

    Doroszuk, A.; Brake, te E.; Crespo-Gonzalez, D.; Kammenga, J.E.

    2007-01-01

    Realistic measures of the impact of individual or multiple stressors are important for ecological risk assessment. Although multiple anthropogenic stressors are common in human-dominated environments, knowledge of their influence on functional population parameters such as secondary production (P)

  14. Two-temperature LATE-PCR endpoint genotyping

    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

  15. The immunoglobulin class of anti-hapten antibody secreted during secondary responses in vitro and in vivo.

    North, J R; Dresser, D W

    1977-05-01

    A comparison has been made of the in vitro and in vivo response of primed mouse spleen cells to the hapten DNP. The responses were analysed in terms of six classes (sub-classes) of humoral antibody directed against the cross-reacting hapten TNP. By comparison with the response in intact mice the adoptive secondary response is delayed by 3 days in addition to being somewhat lesser in magnitude. The timing of the response in vitro is similar to that observed in intact mice. The preponderant class in all three responses was gammaG1 with gammaA and gammaG3 secreting cells consistently comprising the smallest proportion of the total of antibody-secreting cells.

  16. Partial response to cinacalcet treatment in a patient with secondary hyperparathyroidism undergoing hemodialysis: a case report

    Conzo Giovanni

    2012-12-01

    Full Text Available Abstract Introduction In the treatment of secondary hyperparathyroidism of chronic kidney disease, calcimimetics - allosteric modulators of the calcium-sensing receptor - inhibit glandular hyperplasia and significantly reduce circulating parathyroid hormone levels. They have a major impact on the management of secondary hyperparathyroidism. Case presentation We present the clinical case of a 41-year-old Caucasian man undergoing chronic hemodialysis, who had a parathyroidectomy to treat severe secondary hyperparathyroidism resistant to cinacalcet treatment. Preoperatively, 24 months after high-dose cinacalcet hydrochloride, we observed a persistently elevated intact parathyroid hormone serum level, and detected clear parathyroid gland hyperplasia regression on ultrasound. We performed a three-gland parathyroidectomy, which was assumed to be total, associated with a hemithyroidectomy. Our patient then entered a hypoparathyroid state. A histopathological examination showed that the removed parathyroid glands were of small size, with a total weight of 1g, associated with a multifocal small papillary thyroid cancer. Conclusion In the management of secondary hyperparathyroidism, cinacalcet hydrochloride effectively reduces total parathyroid gland hyperplasia. However, a persisting elevated intact parathyroid hormone serum level may be observed, demonstrating that reduced parathyroid hyperplastic tissue may still be associated with severe secondary hyperparathyroidism. Even if calcimimetics are very effective in secondary hyperparathyroidism treatment, further studies are necessary for a better understanding of their actions.

  17. Secondary IgG responses to type III pneumococcal polysaccharide. II. Different cellular requirements for induction and elicitation.

    Braley-Mullen, H

    1976-04-01

    Mice primed with a thymus- (T) dependent form of Type III pneumococcal polysaccharide (S3), i.e., S3 coupled to erythrocytes (S3-RBC) produce S3-specific IgG antibody after secondary challenge with either S3 or S3-RBC. The production of IgG antibody by mice challenged with S3 was shown to be T independent since secondary responses were enhanced when mice were treated with anti-lymphocyte serum (ALS) at the time of secondary challenge with S3 and T-depleted spleen cells responded as well as unfractionated spleen cells to S3 in an adoptive transfer system. Secondary S3-specific IgG responses in mice challenged with S3-RBC were shown to be T dependent by the same criteria. The results obtained by using S3 as the antigen indicate that IgG-producing B cells (B lambda cells) can recognize and respond to antigen in the absence of helper T cells. On the other hand, T cells were required for the induction of S3-specific memory B lambda cells since mice depleted of T cells by treatment with ALS at the time of priming with S3-RBC failed to produce S3-specific IgG antibody after secondary challenge with either S3-specific IgG antibody after secondary chall-nge with either S3 or S3rbc. Since RBC-specific memory cells were induced in T-deprived mice the results suggest that T cell regulation of IgG antibody production may vary for different antigens.

  18. Extracting gluino endpoints with event topology patterns

    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.

  19. Regression analysis for secondary response variable in a case-cohort study.

    Pan, Yinghao; Cai, Jianwen; Kim, Sangmi; Zhou, Haibo

    2017-12-29

    Case-cohort study design has been widely used for its cost-effectiveness. In any real study, there are always other important outcomes of interest beside the failure time that the original case-cohort study is based on. How to utilize the available case-cohort data to study the relationship of a secondary outcome with the primary exposure obtained through the case-cohort study is not well studied. In this article, we propose a non-parametric estimated likelihood approach for analyzing a secondary outcome in a case-cohort study. The estimation is based on maximizing a semiparametric likelihood function that is built jointly on both time-to-failure outcome and the secondary outcome. The proposed estimator is shown to be consistent, efficient, and asymptotically normal. Finite sample performance is evaluated via simulation studies. Data from the Sister Study is analyzed to illustrate our method. © 2017, The International Biometric Society.

  20. The intermediate endpoint effect in logistic and probit regression

    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

  1. 33 CFR 155.1045 - Response plan requirements for vessels carrying oil as a secondary cargo.

    2010-07-01

    ... PREVENTION REGULATIONS FOR VESSELS Tank Vessel Response Plans for Oil § 155.1045 Response plan requirements... actions. (4) The organizational structure that will be used to manage the response actions. This structure... with government agencies; (v) Spill response operations; (vi) Planning; (vii) Logistics support; and...

  2. Creating Culturally Responsive Environments: Ethnic Minority Teachers' Constructs of Cultural Diversity in Hong Kong Secondary Schools

    Hue, Ming-tak; Kennedy, Kerry John

    2014-01-01

    One of the challenges facing Hong Kong schools is the growing cultural diversity of the student population that is a result of the growing number of ethnic minority students in the schools. This study uses semi-structured interviews with 12 American, Canadian, Indian, Nepalese and Pakistani teachers working in three secondary schools in the public…

  3. Approaches of a Secondary Music Teacher in Response to the Social and Emotional Lives of Students

    Edgar, Scott

    2015-01-01

    Music teachers interact regularly with students experiencing social and emotional challenges and are often under-prepared to do so. The purpose of this study was to examine approaches of a secondary general music teacher in responding to the social and emotional challenges of eight students in a music classroom at an alternative high school. A…

  4. Secondary School Learners' Response to the Teaching of Evolution in Limpopo Province, South Africa

    Mpeta, M.; de Villiers, J. J. R.; Fraser, W. J.

    2015-01-01

    One of the major causes of the problems affecting evolution education is a lack of acceptance of this concept, particularly by some people who have strongly entrenched religious beliefs. This paper reports on a section of a study which explored the influence of the beliefs of learners in some secondary schools from the Vhembe District in the…

  5. Global Warming Responses at the Primary Secondary Interface: 2. Potential Effectiveness of Education

    Skamp, Keith; Boyes, Eddie; Stannistreet, Martin

    2009-01-01

    In an earlier paper (Skamp, Boyes, & Stanisstreet, 2009b), students' beliefs and willingness to act in relation to 16 specific actions related to global warming were compared across the primary secondary interface. More primary students believed in the effectiveness of most actions to reduce global warming and were willing to take those…

  6. Global Warming Responses at the Primary Secondary Interface: 1. Students' Beliefs and Willingness to Act

    Skamp, Keith; Boyes, Eddie; Stannistreet, Martin

    2009-01-01

    Using survey methodology, students' beliefs, and willingness to act, about 16 specific actions related to global warming are compared across the primary secondary interface. More primary students believed in the effectiveness of most actions to reduce global warming and were willing to take those actions. In general there was a disparity between…

  7. Test of Achievement in Quantitative Economics for Secondary Schools: Construction and Validation Using Item Response Theory

    Eleje, Lydia I.; Esomonu, Nkechi P. M.

    2018-01-01

    A Test to measure achievement in quantitative economics among secondary school students was developed and validated in this study. The test is made up 20 multiple choice test items constructed based on quantitative economics sub-skills. Six research questions guided the study. Preliminary validation was done by two experienced teachers in…

  8. Case Study of a Post-Secondary Institution and Its Response to Student Homelessness

    K. Kovacs Burns (Kathy); M.S. Richter (Magdalena); Y. Mao (Yuping); S. Mogale (Shirley); M. Danko (Margaret)

    2016-01-01

    textabstractFrom the moment students are accepted into post-secondary institutions, the focus is on their studies and successful completion. Far less is known about what institutions understand about students’ personal stresses and issues with their finances, housing and especially student

  9. Endpoint distinctiveness facilitates analogical mapping in pigeons.

    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.

  10. Endpoint Distinctiveness Facilitates Analogical Mapping in Pigeons

    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

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

    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.

  12. Ordered kinematic endpoints for 5-body cascade decays

    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.

  13. Rail vehicle dynamic response to a nonlinear physical 'in-service' model of its secondary suspension hydraulic dampers

    Wang, W. L.; Zhou, Z. R.; Yu, D. S.; Qin, Q. H.; Iwnicki, S.

    2017-10-01

    A full nonlinear physical 'in-service' model was built for a rail vehicle secondary suspension hydraulic damper with shim-pack-type valves. In the modelling process, a shim pack deflection theory with an equivalent-pressure correction factor was proposed, and a Finite Element Analysis (FEA) approach was applied. Bench test results validated the damper model over its full velocity range and thus also proved that the proposed shim pack deflection theory and the FEA-based parameter identification approach are effective. The validated full damper model was subsequently incorporated into a detailed vehicle dynamics simulation to study how its key in-service parameter variations influence the secondary-suspension-related vehicle system dynamics. The obtained nonlinear physical in-service damper model and the vehicle dynamic response characteristics in this study could be used in the product design optimization and nonlinear optimal specifications of high-speed rail hydraulic dampers.

  14. Instructional Reasoning about Interpretations of Student Thinking That Supports Responsive Teaching in Secondary Mathematics

    Dyer, Elizabeth B.; Sherin, Miriam Gamoran

    2016-01-01

    Basing instruction on the substance of student thinking, or responsive teaching, is a critical strategy for supporting student learning. Previous research has documented responsive teaching by identifying observable teaching practices in a broad range of disciplines and classrooms. However, this research has not provided access to the teacher…

  15. Changes of main secondary metabolites in leaves of Ginkgo biloba in response to ozone fumigation

    HE Xingyuan; HUANG Wei; CHEN Wei; DONG Tian; LIU Changbing; CHEN Zhenju; XU Sheng; RUAN Yanan

    2009-01-01

    To investigate the effect of elevated O3 on the accumulation of main secondary metabolites in leaves of Ginkgo biloba L., four-year-old trees were exposed in open-top chambers with ambient air and the air with twice ambient O3 concentration in Shenyang in 2006.Elevated O3 increased the concentrations of terpenes, but decreased the concentrations of phenolics in G.biloba leaves.The results showed that secondary compounds from G.biloba leaves responded to the elevated O3 exposure in a different way when compared to previous studies which showed elevated O3 increased the concentrations of phenolics but had no effect on the terpenes in leaves of other deciduous trees.Furthermore, reduced synthesis of phenolics may decrease the resistance of G.biloba to O3 and other environmental factors.On the other hand, the induced synthesis of terpenes may enhance the antioxidant abilities in G.biloba leaves at the end of O3 fumigation.

  16. Marijuana smoking among secondary school students in Zaria, Nigeria: factors responsible and effects on academic performance.

    Shehu, A U; Idris, S H

    2008-12-01

    The use of Marijuana is on the increase worldwide especially among adolescents and youths. Marijuana smoking has gained a foothold in our environment because of peer group influence, accessibility and availability. Its medico-social effects could ruin the life and future of our youths. This study was undertaken to determine the prevalence and the factors that influence secondary school students in Zaria LGA to smoke and the effects on academic performance. A cross-sectional descriptive study was employed to generate data among secondary school students. A multi-stage sampling technique was used. Data was collected with the use of a structured, pre tested self-administered questionnaire. F2 test was used to test for significance of association between categorical variables. Of the 350 respondents, 262 (74.9%) were males, while 88 (25.1%) were females. The study shows that 33 of the students smoke marijuana giving a prevalence of 9.4%. There were more smokers in the age group 15-19 years (54.6%). Other factors that influence marijuana smoking include family background, peer pressure and attendance of social functions. There was better academic performance (51.1%) among non smokers as compared to smokers (27.2%), and this was found to be statistically significant (chi2 = 11.73, df = 5, P family background, peer pressure and attendance of social function influence marijuana smoking. A comprehensive school health education program should be instituted to curtail this menace.

  17. Hippeastrum hybridum anthocyanins as indicators of endpoint in acid

    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.

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

    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 ...

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

    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

  20. Lichen secondary metabolites are responsible for induction of apoptosis in HT-29 and A2780 human cancer cell lines.

    Bačkorová, M; Jendželovský, R; Kello, M; Bačkor, M; Mikeš, J; Fedoročko, P

    2012-04-01

    Lichens are a known source of approximately 800 unique secondary metabolites, many of which play important ecological roles, including regulating the equilibrium between symbionts. However, only a few of these compounds have been assessed for their effectiveness against various in vitro cancer models. Moreover, the mechanisms of biological activity of lichen secondary metabolites on living cells (including cancer cells) are still almost entirely unknown. In the present study, we investigated the mechanisms of cytotoxicity of four lichen secondary metabolites (parietin, atranorin, usnic acid and gyrophoric acid) on A2780 and HT-29 cancer cell lines. We found that usnic acid and atranorin were more effective anti-cancer compounds when compared to parietin and gyrophoric acid. Usnic acid and atranorin were capable of inducing a massive loss in the mitochondrial membrane potential, along with caspase-3 activation (only in HT-29 cells) and phosphatidylserine externalization in both tested cell lines. Induction of both ROS and especially RNS may be responsible, at least in part, for the cytotoxic effects of the tested compounds. Based on the detection of protein expression (PARP, p53, Bcl-2/Bcl-xL, Bax, p38, pp38) we found that usnic acid and atranorin are activators of programmed cell death in A2780 and HT-29, probably through the mitochondrial pathway. Copyright © 2012 Elsevier Ltd. All rights reserved.

  1. Responses to mild water deficit and rewatering differ among secondary metabolites but are similar among provenances within Eucalyptus species.

    McKiernan, Adam B; Potts, Brad M; Brodribb, Timothy J; Hovenden, Mark J; Davies, Noel W; McAdam, Scott A M; Ross, John J; Rodemann, Thomas; O'Reilly-Wapstra, Julianne M

    2016-02-01

    Water deficit associated with drought can severely affect plants and influence ecological interactions involving plant secondary metabolites. We tested the effect of mild water deficit and rewatering on physiological, morphological and chemical traits of juvenile Eucalyptus globulus Labill. and Eucalyptus viminalis Labill. We also tested if responses of juvenile eucalypts to water deficit and rewatering varied within species using provenances across a rainfall gradient. Both species and all provenances were similarly affected by mild water deficit and rewatering, as only foliar abscisic acid levels differed among provenances during water deficit. Across species and provenances, water deficit decreased leaf water potential, above-ground biomass and formylated phloroglucinol compound concentrations, and increased condensed tannin concentrations. Rewatering reduced leaf carbon : nitrogen, and total phenolic and chlorogenic acid concentrations. Water deficit and rewatering had no effect on total oil or individual terpene concentrations. Levels of trait plasticity due to water deficit and rewatering were less than levels of constitutive trait variation among provenances. The overall uniformity of responses to the treatments regardless of native provenance indicates limited diversification of plastic responses when compared with the larger quantitative variation of constitutive traits within these species. These responses to mild water deficit may differ from responses to more extreme water deficit or to responses of juvenile/mature eucalypts growing at each locality. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  2. Colloidal chirality in wormlike micellar systems exclusively originated from achiral species: Role of secondary assembly and stimulus responsivity.

    Zhao, Wenrong; Hao, Jingcheng

    2016-09-15

    Colloidal chirality in wormlike micellar systems exclusively originated from achiral species and discussion of the role of secondary assembly of fiber-like aggregates in chirality generation were presented in this paper. Herein, formation of colloidal wormlike micelles for the first time incorporated chirality and redox-responsiveness into one design via noncovalent interaction. A dual-stimuli-responsive gel of wormlike micelles which were designed by employing a dual-responsive cationic surfactant (FTMA) and a strong gelator (AzoNa4) and regulated by redox reaction and host-guest inclusion is presented. Both the redox and host-guest interaction play an important role in regulating the viscosity and supramolecular chirality of gels of the wormlike micelles. The supramolecular chirality and viscosity of the wormlike micelle gels were switched reversibly by exerting chemical redox onto the ferrocenyl groups. For the amphiphile FTMA containing redox-active ferrocenyl group, reversible control of the oxidation state of ferrocenyl groups leads to the charge and hydrophobicity changes of FTMA, therefore change its self-assembly behavior. Of equal interest, β-CD successfully detached the wormlike micelles via the recognition-inclusion behavior with FTMA and invalidate the H-bond and hydrophobic interaction between FTMA and AzoH4. This designed system provides a new strategy to tune the supramolecular chirality of colloidal aggregates and explore the specific packing mode detail within the micelles or the secondary assembly of the inter-micelles. We anticipate this dual-responsive H-bond-directed chiral gel switch could propose a new strategy when researchers designing new, multi-responsive functional gel materials. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Discerning Primary and Secondary Factors Responsible for Clinical Fatigue in Multisystem Diseases

    David Maughan

    2014-09-01

    Full Text Available Fatigue is a common symptom of numerous acute and chronic diseases, including myalgic encephalomyelitis/chronic fatigue syndrome, multiple sclerosis, heart failure, cancer, and many others. In these multi-system diseases the physiological determinants of enhanced fatigue encompass a combination of metabolic, neurological, and myofibrillar adaptations. Previous research studies have focused on adaptations specific to skeletal muscle and their role in fatigue. However, most have neglected the contribution of physical inactivity in assessing disease syndromes, which, through deconditioning, likely contributes to symptomatic fatigue. In this commentary, we briefly review disease-related muscle phenotypes in the context of whether they relate to the primary disease or whether they develop secondary to reduced physical activity. Knowledge of the etiology of the skeletal muscle adaptations in these conditions and their contribution to fatigue symptoms is important for understanding the utility of exercise rehabilitation as an intervention to alleviate the physiological precipitants of fatigue.

  4. Hepatocellular Carcinoma after Sustained Viral Response to Interferon and Ribavirin Therapy in Cirrhosis Secondary to Chronic Hepatitis C

    Khokhar, N.; Qureshi, M.U.; Niazi, T.K.

    2013-01-01

    Objective: To determine the frequency of development of hepatocellular carcinoma in patients with chronic liver disease secondary to hepatitis C who had achieved sustained virological response with Interferon and Ribavirin therapy. Study Design: Retrospective descriptive study. Place and Duration of Study: Shifa International Hospital, Islamabad, Pakistan, from January 2007 to January 2012. Methodology: Hepatitis C related chronic liver disease patients who were treated with interferon and ribavirin, after they achieved sustained virological response, they were followed for a mean of 42 A+- 17 months. During this time, development of hepatocellular carcinoma was ascertained. All underwent surveillance with alpha-feto-protein and ultrasonography every 6 months. Results: Out of the 58 patients who had achieved sustained virological response, 3 developed hepatocellular carcinoma after a mean follow-up of 38 A+- 14 months. It was multifocal in 2 cases and was single lesion in the 3rd. Two patients ultimately died, one with upper GI bleeding and the other with hepatic encephalopathy, while 3rd patient with single lesion is still surviving. Conclusion: Three out of 58 patients of hepatitis C related chronic liver disease developed hepatocellular carcinoma during follow-up in patients who had achieved sustained virological response. These patients need closer follow-up, for development of complications, even if they have achieved sustained viral response. (author)

  5. Vasovagal response secondary to permanent contraception device in pulmonary arterial hypertension

    Cope, Jessica; Alnuaimat, Hassan

    2015-01-01

    Abstract Adequate contraception is an essential component of managing pulmonary hypertension in women of childbearing age. Intrauterine devices are a popular contraceptive choice for many women but are associated with a risk of vagal response upon placement in certain patients with pulmonary hypertension, which may not be well tolerated. More recently, newer permanent contraception devices have emerged in the market, such as the Essure. We describe the first case, to our knowledge, of vagal-associated response due to an Essure device placement. PMID:26697184

  6. The initial response of secondary mathematics teachers to a one-to-one laptop program

    Zuber, Edward Nordin; Anderson, Judy

    2013-06-01

    Studies of one-to-one programs consistently report lower use of laptops in mathematics classrooms compared to other subjects but do not elaborate reasons for these observations. This mixed-method study investigated the experiences and beliefs of 28 mathematics teachers at five secondary schools during the second year of the New South Wales Digital Education Revolution laptop program. While some mathematics teachers planned for students to use their laptops up to once a week, most reported less frequent use in the classroom. Teachers were grouped into categories "Non Adopters," "Cautious Adopters," and "Early Adopters" according to reported classroom use of laptops, then analysed for differences in confidence, knowledge, and beliefs relating to technology for teaching and learning mathematics. A prevalent belief limiting laptop use is that students authentically learn mathematics only using pen and paper. Cautious Adopters and Non Adopters expressed beliefs that laptops exacerbate classroom management problems, especially for lower-achieving students. In the context of ability-streamed classes these beliefs effectively ruled out use of laptops for entire classrooms.

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

    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

  8. Blocking of PDL-1 interaction enhances primary and secondary CD8 T cell response to herpes simplex virus-1 infection.

    Rudragouda Channappanavar

    Full Text Available The blocking of programmed death ligand-1 (PDL-1 has been shown to enhance virus-specific CD8 T cell function during chronic viral infections. Though, how PDL-1 blocking at the time of priming affects the quality of CD8 T cell response to acute infections is not well understood and remains controversial. This report demonstrates that the magnitude of the primary and secondary CD8 T cell responses to herpes simplex virus-1 (HSV-1 infection is subject to control by PDL-1. Our results showed that after footpad HSV-1 infection, PD-1 expression increases on immunodominant SSIEFARL peptide specific CD8 T cells. Additionally, post-infection, the level of PDL-1 expression also increases on CD11c+ dendritic cells. Intraperitoneal administration of anti-PDL-1 monoclonal antibody given one day prior to and three days after cutaneous HSV-1 infection, resulted in a marked increase in effector and memory CD8 T cell response to SSIEFARL peptide. This was shown by measuring the quantity and quality of SSIEFARL-specific CD8 T cells by making use of ex-vivo assays that determine antigen specific CD8 T cell function, such as intracellular cytokine assay, degranulation assay to measure cytotoxicity and viral clearance. Our results are discussed in terms of the beneficial effects of blocking PDL-1 interactions, while giving prophylactic vaccines, to generate a more effective CD8 T cell response to viral infection.

  9. Spongionella secondary metabolites, promising modulators of immune response through CD147 receptor modulation

    Jon Andoni Sánchez

    2016-10-01

    Full Text Available The modulation of the immune system can have multiple applications such as cancer treatment, and a wide type of processes involving inflammation where the potent chemotactic agent cyclophilin A (Cyp A is implicated. The Porifera phylum, in which Spongionella is encompassed, is the main producer of marine bioactive compounds. Four secondary metabolites obtained from Spongionella (Gracilin H, A, L and Tetrahydroaplysulphurin-1 were described to hit Cyp A and to block the release of inflammation mediators. Based on these results some role of Spongionella compounds on other steps of the signalling pathway mediated by this chemotactic agent can be hypothesised. In the present paper we studied the effect of these four compounds on the surface membrane CD147 receptor expression, on the extracellular levels of Cyp A and on the ability to migrate of concanavalin (Con A-activated T lymphocytes. Similarly to a well-known immunosuppressive agent cyclosporine A (CsA, Gracilin H, A, L and tetrahydroaplysulphurin-1 were able to reduce the CD147 membrane expression and to block the release of Cyp A to the medium. Besides, by using Cyp A as chemotactic agent, T cell migration was inhibited when cells were previously incubated with Gracilin A and Gracilin L. These positive results lead us to test the in vivo effect of Gracilin H and L in a mouse ear delayed hypersensitive reaction. Thus, both compounds efficiently reduce the ear swelling as well as the inflammatory cell infiltration. These results provide more evidences for their potential therapeutic application in immune related diseases of Spongionella compounds.

  10. Planning and analyzing clinical trials with composite endpoints

    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...

  11. Gastroenterological endpoints in drug trials for cystic fibrosis

    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.

  12. Endpoint behavior of high-energy scattering cross sections

    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.

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

    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.

  14. Failed Switching off in the MIBI-Parathyroid Scintigraphy in a Dialyzed Patient with Secondary Hyperparathyroidism Responsive to Cinacalcet Therapy

    Piergiorgio Bolasco

    2010-01-01

    Full Text Available The aims of your case report is to show the predictivity of Tc99m-sestamibi (MIBI scintigraphy and doppler ultrasound imaging on secondary hyperparathyroidism (SHPT in a patient responsive to calcimimetic treatment. Moreover, it has been reported that calcimimetic has great potential in reducing the volume of the parathyroid gland. On the other hand, the MIBI scintigraphy is considered a crucial diagnostic procedure to monitor the response to therapy in terms of turnover and cellular metabolism; whereas, ultrasound to monitor the volume variation in response to treatment. It is described the case of a 73-year-old man on hemodialysis from 1995 for ESRD. Within 2 years the patient gradually developed SHPT with progressively increased iPTH up to 1,000 ρg/ml. The ultrasound, highlighted the presence of two parathyroid hyperplasia, confirmed by scintigraphy, showing focal increase uptake of sestamibi in the same anatomical areas. As a result of the patient's refusal to perform a parathyroidectomy, cinacalcet, was administered (65 mg overage daily dose. After a year of treatment, there was a striking decrease of iPTH (from 1300 to 57 ρg/ml, −95%; but, on the contrary to expectations, this positive metabolic outcome, was not followed by parathyroid changes in ultrasound and scintigraphic findings.

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

    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

  16. Functional and compositional responses in soil microbial communities along two metal pollution gradients: does the level of historical pollution affect resistance against secondary stress?

    Azarbad, H.; Niklinska, M.; Nikiel, K.; van Straalen, N.M.; Röling, W.F.M.

    2015-01-01

    We examined how the exposure to secondary stressors affected the functional and compositional responses of microbial communities along two metal pollution gradients in Polish forests and whether responses were influenced by the level of metal pollution. Basal respiration rate and community

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

    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

  18. A Study of the Effectiveness of Group Spiritual Intelligence Training on Self-Efficacy and Social Responsibility of Secondary School Girls in Shahrekord

    Katayoun Safa Chaleshtari; Tayebe Sharifi; Mohammad Ghasemi Pirbalooti

    2017-01-01

    Background: The purpose of this study was to investigate the effectiveness of group spiritual intelligence training on self-efficacy and social responsibility of high school secondary school students in Shahrekord. Methods: The parallel intervention research method was used in this study. The statistical population included all female secondary school students in Shahrekord during the academic year 1393 - 1394. Random cluster sampling was used to select the samples. Then, schools were rand...

  19. Preliminary remediation goals for ecological endpoints

    Efroymson, R.A.; Suter, G.W. II; Sample, B.E.; Jones, D.S.

    1996-07-01

    Preliminary remediation goals (PRGs) are useful for risk assessment and decision making at Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) sites. PRGs are upper concentration limits for specific chemicals in specific environmental media that are anticipated to protect human health or the environment. They can be used for multiple remedial investigations at multiple facilities. In addition to media and chemicals of potential concern, the development of PRGs generally requires some knowledge or anticipation of future land use. In Preliminary Remediation Goals for Use at the U.S. Department of Energy Oak Ridge Operations Office (Energy Systems 1995), PRGs intended to protect human health were developed with guidance from Risk Assessment Guidance for Superfund: Volume I - Human Health Evaluation Manual, Part B (RAGS) (EPA 1991). However, no guidance was given for PRGs based on ecological risk. The numbers that appear in this volume have, for the most part, been extracted from toxicological benchmarks documents for Oak Ridge National Laboratory (ORNL) and have previously been developed by ORNL. The sources of the quantities, and many of the uncertainties associated with their derivation, are described in this technical memorandum

  20. Preliminary remediation goals for ecological endpoints

    Efroymson, R.A.; Suter, G.W. II.

    1995-09-01

    Preliminary remediation goals (PRGs) are useful for risk assessment and decision making at Comprehensive Environmental Response, compensation, and Liability Act (CERCLA) sites. PRGs are upper concentration limits for specific chemicals in specific environmental media that are anticipated to protect human health or the environment. They can be used for multiple remedial investigations at multiple facilities. In addition to media and chemicals of potential concern, the development of PRGs generally requires some knowledge or anticipation of future land use. In Preliminary Remediation Goals for Use at the US Department of Energy Oak Ridge Operations Office (Energy Systems 1995), PRGs intended to protect human health were developed with guidance from Risk Assessment Guidance for Superfund: Volume I-Human Health Evaluation Manual, Part B (RAGS) (EPA 1991). However, no guidance was given for PRGs based on ecological risk. The numbers that appear in this volume have, for the most part, been extracted from toxicological benchmarks documents for Oak Ridge National Laboratory (ORNL) and have previously been developed by ORNL. The sources of the quantities, and many of the uncertainties associated with their derivation, are described in this technical memorandum

  1. Biochemical endpoints of glucocorticoid hormone action

    Young, D.A.; Nicholson, M.L.; Guyette, W.A.; Giddings, S.J.; Mendelsohn, S.L.; Nordeen, S.K.; Lyons, R.T.

    1978-01-01

    Both the rapidly evolving metabolic effects of glucocorticoids and the more slowly developing lethal actions appear to be initiated via the synthesis of new mRNAs and proteins. The chronic suppression of cell growth may be the consequence of suppression of overall rates of protein synthesis (and probably RNA and DNA synthesis as well) that in turn may represent the cellular response to the small changes in ratios of adenine nucleotides that result from the suppression of oxidative ATP production. The inhibition of glucose transport may also play a role here to prevent a compensatory increase in glycolytic ATP production. Some other hormone actions, the decrease in the ability of cells to concentrate AIB and the increase in nuclear fragility are unrelated to, and evolve separately from, the hormonal inhibitions on energy production. Cell killing is not the result of suppression of protein synthesis, nor of hormone-induced increases in calcium uptake. While the mechanisms are unknown, the increase in nuclear fragility appears to be the earliest measure of their operation. In tumor cells resistance to lethal actions of glucocorticoids may emerge via the selection of cells with hardier membranes, that are better able to withstand the intracellular destructive events set in motion by high levels of glucocorticoids.

  2. Bystander effect: Biological endpoints and microarray analysis

    Chaudhry, M. Ahmad [Department of Medical Laboratory and Radiation Sciences, College of Nursing and Health Sciences, University of Vermont, 302 Rowell Building, Burlington, VT 05405 (United States) and DNA Microarray Facility, University of Vermont, Burlington, VT 05405 (United States)]. E-mail: mchaudhr@uvm.edu

    2006-05-11

    In cell populations exposed to ionizing radiation, the biological effects occur in a much larger proportion of cells than are estimated to be traversed by radiation. It has been suggested that irradiated cells are capable of providing signals to the neighboring unirradiated cells resulting in damage to these cells. This phenomenon is termed the bystander effect. The bystander effect induces persistent, long-term, transmissible changes that result in delayed death and neoplastic transformation. Because the bystander effect is relevant to carcinogenesis, it could have significant implications for risk estimation for radiation exposure. The nature of the bystander effect signal and how it impacts the unirradiated cells remains to be elucidated. Examination of the changes in gene expression could provide clues to understanding the bystander effect and could define the signaling pathways involved in sustaining damage to these cells. The microarray technology serves as a tool to gain insight into the molecular pathways leading to bystander effect. Using medium from irradiated normal human diploid lung fibroblasts as a model system we examined gene expression alterations in bystander cells. The microarray data revealed that the radiation-induced gene expression profile in irradiated cells is different from unirradiated bystander cells suggesting that the pathways leading to biological effects in the bystander cells are different from the directly irradiated cells. The genes known to be responsive to ionizing radiation were observed in irradiated cells. Several genes were upregulated in cells receiving media from irradiated cells. Surprisingly no genes were found to be downregulated in these cells. A number of genes belonging to extracellular signaling, growth factors and several receptors were identified in bystander cells. Interestingly 15 genes involved in the cell communication processes were found to be upregulated. The induction of receptors and the cell

  3. Bystander effect: Biological endpoints and microarray analysis

    Chaudhry, M. Ahmad

    2006-01-01

    In cell populations exposed to ionizing radiation, the biological effects occur in a much larger proportion of cells than are estimated to be traversed by radiation. It has been suggested that irradiated cells are capable of providing signals to the neighboring unirradiated cells resulting in damage to these cells. This phenomenon is termed the bystander effect. The bystander effect induces persistent, long-term, transmissible changes that result in delayed death and neoplastic transformation. Because the bystander effect is relevant to carcinogenesis, it could have significant implications for risk estimation for radiation exposure. The nature of the bystander effect signal and how it impacts the unirradiated cells remains to be elucidated. Examination of the changes in gene expression could provide clues to understanding the bystander effect and could define the signaling pathways involved in sustaining damage to these cells. The microarray technology serves as a tool to gain insight into the molecular pathways leading to bystander effect. Using medium from irradiated normal human diploid lung fibroblasts as a model system we examined gene expression alterations in bystander cells. The microarray data revealed that the radiation-induced gene expression profile in irradiated cells is different from unirradiated bystander cells suggesting that the pathways leading to biological effects in the bystander cells are different from the directly irradiated cells. The genes known to be responsive to ionizing radiation were observed in irradiated cells. Several genes were upregulated in cells receiving media from irradiated cells. Surprisingly no genes were found to be downregulated in these cells. A number of genes belonging to extracellular signaling, growth factors and several receptors were identified in bystander cells. Interestingly 15 genes involved in the cell communication processes were found to be upregulated. The induction of receptors and the cell

  4. Responses of secondary chemicals in sugar maple (Acer saccharum) seedlings to UV-B, springtime warming and nitrogen additions

    Sager, E.P.S.; Hutchinson, T.C. [Trent Univ., Peterborough, ON (Canada). Environmental Studies

    2006-10-15

    Elevated UV-B radiation due to climatic change and ozone depletion may represent a significant springtime environmental stressor to germinating seedlings in temperate forest regions. This study aimed to determine the effects of UV-B, nitrogen (N) fertilization and climate warming on the concentrations of base cations and secondary metabolites in the foliage of sugar maple seedlings growing in acid or alkaline soils. The influence of measured flavonoids and phenolics on herbivore activity was examined, as well as the relationship between foliar concentrations of calcium (Ca); manganese (Mn); and N and the production of phenolic and flavonoid compounds. Experimental plots were established in mature hardwood forests in alkaline and acid soil locations in Bobcaygeon and Haliburton, Ontario. Pentagonal open-top chambers were used to lengthen the growing season and simulate an earlier spring. Ammonium nitrate was applied at a rate comparable with an additional deposition of 5 g N per m per year. Fertilizer was applied on 3 separate occasions. Ambient UV-B radiation was screened out with Mylar D polyester film. Sites, treatments and time of sampling had complex effects on foliar elemental chemistry, production of secondary compounds and herbivory. Foliar concentrations of individual phenols were higher in seedlings in the UV-B exclusion treatments. At both sites, removal of ambient UV-B led to increases in flavonoids and chlorogenic acid, and reduced herbivore activity. At Haliburton, ammonium nitrate fertilization led to further increases in foliar Mn. Nitrogen additions led to decreases in the concentrations of some flavonoids at both sites. It was concluded that the composition of the forest soil governs the response of seedlings when they are exposed to abiotic stressors. 63 refs., 5 tabs., 8 figs.

  5. Response of primary and secondary rainforest flowers and fruits to a cyclone, and implications for plant-servicing bats.

    Scanlon, Annette T; Petit, Sophie; Tuiwawa, Marika; Naikatini, Alivereti

    2018-02-24

    The response of primary (PF) and secondary (SF) rainforests to cyclones has broad implications for servicing fauna and the resilience of forest functions. We collected fine-scale data on the reproductive phenology of plant communities in Fijian PF and SF in 12 monthly surveys before and after Cyclone Tomas (2010). We generated a resource index from the reproductive loads of 2218 trees and 1150 non-trees (>190 species) and trunk and stem diameter to assess patterns in resource abundance for nectarivores and frugivores (hereafter NF resources). We aimed to determine (i) whether species richness of NF resources differed between forests; (ii) the patterns of resilience of NF resources at community level in both forests after a cyclone; and (iii) the effect of response on NF resources for plant-servicing bats (Pteropodidae). In 12 months preceding the cyclone, NF resources were greater in PF trees; non-tree resources fluctuated and were greater in SF. Lower species richness of NF resources in SF indicated that fewer opportunities exist there for exploitation by a diverse fauna. More resources were available for bats in PF. In 12 months following the cyclone, PF flowers and fruits, and SF fruits specifically used by pteropodid bats decreased for trees. Non-tree resources were especially susceptible to the cyclone. No universal pattern of decline was associated with the cyclone; instead, some NF resources declined and others were resilient or responded rapidly to a post-cyclone environment. Both PF and SF demonstrated resilience at the community level via increased flower survival (PF) and rapid flower production (SF). Reduced species richness of NF resources in SF will compromise future resilience and response to disturbance, including for threatened pteropodid bat species. These findings are critical for long-term management of forests, given predicted increases in cyclone frequency and intensity associated with anthropogenic climate change. © 2018 John Wiley & Sons

  6. Sample size determination in clinical trials with multiple endpoints

    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...

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

    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

  8. IL-23 p19 knockout mice exhibit minimal defects in responses to primary and secondary infection with Francisella tularensis LVS.

    Sherry L Kurtz

    Full Text Available Our laboratory's investigations into mechanisms of protective immunity against Francisella tularensis Live Vaccine Strain (LVS have uncovered mediators important in host defense against primary infection, as well as those correlated with successful vaccination. One such potential correlate was IL-12p40, a pleiotropic cytokine that promotes Th1 T cell function as part of IL-12p70. LVS-infected IL-12p40 deficient knockout (KO mice maintain a chronic infection, but IL-12p35 KO mice clear LVS infection; thus the role that IL-12p40 plays in immunity to LVS is independent of the IL-12p70 heterodimer. IL-12p40 can also partner with IL-23p19 to create the heterodimeric cytokine IL-23. Here, we directly tested the role of IL-23 in LVS resistance, and found IL-23 to be largely dispensable for immunity to LVS following intradermal or intranasal infection. IL-23p19 KO splenocytes were fully competent in controlling intramacrophage LVS replication in an in vitro overlay assay. Further, antibody responses in IL-23p19 KO mice were similar to those of normal wild type mice after LVS infection. IL-23p19 KO mice or normal wild type mice that survived primary LVS infection survived maximal doses of LVS secondary challenge. Thus p40 has a novel role in clearance of LVS infection that is unrelated to either IL-12 or IL-23.

  9. The Genome Sequence of the Cyanobacterium Oscillatoria sp. PCC 6506 Reveals Several Gene Clusters Responsible for the Biosynthesis of Toxins and Secondary Metabolites▿

    Méjean, Annick; Mazmouz, Rabia; Mann, Stéphane; Calteau, Alexandra; Médigue, Claudine; Ploux, Olivier

    2010-01-01

    We report a draft sequence of the genome of Oscillatoria sp. PCC 6506, a cyanobacterium that produces anatoxin-a and homoanatoxin-a, two neurotoxins, and cylindrospermopsin, a cytotoxin. Beside the clusters of genes responsible for the biosynthesis of these toxins, we have found other clusters of genes likely involved in the biosynthesis of not-yet-identified secondary metabolites. PMID:20675499

  10. The Asthma Control Questionnaire as a clinical trial endpoint

    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...

  11. Secondary Hypertension

    Secondary hypertension Overview Secondary hypertension (secondary high blood pressure) is high blood pressure that's caused by another medical condition. Secondary hypertension can be caused by conditions that affect your kidneys, ...

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

    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.

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

    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

  14. Influence of age on brain edema formation, secondary brain damage and inflammatory response after brain trauma in mice.

    Ralph Timaru-Kast

    Full Text Available After traumatic brain injury (TBI elderly patients suffer from higher mortality rate and worse functional outcome compared to young patients. However, experimental TBI research is primarily performed in young animals. Aim of the present study was to clarify whether age affects functional outcome, neuroinflammation and secondary brain damage after brain trauma in mice. Young (2 months and old (21 months male C57Bl6N mice were anesthetized and subjected to a controlled cortical impact injury (CCI on the right parietal cortex. Animals of both ages were randomly assigned to 15 min, 24 h, and 72 h survival. At the end of the observation periods, contusion volume, brain water content, neurologic function, cerebral and systemic inflammation (CD3+ T cell migration, inflammatory cytokine expression in brain and lung, blood differential cell count were determined. Old animals showed worse neurological function 72 h after CCI and a high mortality rate (19.2% compared to young (0%. This did not correlate with histopathological damage, as contusion volumes were equal in both age groups. Although a more pronounced brain edema formation was detected in old mice 24 hours after TBI, lack of correlation between brain water content and neurological deficit indicated that brain edema formation is not solely responsible for age-dependent differences in neurological outcome. Brains of old naïve mice were about 8% smaller compared to young naïve brains, suggesting age-related brain atrophy with possible decline in plasticity. Onset of cerebral inflammation started earlier and primarily ipsilateral to damage in old mice, whereas in young mice inflammation was delayed and present in both hemispheres with a characteristic T cell migration pattern. Pulmonary interleukin 1β expression was up-regulated after cerebral injury only in young, not aged mice. The results therefore indicate that old animals are prone to functional deficits and strong ipsilateral cerebral

  15. SOS response in bacteria: Inhibitory activity of lichen secondary metabolites against Escherichia coli RecA protein.

    Bellio, Pierangelo; Di Pietro, Letizia; Mancini, Alisia; Piovano, Marisa; Nicoletti, Marcello; Brisdelli, Fabrizia; Tondi, Donatella; Cendron, Laura; Franceschini, Nicola; Amicosante, Gianfranco; Perilli, Mariagrazia; Celenza, Giuseppe

    2017-06-15

    RecA is a bacterial multifunctional protein essential to genetic recombination, error-prone replicative bypass of DNA damages and regulation of SOS response. The activation of bacterial SOS response is directly related to the development of intrinsic and/or acquired resistance to antimicrobials. Although recent studies directed towards RecA inactivation via ATP binding inhibition described a variety of micromolar affinity ligands, inhibitors of the DNA binding site are still unknown. Twenty-seven secondary metabolites classified as anthraquinones, depsides, depsidones, dibenzofurans, diphenyl-butenolides, paraconic acids, pseudo-depsidones, triterpenes and xanthones, were investigated for their ability to inhibit RecA from Escherichia coli. They were isolated in various Chilean regions from 14 families and 19 genera of lichens. The ATP hydrolytic activity of RecA was quantified detecting the generation of free phosphate in solution. The percentage of inhibition was calculated fixing at 100µM the concentration of the compounds. Deeper investigations were reserved to those compounds showing an inhibition higher than 80%. To clarify the mechanism of inhibition, the semi-log plot of the percentage of inhibition vs. ATP and vs. ssDNA, was evaluated. Only nine compounds showed a percentage of RecA inhibition higher than 80% (divaricatic, perlatolic, alpha-collatolic, lobaric, lichesterinic, protolichesterinic, epiphorellic acids, sphaerophorin and tumidulin). The half-inhibitory concentrations (IC 50 ) calculated for these compounds were ranging from 14.2µM for protolichesterinic acid to 42.6µM for sphaerophorin. Investigations on the mechanism of inhibition showed that all compounds behaved as uncompetitive inhibitors for ATP binding site, with the exception of epiphorellic acid which clearly acted as non-competitive inhibitor of the ATP site. Further investigations demonstrated that epiphorellic acid competitively binds the ssDNA binding site. Kinetic data were

  16. 78 FR 46351 - Trial Designs and Endpoints for Liver Disease Secondary to Nonalcoholic Steatohepatitis; Public...

    2013-07-31

    ... procedures will be performed. For parking and security information, please refer to http://www.fda.gov/About...-come, first-served basis. Those without Internet access should contact Anissa Davis (see Contact Person...

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

    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

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

    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.

  19. Characterization of the CD8+ T cell responses directed against respiratory syncytial virus during primary and secondary infection in C57BL/6 mice

    Lukens, Michael V.; Claassen, Erwin A.W.; Graaff, Patricia M.A. de; Dijk, Mariska E.A. van; Hoogerhout, Peter; Toebes, Mireille; Schumacher, Ton N.; Most, Robbert G. van der; Kimpen, Jan L.L.; Bleek, Grada M. van

    2006-01-01

    The BALB/c mouse model for human respiratory syncytial virus infection has contributed significantly to our understanding of the relative role for CD4 + and CD8 + T cells to immune protection and pathogenic immune responses. To enable comparison of RSV-specific T cell responses in different mouse strains and allow dissection of immune mechanisms by using transgenic and knockout mice that are mostly available on a C57BL/6 background, we characterized the specificity, level and functional capabilities of CD8 + T cells during primary and secondary responses in lung parenchyma, airways and spleens of C57BL/6 mice. During the primary response, epitopes were recognized originating from the matrix, fusion, nucleo- and attachment proteins, whereas the secondary response focused predominantly on the matrix epitope. C57BL/6 mice are less permissive for hRSV infection than BALB/c mice, yet we found CD8 + T cell responses in the lungs and bronchoalveolar lavage, comparable to the responses described for BALB/c mice

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

    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.

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

    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

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

    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.

  3. Exposing the cancer genome atlas as a SPARQL endpoint

    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

  4. Overview of Biomarkers and Surrogate Endpoints in Drug Development

    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.

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

    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.

  6. EFFECTS OF TWO METHODS OF INSTRUCTION ON STUDENTS’ CRITICAL RESPONSE TO PROSE LITERATURE TEXT IN ENGLISH IN SOME SECONDARY SCHOOLS IN BENIN CITY

    F. O. EZEOKOLI

    2016-08-01

    Full Text Available This study investigated the effects of two methods of instruction on secondary school students’ critical response to Prose Literature text. The study adopted a pretest, posttest, control group quasi experimental design. The participants in the study were 84 Senior Secondary II students of Literature-in-English purposively selected from four Schools in Ikpoba-Okha Local Government Area of Edo State. Two intact classes were randomly assigned to each of the treatment and control groups. Three hypotheses were tested at 0.05 alpha level. The instruments used were: Critical Response to Prose Literature Test (r = .75, Questionnaire on Home Background of Students (r = .82, and Critical Response to Prose Literature Test Marking Guide. Data obtained were subjected to Analysis of Covariance and graph. The results showed significant main effect of treatment on students’ critical response to Prose Literature (F (1, 77 = 44.731; p < .05. Students exposed to Engagement Strategies Method performed better than those exposed to the Conventional Method of instruction. Further, home background of students had no significant effect on students’ critical response to Prose Literature text (F (2, 77 = 4.902; p < .05. There was significant interaction effect of treatment and home background of students on students’ critical response to Prose Literature text (F (2, 77 = 3.508; p < .05. It was concluded that Engagement Strategies Method is effective in promoting students’ critical response to Prose Literature text. Teachers of Literature-in-English should employ Engagement Strategies Method in teaching Prose Literature to students in Senior Secondary Schools.

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

    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.

  8. Response to Intervention for Middle School Students with Reading Difficulties: Effects of a Primary and Secondary Intervention

    Vaughn, Sharon; Cirino, Paul T.; Wanzek, Jeanne; Wexler, Jade; Fletcher, Jack M.; Denton, Carolyn D.; Barth, Amy; Romain, Melissa; Francis, David J.

    2010-01-01

    This study examined the effectiveness of a yearlong, researcher-provided, Tier 2 (secondary) intervention with a group of sixth-graders. The intervention emphasized word recognition, vocabulary, fluency, and comprehension. Participants scored below a proficiency level on their state accountability test and were compared to a similar group of…

  9. Primary, Secondary Metabolites, H2O2, Malondialdehyde and Photosynthetic Responses of Orthosiphon stimaneus Benth. to Different Irradiance Levels

    Mohd Hafiz Ibrahim

    2012-01-01

    Full Text Available The resource availability hypothesis predicts an increase in the allocation to secondary metabolites when carbon gain is improved relative to nutrient availability, which normally occurs during periods of low irradiance. The present work was carried out to confirm this hypothesis by investigating the effects of decreasing irradiance on the production of plant secondary metabolites (flavonoids and phenolics in the herbal plant Orthosiphon stamineus, and to characterize this production by carbohydrate, H2O2, and malondialdehyde (MDA levels, net photosynthesis, leaf chlorophyll content and carbon to nitrogen ratio (C/N. Four levels of irradiance (225, 500, 625 and 900 µmol/m2/s were imposed onto two-week old seedlings for 12 weeks in a randomized complete block design experiment. Peak production of total flavonoids, phenolics, soluble sugar, starch and total non-structural carbohydrate ocurred under low irradiance of 225 µmol/m2/s, and decreased with increasing irradiance. The up-regulation of secondary metabolites could be explained by the concomitant increases in H2O2 and MDA activities under low irradiance. This condition also resulted in enhanced C/N ratio signifying a reduction in nitrogen levels, which had established significant negative correlations with net photosynthesis, total biomass and total chlorophyll content, indicating the possible existence of a trade-off between growth and secondary metabolism under low irradiance with reduced nitrogen content. The competition between total chlorophyll and secondary metabolites production, as exhibited by the negative correlation coefficient under low irradiance, also suggests a sign of gradual switch of investment from chlorophyll to polyphenols production.

  10. Lymphocyte density determined by computational pathology validated as a predictor of response to neoadjuvant chemotherapy in breast cancer: secondary analysis of the ARTemis trial.

    Ali, H R; Dariush, A; Thomas, J; Provenzano, E; Dunn, J; Hiller, L; Vallier, A-L; Abraham, J; Piper, T; Bartlett, J M S; Cameron, D A; Hayward, L; Brenton, J D; Pharoah, P D P; Irwin, M J; Walton, N A; Earl, H M; Caldas, C

    2017-08-01

    We have previously shown lymphocyte density, measured using computational pathology, is associated with pathological complete response (pCR) in breast cancer. The clinical validity of this finding in independent studies, among patients receiving different chemotherapy, is unknown. The ARTemis trial randomly assigned 800 women with early stage breast cancer between May 2009 and January 2013 to three cycles of docetaxel, followed by three cycles of fluorouracil, epirubicin and cyclophosphamide once every 21 days with or without four cycles of bevacizumab. The primary endpoint was pCR (absence of invasive cancer in the breast and lymph nodes). We quantified lymphocyte density within haematoxylin and eosin (H&E) whole slide images using our previously described computational pathology approach: for every detected lymphocyte the average distance to the nearest 50 lymphocytes was calculated and the density derived from this statistic. We analyzed both pre-treatment biopsies and post-treatment surgical samples of the tumour bed. Of the 781 patients originally included in the primary endpoint analysis of the trial, 609 (78%) were included for baseline lymphocyte density analyses and a subset of 383 (49% of 781) for analyses of change in lymphocyte density. The main reason for loss of patients was the availability of digitized whole slide images. Pre-treatment lymphocyte density modelled as a continuous variable was associated with pCR on univariate analysis (odds ratio [OR], 2.92; 95% CI, 1.78-4.85; P < 0.001) and after adjustment for clinical covariates (OR, 2.13; 95% CI, 1.24-3.67; P = 0.006). Increased pre- to post-treatment lymphocyte density showed an independent inverse association with pCR (adjusted OR, 0.1; 95% CI, 0.033-0.31; P < 0.001). Lymphocyte density in pre-treatment biopsies was validated as an independent predictor of pCR in breast cancer. Computational pathology is emerging as a viable and objective means of identifying predictive biomarkers

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

    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.

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

    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.

  13. Concanavalin A-mediated in vitro activation of a secondary cytotoxic T-cell response in virus-primed splenocytes

    Thomsen, Allan Randrup; Jensen, B L

    1980-01-01

    In a recent report it was shown that what appeared to be secondary cytotoxic T cells could be obtained from lymphocytic choriomeningitis virus (LCMV)-primed splenocytes after stimulation in vitro with the non-specific T cell mitogen concanavalin A (Con A). The present experiments attempt to chara......In a recent report it was shown that what appeared to be secondary cytotoxic T cells could be obtained from lymphocytic choriomeningitis virus (LCMV)-primed splenocytes after stimulation in vitro with the non-specific T cell mitogen concanavalin A (Con A). The present experiments attempt...... to characterize further these effector cells and, in particular, to establish whether the Con A-activated cytotoxic effectors are qualitatively different from the secondary cytotoxic T cells induced by restimulation with the homologous antigen. It was found that: (1) in vitro activation with Con A could......, since no evidence was found to indicate a role for other cell types or soluble (cytotoxic or arming) factors; (4) cytotoxicity was specific with regard to both virus and 'self'. By comparison with previous data on LCMV-induced cytotoxic T cells, it is concluded that Con A induces the generation...

  14. Design and endpoints of clinical and translational trials in advanced colorectal cancer. a proposal from GROUP Español Multidisciplinar en Cancer Digestivo (GEMCAD).

    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. Adalimumab (Humira) restores clinical response in patients with secondary loss of efficacy from infliximab (Remicade) or etanercept (Enbrel): results from the STURE registry at Karolinska University Hospital.

    Wick, M C; Ernestam, S; Lindblad, S; Bratt, J; Klareskog, L; van Vollenhoven, R F

    2005-01-01

    To determine whether the tumour necrosis factor-alpha (TNF-alpha) antagonist adalimumab (Humira) can be efficacious after secondary loss of efficacy (i.e. loss of clinical response in patients who had initially demonstrated clinical response) to infliximab (Remicade) or etanercept (Enbrel). We studied 36 patients from the Stockholm TNF-alpha follow-up registry (STURE) who received adalimumab after secondary loss of efficacy to infliximab (group A, n = 27) or etanercept (group B, n = 9), and 26 patients who were started on adalimumab as the first TNF-alpha antagonist (group C). In group A, the baseline disease activity score 28 (DAS28) at infliximab institution was 5.5+/-0.2. During infliximab treatment, the mean best DAS28 was 3.7+/-0.2 (p<0.001), but increased to 5.2+/-0.3 when infliximab was stopped. After 3 months on adalimumab, the mean DAS28 decreased to 4.5+/-0.3 (p<0.003), and then to 4.2+/-0.2 at 6 months (p<0.001). In group B, the baseline DAS28 at etanercept institution was 6.6+/-0.5. During etanercept treatment, the mean best DAS28 was 4.6+/-0.5 (p<0.01), but increased to 5.7+/-0.4 by the time etanercept was stopped. After 3 months on adalimumab, the mean DAS28 decreased to 4.8+/-0.3 (p<0.005), and to 4.1+/-0.2 at 6 months (p<0.001). In group C, the mean baseline DAS28 was 5.6+/-0.3. After 6 months of adalimumab therapy, the DAS28 decreased to 3.5+/-0.4 (p<0.001). ACR20 responses with adalimumab in groups A, B, and C were similar (70-78%). For patients with secondary loss of efficacy from infliximab or etanercept, switching to adalimumab can restore a good clinical response.

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

    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.

  17. Imaging biomarkers as surrogate endpoints for drug development

    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.)

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

    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.

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

    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.)

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

    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.

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

    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

  2. Root depth and morphology in response to soil drought: comparing ecological groups along the secondary succession in a tropical dry forest.

    Paz, Horacio; Pineda-García, Fernando; Pinzón-Pérez, Luisa F

    2015-10-01

    Root growth and morphology may play a core role in species-niche partitioning in highly diverse communities, especially along gradients of drought risk, such as that created along the secondary succession of tropical dry forests. We experimentally tested whether root foraging capacity, especially at depth, decreases from early successional species to old-growth forest species. We also tested for a trade-off between two mechanisms for delaying desiccation, the capacity to forage deeper in the soil and the capacity to store water in tissues, and explored whether successional groups separate along such a trade-off. We examined the growth and morphology of roots in response to a controlled-vertical gradient of soil water, among seedlings of 23 woody species dominant along the secondary succession in a tropical dry forest of Mexico. As predicted, successional species developed deeper and longer root systems than old-growth forest species in response to soil drought. In addition, shallow root systems were associated with high plant water storage and high water content per unit of tissue in stems and roots, while deep roots exhibited the opposite traits, suggesting a trade-off between the capacities for vertical foraging and water storage. Our results suggest that an increased capacity of roots to forage deeper for water is a trait that enables successional species to establish under the warm-dry conditions of the secondary succession, while shallow roots, associated with a higher water storage capacity, are restricted to the old-growth forest. Overall, we found evidence that the root depth-water storage trade-off may constrain tree species distribution along secondary succession.

  3. Development of methods to predict both the dynamic and the pseudo-static response of secondary structures subjected to seismic excitations

    Subudhi, M.; Bezler, P.

    1984-01-01

    Multiple independent support excitation time history formulations have been used to investigate simplified methods to predict the inertial (or dynamic) component of response as well as the pseudo-static (or static) component of response of secondary structures subjected to seismic excitations. For the dynamic component the independent response spectrum method is used with current industry practice for the modal and direction of excitation combinations being adopted and various procedures for the group combination and sequence being investigated. SRSS combination between support groups is found to yield satisfactory results. For the static component, support grouping by elevation for preliminary design followed by support grouping by attachment point for final design assure overall safety in the design

  4. Overcoming the response plateau in multiple myeloma: a novel bortezomib-based strategy for secondary induction and high-yield CD34+ stem cell mobilization.

    Niesvizky, Ruben; Mark, Tomer M; Ward, Maureen; Jayabalan, David S; Pearse, Roger N; Manco, Megan; Stern, Jessica; Christos, Paul J; Mathews, Lena; Shore, Tsiporah B; Zafar, Faiza; Pekle, Karen; Xiang, Zhaoying; Ely, Scott; Skerret, Donna; Chen-Kiang, Selina; Coleman, Morton; Lane, Maureen E

    2013-03-15

    This phase II study evaluated bortezomib-based secondary induction and stem cell mobilization in 38 transplant-eligible patients with myeloma who had an incomplete and stalled response to, or had relapsed after, previous immunomodulatory drug-based induction. Patients received up to six 21-day cycles of bortezomib plus dexamethasone, with added liposomal doxorubicin for patients not achieving partial response or better by cycle 2 or very good partial response or better (≥VGPR) by cycle 4 (DoVeD), followed by bortezomib, high-dose cyclophosphamide, and filgrastim mobilization. Gene expression/signaling pathway analyses were conducted in purified CD34+ cells after bortezomib-based mobilization and compared against patients who received only filgrastim ± cyclophosphamide. Plasma samples were similarly analyzed for quantification of associated protein markers. The response rate to DoVeD relative to the pre-DoVeD baseline was 61%, including 39% ≥ VGPR. Deeper responses were achieved in 10 of 27 patients who received bortezomib-based mobilization; postmobilization response rate was 96%, including 48% ≥ VGPR, relative to the pre-DoVeD baseline. Median CD34+ cell yield was 23.2 × 10(6) cells/kg (median of 1 apheresis session). After a median follow-up of 46.6 months, median progression-free survival was 47.1 months from DoVeD initiation; 5-year overall survival rate was 76.4%. Grade ≥ 3 adverse events included thrombocytopenia (13%), hand-foot syndrome (11%), peripheral neuropathy (8%), and neutropenia (5%). Bortezomib-based mobilization was associated with modulated expression of genes involved in stem cell migration. Bortezomib-based secondary induction and mobilization could represent an alternative strategy for elimination of tumor burden in immunomodulatory drug-resistant patients that does not impact stem cell yield.

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

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

    2013-07-01

    to evaluate alternative endpoints for groundwater remediation at complex sites. A statistical analysis of Comprehensive Environmental Response, Compensation and Liability Act (CERCLA) sites receiving TI waivers will be presented as well as case studies of other types of alternative endpoints and alternative remedial strategies that illustrate the variety of approaches used at complex sites and the technical analyses used to predict and document cost, time frame, and potential remedial effectiveness. This presentation is intended to inform DOE program managers, state regulators, practitioners and other stakeholders who are evaluating technical cleanup challenges within their own programs, and establishing programmatic approaches to evaluating and implementing long-term management approaches. Case studies provide examples of long-term management designations and strategies to manage and remediate groundwater at complex sites. At least 13 states consider some designation for groundwater containment in their corrective action policies, such as groundwater management zones, containment zones, and groundwater classification exemption areas. Long-term management designations are not a way to 'do nothing' or walk away from a site. Instead, soil and groundwater within the zone is managed to be protective of human health and the environment. Understanding when and how to adopt a long-term management approach can lead to cost savings and the more efficient use of resources across DOE and at numerous other industrial and military sites across the U.S. This presentation provides context for assessing the use and appropriate role of alternative endpoints and supporting long-term management designations in final remedies. (authors)

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

    Deeb, Rula A.; Hawley, Elisabeth L.

    2013-01-01

    alternative endpoints for groundwater remediation at complex sites. A statistical analysis of Comprehensive Environmental Response, Compensation and Liability Act (CERCLA) sites receiving TI waivers will be presented as well as case studies of other types of alternative endpoints and alternative remedial strategies that illustrate the variety of approaches used at complex sites and the technical analyses used to predict and document cost, time frame, and potential remedial effectiveness. This presentation is intended to inform DOE program managers, state regulators, practitioners and other stakeholders who are evaluating technical cleanup challenges within their own programs, and establishing programmatic approaches to evaluating and implementing long-term management approaches. Case studies provide examples of long-term management designations and strategies to manage and remediate groundwater at complex sites. At least 13 states consider some designation for groundwater containment in their corrective action policies, such as groundwater management zones, containment zones, and groundwater classification exemption areas. Long-term management designations are not a way to 'do nothing' or walk away from a site. Instead, soil and groundwater within the zone is managed to be protective of human health and the environment. Understanding when and how to adopt a long-term management approach can lead to cost savings and the more efficient use of resources across DOE and at numerous other industrial and military sites across the U.S. This presentation provides context for assessing the use and appropriate role of alternative endpoints and supporting long-term management designations in final remedies. (authors)

  7. School Facilities and Sustainability-Related Concepts: A Study of Hellenic Secondary School Principals’, Teachers’, Pupils’ and Parents’ Responses

    Vasiliki Zepatou

    2016-03-01

    Full Text Available Effective building environment sustainability frameworks and practices need to take users’ opinions into account. For this purpose, a survey questionnaire was developed and the “Panhellenic survey of school spaces, materials and environmental-comfort conditions in secondary schools and perceptions, stances and attitudes of pupils, teachers, principals and parents towards sustainable construction and the selection and use of materials in schools that are friendly to the environment and human health” was conducted nationwide with a random stratified sample of 170 Hellenic public secondary schools. Selected findings are presented and discussed here. These show that existing school facilities are primarily rated as good and that selection and use of materials friendly to the environment and human health are extremely important. User groups believe that they should participate in planning/selecting sustainable solutions for schools. An Index of 10 School Environment Desired Outcomes associated with environmentally friendly and health-friendly materials selection and use was devised. Relevant factors were extracted and interpreted. The research establishes users’ subjective opinions that may be considered and integrated into procedures for improving school buildings, assessing and selecting environmentally friendly materials and implementing strategies for sustainable school design, building and operation.

  8. Response of Saturn's ionosphere to solar radiation: Testing parameterizations for thermal electron heating and secondary ionization processes

    Moore, Luke; Galand, Marina; Mueller-Wodarg, Ingo; Mendillo, Michael

    2009-12-01

    We evaluate the effectiveness of two parameterizations in Saturn's ionosphere over a range of solar fluxes, seasons, and latitudes. First, the parameterization of the thermal electron heating rate, Q* e, introduced in [Moore, L., Galand, M., Mueller-Wodarg, I., Yelle, R.V., Mendillo, M., 2008. Plasma temperatures in Saturn's ionosphere. J. Geophys. Res. 113, A10306. doi:10.1029/2008JA013373.] for one specific set of conditions, is found to produce ion and electron temperatures that agree with self-consistent suprathermal electron calculations to within 2% on average under all conditions considered. Next, we develop a new parameterization of the secondary ion production rate at Saturn based on the calculations of [Galand, M., Moore, L., Mueller-Wodarg, I., Mendillo, M., 2009. Modeling the photoelectron secondary ionization process at Saturn. accepted. J. Geophys. Res.]; it is found to be accurate to within 4% on average. The demonstrated effectiveness of these two parameterizations over a wide range of input conditions makes them good candidates for inclusion in 3D Saturn thermosphere-ionosphere general circulation models (TIGCMs).

  9. The therapeutic effect of clinical trials: understanding placebo response rates in clinical trials – A secondary analysis

    Walach Harald

    2005-08-01

    Full Text Available Abstract Background and purpose Placebo response rates in clinical trials vary considerably and are observed frequently. For new drugs it can be difficult to prove effectiveness superior to placebo. It is unclear what contributes to improvement in the placebo groups. We wanted to clarify, what elements of clinical trials determine placebo variability. Methods We analysed a representative sample of 141 published long-term trials (randomized, double-blind, placebo-controlled; duration > 12 weeks to find out what study characteristics predict placebo response rates in various diseases. Correlational and regression analyses with study characteristics and placebo response rates were carried out. Results We found a high and significant correlation between placebo and treatment response rate across diseases (r = .78; p Conclusion Medication response rates and placebo response rates in clinical trials are highly correlated. Trial characteristics can explain some portion of the variance in placebo healing rates in RCTs. Placebo response in trials is only partially due to methodological artefacts and only partially dependent on the diagnoses treated.

  10. Hausdorff dimension of exponential parameter rays and their endpoints

    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

  11. Biomarkers of intermediate endpoints in environmental and occupational health

    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...

  12. Salt Stress Effects on Secondary Metabolites of Cotton in Relation to Gene Expression Responsible for Aphid Development.

    Qi Wang

    Full Text Available Many secondary metabolites have insecticidal efficacy against pests and may be affected by abiotic stress. However, little is known of how plants may respond to such stress as pertains the growth and development of pests. The objective of this study was to determine if and how salt stress on cotton plants affects the population dynamics of aphids. The NaCl treatment (50 mM, 100 mM, 150 mM and 200 mM increased contents of gossypol in cotton by 26.8-51.4%, flavonoids by 22.5-37.6% and tannic by 15.1-24.3% at 7-28 d after salt stress. Compared with non-stressed plants, the population of aphids on 150 and 200 mM NaCl stressed plants was reduced by 46.4 and 65.4% at 7d and by 97.3 and 100% at 14 days after infestation. Reductions in aphid population were possibly attributed to the elevated secondary metabolism under salt stress. A total of 796 clones for aphids transcriptome, 412 clones in the positive- library (TEST and 384 clones in the reverse-library (Ck, were obtained from subtracted cDNA libraries and sequenced. Gene ontology (GO functional classification and KEGG pathway analysis showed more genes related to fatty acid and lipid biosynthesis, and fewer genes related to carbohydrate metabolism, amino acid metabolism, energy metabolism and cell motility pathways in TEST than in Ck library, which might be the reason of aphids population reduction. A comparative analysis with qRT-PCR indicated high expression of transcripts CYP6A14, CYP6A13, CYP303A1, NADH dehydrogenase and fatty acid synthase in the TEST group. However, CYP307A1 and two ecdysone-induced protein genes were down regulated. The results indicate that genes of aphids related to growth and development can express at a higher level in reaction to the enhanced secondary metabolism in cotton under salinity stress. The expression of CYP307A1 was positively correlated with the population dynamics of aphids since it was involved in ecdysone synthesis.

  13. Acute exposure to offshore produced water has an effect on stress- and secondary stress responses in three-spined stickleback Gasterosteus aculeatus.

    Knag, Anne Christine; Taugbøl, Annette

    2013-09-01

    Pollution is one of today's greatest problems, and the release of contaminants into the environment can cause adverse changes in vitally important biological pathways. In this study, we exposed three-spined stickleback Gasterosteus aculeatus to produced water (PW), i.e. wastewater from offshore petroleum production. PW contains substances such as alkylphenols (APs) and aromatic hydrocarbons (PAHs) known to induce toxicant stress and endocrine disruption in a variety of organisms. Following exposure to PW, a standardized confinement treatment was applied as a second stressor (PW-stress), testing how fish already under stress from the pollutant would respond to an additional stressor. The endpoint for analysis was a combination of blood levels of cortisol and glucose, in addition to transcribed levels of a set of genes related to toxicant stress, endocrine disruption and general stress. The findings of this study indicate that low doses of PW do not induce vitellogenin in immature female stickleback, but do cause an upregulation of cytochrome (CYP1A) and UDP-glucuronsyltransferase (UDP-GT), two biomarkers related to toxicant stress. However, when the second stressor was applied, both genes were downregulated, indicating that the confinement exposure had a suppressive effect on the expression of toxicant biomarkers (CYP1A and UDP-GT). Further, two of the stress related genes, heat shock protein 90 (HSP90) and stress-induced phosphoprotein (STIP), were upregulated in both PW- and PW-stress-treatment, but not in the water control confinement treatment, indicating that PW posed as a larger stress-factor than confinement for these genes. The confinement stressor caused an increased level of glucose in both control and PW-treated fish, indicating hyperglycemia, a commonly reported stress response in fish. © 2013.

  14. Extended Evaluation of Virological, Immunological and Pharmacokinetic Endpoints of CELADEN: A Randomized, Placebo-Controlled Trial of Celgosivir in Dengue Fever Patients.

    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

  15. Dynamic response of the EBR-II secondary sodium system to postulated leaks of steam and water into sodium

    Srinivas, S.; Chopra, P.S.; Stone, C.C.

    1976-01-01

    The paper presents evaluations of the dynamic response of a steam generator system to postulated leaks of steam and water into sodium. This work is part of a comprehensive fail-safe analysis of the EBR-II steam generator system

  16. A Survey of Elementary and Secondary Music Educators' Professional Background, Teaching Responsibilities and Job Satisfaction in the United States

    Matthews, Wendy K.; Koner, Karen

    2017-01-01

    The focus of this exploratory study was to examine the current trends of K-12 music educators in the United States regarding their (a) professional background, (b) classroom teaching responsibilities, and (c) job satisfaction. Participants included seven thousand four hundred and sixty-three (N = 7,463) currently employed music teachers who were…

  17. Teachers Exploring Mobile Device Integration: A Case Study of Secondary Teachers’ Responses to iPads in the Classroom

    Stella Erbes

    2016-10-01

    Full Text Available This qualitative study seeks to understand and resolve the difficulties that teachers encounter when integrating mobile devices in classrooms. To address the issue of teacher receptiveness, three undergraduate researchers collaborated with an education professor in spring 2012 to complete a qualitative study with a two-fold purpose: 1 to investigate how two secondary teachers in an independent school responded when adopting a class set of iPads throughout one school cycle (six school days; and 2 to elucidate what a school could do better to support teachers who are piloting mobile device integration. Although previous studies have commonly focused on the impact of 1:1 programs on student achievement, this study focuses on the role of the instructor when designing and delivering instruction with or without iPads. Qualitative data were collected and recorded after a series of observations and interviews with the teachers and the information technology director. All interviews were roughly transcribed and coded systematically so that patterns could be noted. Results found that both instructors commented about their instructional philosophy, instructional objectives, technology support, teacher efficacy, and classroom. At the conclusion of the experiments, the teachers had favorable impressions of the technology, despite initial misgivings and early technical issues.

  18. A study on emergency response guideline during the loss of steam generator secondary heat sink in pressurizer water reactor

    Yoon, D. J.; Lee, J. Y.; Song, D. S.

    1999-01-01

    A loss of secondary heat sink can occur as a result of several different initiating events, which are a loss of main feedwater during power operation, a loss of off-site power, or any other scenario for which main feedwater is isolated or lost. At this point the opening and closing of the PORV or safety valves will result in a loss of RCS inventory similar in nature to a small break loss of coolant accident. If operator action is not taken, the pressurizer PORV or safety valves will continue to cycle open and closed at the valve setpoint pressure removing RCS inventory and a limited amount of core decay heat until eventually enough inventory will be lost to result in core uncovery. We conclude that a requirement to successfully initiate bleed and feed on steam generator dryout, without any significant core uncovery expected to occur, is that the PORV flow to power ratio must exceed 140 (lbm/hr)/Mwt. For all plants whose PORV capacity is less than 140 (lbm/hr)/Mwt, since symptoms of SG dryout cannot be used to initiate bleed and feed, increasing RCS pressure and temperature or pressure greater than 2335 psig cannot be used. The only alternative symptom available is SG narrow range level. Since Kori 1,2,3 and 4' PORV capacity is more than the criteria, the bleed and feed operation can be initiated at steam generator dryout

  19. Exposure and materiality of the secondary room and its impact on the impulse response of coupled-volume concert halls

    Ermann, Michael; Johnson, Marty

    2005-06-01

    How does sound decay when one room is partially exposed to another (acoustically coupled)? More specifically, this research aims to quantify how operational and design decisions impact sound fields in the design of concert halls with acoustical coupling. By adding a second room to a concert hall, and designing doors to control the sonic transparency between the two rooms, designers can create a new, coupled acoustic. Concert halls use coupling to achieve a variable, longer, and distinct reverberant quality for their musicians and listeners. For this study a coupled-volume shoebox concert hall is conceived with a fixed geometric volume, form, and primary-room sound absorption. Aperture size and secondary-room sound absorption levels are established as variables. Statistical analysis of sound decay in this simulated hall suggests a highly sensitive relationship between the double-sloped condition and (1) architectural composition, as defined by the aperture size exposing the chamber and (2) materiality, as defined by the sound absorptance in the coupled volume. The theoretical, mathematical predictions are compared with coupled-volume concert hall field measurements and guidelines are suggested for future designs of coupled-volume concert halls.

  20. Preliminary test of the MONDO project secondary fast and ultrafast neutrons tracker response using protons and MIP particles

    Traini, G.; Battistoni, G.; Giacometti, V.; Gioscio, E.; Marafini, M.; Mirabelli, R.; Pinci, D.; Sarti, A.; Sciubba, A.; Patera, V.

    2018-04-01

    The risk of developing a second malignant cancer as a late time consequence of undergoing a treatment, is one of the main concerns in particle therapy (PT). Since neutrons can release a significant dose far away from the tumour region, a precise characterisation of their production point, kinetic energy and abundance is eagerly needed. The treatment planning system (TPS) software that predicts the normal tissue toxicity in the target region and the risk of late complications in the whole body is currently based on the poorly known production cross-sections and will greatly benefit from improved precision double differential measurements. The MONDO (MOnitor for Neutron Dose in hadrOntherapy) project aims to build an ultrafast neutron tracker that could be used to characterise the production of secondary neutrons with energies in the 20–400 MeV range. The neutron tracking will proceed via the detection of recoil protons produced in two consecutive (n, p) elastic scattering interactions. The MONDO detector consists of a 10 × 10 × 20 cm3 matrix of thin scintillating fibres, arranged in orthogonally oriented layers. A compact read-out sensor with single photon detection capabilities employing the CMOS SPAD technology has been developed in collaboration with Fondazione Bruno Kessler (FBK). The detector will be completed by the end of 2018. A 4 × 4 × 4.8 cm3 prototype has been built using 250 μ m thick scintillating fibres of squared section and was tested using a proton beam and minimum ionising particles. In this contribution we present the experimental results related to the prototype test performed with a proton beam at the Proton Therapy Centre of the Trento Hospital (PTC) in May 2017. The results are compared with the results of a Monte Carlo simulation performed with the FLUKA software.

  1. [Secondary hypertension].

    Yoshida, Yuichi; Shibata, Hirotaka

    2015-11-01

    Hypertension is a common disease and a crucial predisposing factor of cardiovascular diseases. Approximately 10% of hypertensive patients are secondary hypertension, a pathogenetic factor of which can be identified. Secondary hypertension consists of endocrine, renal, and other diseases. Primary aldosteronism, Cushing's syndrome, pheochromocytoma, hyperthyroidism, and hypothyroidism result in endocrine hypertension. Renal parenchymal hypertension and renovascular hypertension result in renal hypertension. Other diseases such as obstructive sleep apnea syndrome are also very prevalent in secondary hypertension. It is very crucial to find and treat secondary hypertension at earlier stages since most secondary hypertension is curable or can be dramatically improved by specific treatment. One should keep in mind that screening of secondary hypertension should be done at least once in a daily clinical practice.

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

    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.

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

    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.

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

    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...

  5. Secondary and tertiary hyperparathyroidism.

    Jamal, Sophie A; Miller, Paul D

    2013-01-01

    We reviewed the etiology and management of secondary and tertiary hyperparathyroidism. Secondary hyperparathyroidism is characterized by an increase in parathyroid hormone (PTH) that is appropriate and in response to a stimulus, most commonly low serum calcium. In secondary hyperparathyroidism, the serum calcium is normal and the PTH level is elevated. Tertiary hyperparathyroidism is characterized by excessive secretion of PTH after longstanding secondary hyperparathyroidism, in which hypercalcemia has ensued. Tertiary hyperparathyroidism typically occurs in men and women with chronic kidney disease usually after kidney transplant. The etiology and treatment of secondary hyperparathyroidism is relatively straightforward whereas data on the management of tertiary hyperparathyroidism is limited to a few small trials with short follow-up. Copyright © 2013 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.

  6. Secondary Psychometric Examination of the Dimensional Obsessive-Compulsive Scale: Classical Testing, Item Response Theory, and Differential Item Functioning.

    Thibodeau, Michel A; Leonard, Rachel C; Abramowitz, Jonathan S; Riemann, Bradley C

    2015-12-01

    The Dimensional Obsessive-Compulsive Scale (DOCS) is a promising measure of obsessive-compulsive disorder (OCD) symptoms but has received minimal psychometric attention. We evaluated the utility and reliability of DOCS scores. The study included 832 students and 300 patients with OCD. Confirmatory factor analysis supported the originally proposed four-factor structure. DOCS total and subscale scores exhibited good to excellent internal consistency in both samples (α = .82 to α = .96). Patient DOCS total scores reduced substantially during treatment (t = 16.01, d = 1.02). DOCS total scores discriminated between students and patients (sensitivity = 0.76, 1 - specificity = 0.23). The measure did not exhibit gender-based differential item functioning as tested by Mantel-Haenszel chi-square tests. Expected response options for each item were plotted as a function of item response theory and demonstrated that DOCS scores incrementally discriminate OCD symptoms ranging from low to extremely high severity. Incremental differences in DOCS scores appear to represent unbiased and reliable differences in true OCD symptom severity. © The Author(s) 2014.

  7. 21 CFR 314.510 - Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival...

    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. ...

  8. Secondary Evaluations.

    Cook, Thomas D.

    Secondary evaluations, in which an investigator takes a body of evaluation data collected by a primary evaluation researcher and examines the data to see if the original conclusions about the program correspond with his own, are discussed. The different kinds of secondary evaluations and the advantages and disadvantages of each are pointed out,…

  9. Comprehensive transcriptome analysis reveals novel genes involved in cardiac glycoside biosynthesis and mlncRNAs associated with secondary metabolism and stress response in Digitalis purpurea

    Wu Bin

    2012-01-01

    Full Text Available Abstract Background Digitalis purpurea is an important ornamental and medicinal plant. There is considerable interest in exploring its transcriptome. Results Through high-throughput 454 sequencing and subsequent assembly, we obtained 23532 genes, of which 15626 encode conserved proteins. We determined 140 unigenes to be candidates involved in cardiac glycoside biosynthesis. It could be grouped into 30 families, of which 29 were identified for the first time in D. purpurea. We identified 2660 mRNA-like npcRNA (mlncRNA candidates, an emerging class of regulators, using a computational mlncRNA identification pipeline and 13 microRNA-producing unigenes based on sequence conservation and hairpin structure-forming capability. Twenty five protein-coding unigenes were predicted to be targets of these microRNAs. Among the mlncRNA candidates, only 320 could be grouped into 140 families with at least two members in a family. The majority of D. purpurea mlncRNAs were species-specific and many of them showed tissue-specific expression and responded to cold and dehydration stresses. We identified 417 protein-coding genes with regions significantly homologous or complementary to 375 mlncRNAs. It includes five genes involved in secondary metabolism. A positive correlation was found in gene expression between protein-coding genes and the homologous mlncRNAs in response to cold and dehydration stresses, while the correlation was negative when protein-coding genes and mlncRNAs were complementary to each other. Conclusions Through comprehensive transcriptome analysis, we not only identified 29 novel gene families potentially involved in the biosynthesis of cardiac glycosides but also characterized a large number of mlncRNAs. Our results suggest the importance of mlncRNAs in secondary metabolism and stress response in D. purpurea.

  10. Athletic Trainers' Roles and Responsibilities Regarding Academic Adjustments as Part of the Concussion-Management Process in the Secondary School Setting.

    Bacon, Cailee E Welch; Kay, Melissa C; McLeod, Tamara C Valovich

    2017-10-01

      Athletic trainers (ATs) play a vital role in managing the care of student-athletes after a sport-related concussion, yet little is known about their specific involvement in the implementation of academic adjustments as part of the concussion-management plan.   To explore ATs' perceived roles and responsibilities regarding the implementation of academic adjustments for concussed student-athletes.   Qualitative study.   Individual telephone interviews.   Sixteen ATs employed in the secondary school setting (8 women, 8 men; age = 39.6 ± 7.9 years; athletic training experience = 15.1 ± 5.6 years), representing 12 states, were interviewed.   One telephone interview was conducted with each participant. After the interviews were transcribed, the data were analyzed and coded into themes and categories, which were determined via consensus of a 4-person research team. To decrease researcher bias, triangulation occurred through participant member checking, the inclusion of multiple researchers, and an internal auditor.   Several categories related to participants' perceptions regarding their roles and responsibilities within the academic-adjustments process emerged from data analysis: (1) understanding of academic adjustments, (2) perceptions of their roles in academic adjustments, (3) initiation of academic adjustments, (4) facilitation of academic adjustments, and (5) lack of a role in the academic-adjustments process. Although most ATs perceived that they had a role in the initiation and facilitation of academic adjustments for concussed student-athletes, some reported they did not want a role in the process. Regardless, participants frequently suggested the need for further education.   These findings highlight that ATs either wanted to be involved in the implementation of academic adjustments but felt further education was needed or they did not want to be involved because they felt that it was not in their area of expertise. To create a cohesive

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

    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

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

    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. Influence of nutrient medium composition on uranium toxicity and choice of the most sensitive growth related endpoint in Lemna minor.

    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.

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

    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.

  15. Visual impairment secondary to congenital glaucoma in children: visual responses, optical correction and use of low vision AIDS

    Maria Aparecida Onuki Haddad

    2009-01-01

    Full Text Available INTRODUCTION: Congenital glaucoma is frequently associated with visual impairment due to optic nerve damage, corneal opacities, cataracts and amblyopia. Poor vision in childhood is related to global developmental problems, and referral to vision habilitation/rehabilitation services should be without delay to promote efficient management of the impaired vision. OBJECTIVE: To analyze data concerning visual response, the use of optical correction and prescribed low vision aids in a population of children with congenital glaucoma. METHOD: The authors analyzed data from 100 children with congenital glaucoma to assess best corrected visual acuity, prescribed optical correction and low vision aids. RESULTS: Fifty-five percent of the sample were male, 43% female. The mean age was 6.3 years. Two percent presented normal visual acuity levels, 29% mild visual impairment, 28% moderate visual impairment, 15% severe visual impairment, 11% profound visual impairment, and 15% near blindness. Sixty-eight percent received optical correction for refractive errors. Optical low vision aids were adopted for distance vision in 34% of the patients and for near vision in 6%. A manual monocular telescopic system with 2.8 × magnification was the most frequently prescribed low vision aid for distance, and for near vision a +38 diopter illuminated stand magnifier was most frequently prescribed. DISCUSSION AND CONCLUSION: Careful low vision assessment and the appropriate prescription of optical corrections and low vision aids are mandatory in children with congenital glaucoma, since this will assist their global development, improving efficiency in daily life activities and promoting social and educational inclusion.

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

    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

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

    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 ...

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

    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...

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

    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...

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

    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

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

    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.

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

    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.

  3. Neutralization Assay for Zika and Dengue Viruses by Use of Real-Time-PCR-Based Endpoint Assessment.

    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.

  4. Human dendritic cells sequentially matured with CD4+ T cells as a secondary signal favor CTL and long-term T memory cell responses

    Thomas Simon

    2012-01-01

    Full Text Available Dendritic cells (DCs are professional antigen-presenting cells involved in the control and initiation of immune responses. In vivo, DCs exposed at the periphery to maturation stimuli migrate to lymph nodes, where they receive secondary signals from CD4+ T helper cells. These DCs become able to initiate CD8+ cytotoxic T lymphocyte (CTL responses. However, in vitro investigations concerning human monocyte-derived DCs have never focused on their functional properties after such sequential maturation. Here, we studied human DC phenotypes and functions according to this sequential exposure to maturation stimuli. As first signals, we used TNF-α/polyI:C mimicking inflammatory and pathogen stimuli and, as second signals, we compared activated CD4+ T helper cells to a combination of CD40-L/ IFN-γ. Our results show that a sequential activation with activated CD4+ T cells dramatically increased the maturation of DCs in terms of their phenotype and cytokine secretion compared to DCs activated with maturation stimuli delivered simultaneously. Furthermore, this sequential maturation led to the induction of CTL with a long-term effector and central memory phenotypes. Thus, sequential delivery of maturation stimuli, which includes CD4+ T cells, should be considered in the future to improve the induction of long-term CTL memory in DC-based immunotherapy.

  5. Human dendritic cells sequentially matured with CD4(+) T cells as a secondary signal favor CTL and long-term T memory cell responses.

    Simon, Thomas; Tanguy-Royer, Séverine; Royer, Pierre-Joseph; Boisgerault, Nicolas; Frikeche, Jihane; Fonteneau, Jean-François; Grégoire, Marc

    2012-01-01

    Dendritic cells (DCs) are professional antigen-presenting cells involved in the control and initiation of immune responses. In vivo, DCs exposed at the periphery to maturation stimuli migrate to lymph nodes, where they receive secondary signals from CD4+ T helper cells. These DCs become able to initiate CD8+ cytotoxic T lymphocyte (CTL) responses. However, in vitro investigations concerning human monocyte-derived DCs have never focused on their functional properties after such sequential maturation. Here, we studied human DC phenotypes and functions according to this sequential exposure to maturation stimuli. As first signals, we used TNF-α/polyI:C mimicking inflammatory and pathogen stimuli and, as second signals, we compared activated CD4+ T helper cells to a combination of CD40-L/ IFN-γ. Our results show that a sequential activation with activated CD4+ T cells dramatically increased the maturation of DCs in terms of their phenotype and cytokine secretion compared to DCs activated with maturation stimuli delivered simultaneously. Furthermore, this sequential maturation led to the induction of CTL with a long-term effector and central memory phenotypes. Thus, sequential delivery of maturation stimuli, which includes CD4+ T cells, should be considered in the future to improve the induction of long-term CTL memory in DC-based immunotherapy.

  6. Plant water use responses along secondary forest succession during the 2015-2016 El Niño drought in Panama.

    Bretfeld, Mario; Ewers, Brent E; Hall, Jefferson S

    2018-03-05

    Tropical forests are increasingly being subjected to hotter, drier conditions as a result of global climate change. The effects of drought on forests along successional gradients remain poorly understood. We took advantage of the 2015-2016 El Niño event to test for differences in drought response along a successional gradient by measuring the sap flow in 76 trees, representing 42 different species, in 8-, 25- and 80-yr-old secondary forests in the 15-km 2 'Agua Salud Project' study area, located in central Panama. Average sap velocities and sapwood-specific hydraulic conductivities were highest in the youngest forest. During the dry season drought, sap velocities increased significantly in the 80-yr-old forest as a result of higher evaporative demand, but not in younger forests. The main drivers of transpiration shifted from radiation to vapor pressure deficit with progressing forest succession. Soil volumetric water content was a limiting factor only in the youngest forest during the dry season, probably as a result of less root exploration in the soil. Trees in early-successional forests displayed stronger signs of regulatory responses to the 2015-2016 El Niño drought, and the limiting physiological processes for transpiration shifted from operating at the plant-soil interface to the plant-atmosphere interface with progressing forest succession. © 2018 The Authors. New Phytologist © 2018 New Phytologist Trust.

  7. Secondary Headaches

    ... in the medical history or examination to suggest secondary headache. Headache can be caused by general medical conditions such as severe hypertension, or by conditions that affect the brain and ...

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

    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.

  9. UV-B Irradiation Changes Specifically the Secondary Metabolite Profile in Broccoli Sprouts: Induced Signaling Overlaps with Defense Response to Biotic Stressors

    Mewis, Inga; Schreiner, Monika; Nguyen, Chau Nhi; Krumbein, Angelika; Ulrichs, Christian; Lohse, Marc; Zrenner, Rita

    2012-01-01

    Only a few environmental factors have such a pronounced effect on plant growth and development as ultraviolet light (UV). Concerns have arisen due to increased UV-B radiation reaching the Earth’s surface as a result of stratospheric ozone depletion. Ecologically relevant low to moderate UV-B doses (0.3–1 kJ m–2 d–1) were applied to sprouts of the important vegetable crop Brassica oleracea var. italica (broccoli), and eco-physiological responses such as accumulation of non-volatile secondary metabolites were related to transcriptional responses with Agilent One-Color Gene Expression Microarray analysis using the 2×204 k format Brassica microarray. UV-B radiation effects have usually been linked to increases in phenolic compounds. As expected, the flavonoids kaempferol and quercetin accumulated in broccoli sprouts (the aerial part of the seedlings) 24 h after UV-B treatment. A new finding is the specific UV-B-mediated induction of glucosinolates (GS), especially of 4-methylsulfinylbutyl GS and 4-methoxy-indol-3-ylmethyl GS, while carotenoids and Chl levels remained unaffected. Accumulation of defensive GS metabolites was accompanied by increased expression of genes associated with salicylate and jasmonic acid signaling defense pathways and up-regulation of genes responsive to fungal and bacterial pathogens. Concomitantly, plant pre-exposure to moderate UV-B doses had negative effects on the performance of the caterpillar Pieris brassicae (L.) and on the population growth of the aphid Myzus persicae (Sulzer). Moreover, insect-specific induction of GS in broccoli sprouts was affected by UV-B pre-treatment. PMID:22773681

  10. Determining significant endpoints for ecological risk analyses. 1997 annual progress report

    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.'

  11. Inducible deletion of CD28 prior to secondary nippostrongylus brasiliensis infection impairs worm expulsion and recall of protective memory CD4⁺ T cell responses.

    Hlumani Ndlovu

    2014-02-01

    Full Text Available IL-13 driven Th2 immunity is indispensable for host protection against infection with the gastrointestinal nematode Nippostronglus brasiliensis. Disruption of CD28 mediated costimulation impairs development of adequate Th2 immunity, showing an importance for CD28 during the initiation of an immune response against this pathogen. In this study, we used global CD28⁻/⁻ mice and a recently established mouse model that allows for inducible deletion of the cd28 gene by oral administration of tamoxifen (CD28(-/loxCre⁺/⁻+TM to resolve the controversy surrounding the requirement of CD28 costimulation for recall of protective memory responses against pathogenic infections. Following primary infection with N. brasiliensis, CD28⁻/⁻ mice had delayed expulsion of adult worms in the small intestine compared to wild-type C57BL/6 mice that cleared the infection by day 9 post-infection. Delayed expulsion was associated with reduced production of IL-13 and reduced serum levels of antigen specific IgG1 and total IgE. Interestingly, abrogation of CD28 costimulation in CD28(-/loxCre⁺/⁻ mice by oral administration of tamoxifen prior to secondary infection with N. brasiliensis resulted in impaired worm expulsion, similarly to infected CD28⁻/⁻ mice. This was associated with reduced production of the Th2 cytokines IL-13 and IL-4, diminished serum titres of antigen specific IgG1 and total IgE and a reduced CXCR5⁺ T(FH cell population. Furthermore, total number of CD4⁺ T cells and B220⁺ B cells secreting Th1 and Th2 cytokines were significantly reduced in CD28⁻/⁻ mice and tamoxifen treated CD28(-/loxCre⁺/⁻ mice compared to C57BL/6 mice. Importantly, interfering with CD28 costimulatory signalling before re-infection impaired the recruitment and/or expansion of central and effector memory CD4⁺ T cells and follicular B cells to the draining lymph node of tamoxifen treated CD28(-/loxCre⁺/⁻ mice. Therefore, it can be concluded that CD28

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

    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.

  13. 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.

    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.

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

    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

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

    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

  16. Chloride and sulphate toxicity to Hydropsyche exocellata (Trichoptera, Hydropsychidae): Exploring intraspecific variation and sub-lethal endpoints

    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

  17. Chloride and sulphate toxicity to Hydropsyche exocellata (Trichoptera, Hydropsychidae): Exploring intraspecific variation and sub-lethal endpoints

    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

  18. 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.

    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

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

    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.

  20. The PacC transcription factor regulates secondary metabolite production and stress response, but has only minor effects on virulence in the insect pathogenic fungus Beauveria bassiana.

    Luo, Zhibing; Ren, Hui; Mousa, Jarrod J; Rangel, Drauzio E N; Zhang, Yongjun; Bruner, Steven D; Keyhani, Nemat O

    2017-02-01

    The PacC transcription factor is an important component of the fungal ambient pH-responsive regulatory system. Loss of pacC in the insect pathogenic fungus Beauveria bassiana resulted in an alkaline pH-dependent decrease in growth and pH-dependent increased susceptibility to osmotic (salt, sorbitol) stress and SDS. Extreme susceptibility to Congo Red was noted irrespective of pH, and ΔBbpacC conidia showed subtle increases in UV susceptibility. The ΔBbPacC mutant showed a reduced ability to acidify media during growth due to failure to produce oxalic acid. The ΔBbPacC mutant also did not produce the insecticidal compound dipicolinic acid, however, production of a yellow-colored compound was noted. The compound, named bassianolone B, was purified and its structure determined. Despite defects in growth, stress resistance, and oxalate/insecticidal compound production, only a small decrease in virulence was seen for the ΔBbpacC strain in topical insect bioassays using larvae from the greater waxmoth, Galleria mellonella or adults of the beetle, Tenebrio molitor. However, slightly more pronounced decreases were seen in virulence via intrahemcoel injection assays (G. mellonella) and in assays using T. molitor larvae. These data suggest important roles for BbpacC in mediating growth at alkaline pH, regulating secondary metabolite production, and in targeting specific insect stages. © 2017 Society for Applied Microbiology and John Wiley & Sons Ltd.

  1. Aperture size, materiality of the secondary room and listener location: Impact on the simulated impulse response of a coupled-volume concert hall

    Ermann, Michael; Johnson, Marty E.; Harrison, Byron W.

    2003-04-01

    By adding a second room to a concert hall, and designing doors to control the sonic transparency between the two rooms, designers can create a new, coupled acoustic. Concert halls use coupling to achieve a variable, longer and distinct reverberant quality for their musicians and listeners. For this study, a coupled-volume concert hall based on an existing performing arts center is conceived and computer-modeled. It has a fixed geometric volume, form and primary-room sound absorption. Ray-tracing software simulates impulse responses, varying both aperture size and secondary-room sound absorption level, across a grid of receiver (listener) locations. The results are compared with statistical analysis that suggests a highly sensitive relationship between the double-sloped condition and the architecture of the space. This line of study aims to quantitatively and spatially correlate the double-sloped condition with (1) aperture size exposing the chamber, (2) sound absorptance in the coupled volume, and (3) listener location.

  2. The rs10401670 variant in resistin gene improved insulin resistance response and metabolic parameters secondaries to weight loss after a hypocaloric diet.

    Antonio de Luis, Daniel; Aller, Rocío; Izaola, Olatz; Primo, David; Bachiller, R

    2016-08-01

    The SNP 3'UTR C/T (rs10401670), it is a polymorphism that has been associated with diabetes mellitus and it has been scarcely studied before. As far as we know, no studies on interaction among diet intervention, rs10401670 variant of RETN and metabolic response has been realized. Our aim was to analyze the effects of the rs10401670 RETN gene polymorphism on insulin resistance response and metabolic changes secondary to weight loss after 3 months of a hypocaloric diet in adults obese patients without diabetes mellitus. A Caucasian population of 135 obese patients without diabetes mellitus was analyzed. Before and after 3 months on a low fat hypocaloric diet, an anthropometric evaluation, an assessment of nutritional intake and a biochemical analysis were performed. The statistical analysis was performed for the combined CT and TT as a group (minor allele group) and wild type CC as second group (major allele group) (dominant model). Forty nine patients (36.3%) had the genotype CC (major allele group) and 86 (63.7%) patients had the next genotypes; CT (67 patients, 49.6%) or TT (19 patients, 14.1%) (minor allele group). After dietary treatment and in major allele group, weight, BMI, fat mass, systolic blood pressure and waist circumference decreases were similar than minor allele group. In T allele carriers, fasting plasma glucose, insulin, HOMA-IR, total cholesterol and LDL cholesterol levels decreased significantly. In non T allele carriers and after dietary treatment, only LDL cholesterol and total cholesterol decreased. In non T Allele carriers, the decrease in total cholesterol was -15.1 ± 18.3 mg/dl (decrease in T Allele carriers -18.3 ± 15.7 mg/dl: p > 0.05), LDL-cholesterol was -14.3 ± 18.5 mg/dl (decrease in T Allele carriers -17.3 ± 10.1 mg/dl:p > 0.05), fasting glucose plasma -2.2 ± 1.5 mg/dL (decrease in T Allele carriers -4.8 ± 1.2 mg/dL: p = 0.02), insulin -1.1 ± 2.0 mUI/L (decrease in T Allele carriers -6.3

  3. Predictive validity of endpoints used in electrophysiological modelling of migraine in the trigeminovascular system.

    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.

  4. Determining significant endpoints for ecological risk analyses. 1998 annual progress report

    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.'

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

    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

    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

    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

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

    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...

  10. Update of the International Consensus on Palliative Radiotherapy Endpoints for Future Clinical Trials in Bone Metastases

    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.

  11. Update of the International Consensus on Palliative Radiotherapy Endpoints for Future Clinical Trials in Bone Metastases

    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.

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

    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 ...

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

    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.

  14. An European inter-laboratory validation of alternative endpoints of the murine local lymph node assay: first round.

    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

    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. Lower education predicts poor response to dietary intervention in pregnancy, regardless of neighbourhood affluence: secondary analysis from the ROLO randomised control trial.

    O'Brien, Eileen C; Alberdi, Goiuri; Geraghty, Aisling A; McAuliffe, Fionnuala M

    2017-11-01

    To determine if response to a low glycaemic index (GI) dietary intervention, measured by changes in dietary intake and gestational weight gain, differed across women of varying socio-economic status (SES). Secondary data analysis of the ROLO randomised control trial. The intervention consisted of a two-hour low-GI dietary education session in early pregnancy. Change in GI was measured using 3 d food diaries pre- and post-intervention. Gestational weight gain was categorised as per the 2009 Institute of Medicine guidelines. SES was measured using education and neighbourhood deprivation. The National Maternity Hospital, Dublin, Ireland. Women (n 625) recruited to the ROLO randomised control trial. The intervention significantly reduced GI and excess gestational weight gain (EGWG) among women with third level education residing in both disadvantaged (GI, mean (sd), intervention v. control: -3·30 (5·15) v. -0·32 (4·22), P=0·024; EGWG, n (%), intervention v. control: 7 (33·6) v. 22 (67·9); P=0·022) and advantaged areas (GI: -1·13 (3·88) v. 0·06 (3·75), P=0·020; EGWG: 41 (34·1) v. 58 (52·6); P=0·006). Neither GI nor gestational weight gain differed between the intervention and control group among women with less than third level education, regardless of neighbourhood deprivation. A single dietary education session was not effective in reducing GI or gestational weight gain among less educated women. Multifaceted, appropriate and practical approaches are required in pregnancy interventions to improve pregnancy outcomes for less educated women.

  17. Celecoxib enhances radiation response of secondary bone tumors of a human non-small cell lung cancer via antiangiogenesis in vivo

    Klenke, Frank Michael [Bern Univ. (Switzerland). Dept. of Orthopedic Surgery; Abdollahi, Amir [Deutsches Krebsforschungszentrum, Heidelberg (Germany). Dept. of Radiation Oncology; Tufts Univ. School of Medicine, Boston, MA (United States). Center of Cancer Systems Biology; Bischof, Marc; Huber, Peter E. [Deutsches Krebsforschungszentrum, Heidelberg (Germany). Dept. of Radiation Oncology; Gebhard, Martha-Maria [Heidelberg Univ. (Germany). Dept. of Experimental Surgery; Ewerbeck, Volker [Heidelberg Univ. (Germany). Dept. of Orthopedic Surgery; Sckell, Axel [Charite Univ. Medical Center, Berlin (Germany). Dept. of Orthopedic, Trauma and Reconstructive Surgery

    2011-01-15

    Purpose: Cyclooxygenase-2 (COX-2) inhibitors mediate a systemic antitumor activity via antiangiogenesis and seem to enhance the response of primary tumors to radiation. Radiosensitizing effects of COX-2 inhibition have not been reported for bone metastases. Therefore, the aim of this study was the investigation of the radiosensitizing effects of the selective COX-2 inhibitor celecoxib in secondary bone tumors of a non-small cell lung carcinoma in vivo. Materials and Methods: Human A549 lung carcinomas were implanted into a cranial window preparation in male SCID mice (n = 24). Animals were treated with either celecoxib or radiation (7 Gy single photon dose) alone or a combination of celecoxib and radiation, respectively. Untreated animals served as controls. The impact of radiation and COX-2 inhibition on angiogenesis, microcirculation, and tumor growth was analyzed over 28 days by means of intravital microscopy and histological methods. Results: Monotherapies with radiation as well as celecoxib had significant antitumor effects compared to untreated controls. Both therapies reduced tumor growth and vascularization to a similar extent. The simultaneous administration of celecoxib and radiation further enhanced the antitumor and antiangiogenic effects of single-beam radiation. With the combined treatment approach, tumor vascularization and tumor size were decreased by 57% and 51%, respectively, as compared to monotherapy with radiation. Conclusion: The combined application of radiation therapy and COX-2 inhibition showed synergistic effects concerning the inhibition of tumor growth and tumor angiogenesis. Therefore, the combination of radiation with COX-2 inhibitor therapy represents a promising approach to improve the therapeutic efficacy of radiotherapy of bone metastases. (orig.)

  18. Enhanced brain responses to C-fiber input in the area of secondary hyperalgesia induced by high-frequency electrical stimulation of the skin.

    van den Broeke, Emanuel N; Mouraux, André

    2014-11-01

    High-frequency electrical stimulation (HFS) of the human skin induces an increase in both mechanical and heat pain sensitivity in the surrounding unconditioned skin. The aim of this study was to investigate the effect of HFS on the intensity of perception and brain responses elicited by the selective activation of C fibers. HFS was applied to the ventral forearm of 15 healthy volunteers. Temperature-controlled CO2 laser stimulation was used to activate selectively low-threshold C-fiber afferents without concomitantly activating Aδ-fiber afferents. These stimuli were detected with reaction times compatible with the conduction velocity of C fibers. The intensity of perception and event-related brain potentials (ERPs) elicited by thermal stimuli delivered to the surrounding unconditioned skin were recorded before (T0) and after HFS (T1: 20 min after HFS; T2: 45 min after HFS). The contralateral forearm served as a control. Mechanical hyperalgesia following HFS was confirmed by measuring the change in the intensity of perception elicited by mechanical punctate stimuli. HFS resulted in increased intensity of perception to mechanical punctate stimulation and selective C-fiber thermal stimulation at both time points. In contrast, the N2 wave of the ERP elicited by C-fiber stimulation (679 ± 88 ms; means ± SD) was enhanced at T1 but not at T2. The P2 wave (808 ± 105 ms) was unaffected by HFS. Our results suggest that HFS enhances the sensitivity to thermal C-fiber input in the area of secondary hyperalgesia. However, there was no significant enhancement of the magnitude of the C-fiber ERPs at T2, suggesting that quickly adapting C fibers do not contribute to this enhancement. Copyright © 2014 the American Physiological Society.

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

    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

  20. Heterogeneity in serum 25-hydroxy-vitamin D response to cholecalciferol in elderly women with secondary hyperparathyroidism and vitamin D deficiency.

    Giusti, Andrea; Barone, Antonella; Pioli, Giulio; Girasole, Giuseppe; Razzano, Monica; Pizzonia, Monica; Pedrazzoni, Mario; Palummeri, Ernesto; Bianchi, Gerolamo

    2010-08-01

    To compare the effects on parathyroid hormone (PTH) and 25-hydroxy-vitamin D (25(OH)D) of two dosing regimens of cholecalciferol in women with secondary hyperparathyroidism (sHPTH) and hypovitaminosis D and to investigate variables affecting 25(OH)D response to cholecalciferol. Randomized-controlled trial with 6-month follow-up. Two osteoporosis centers in northern Italy. Sixty community-dwelling women aged 65 and older with sHPTH and hypovitaminosis D, creatinine clearance greater than 65 mL/min and without diseases or drugs known to influence bone and vitamin D metabolism. Cholecalciferol 300,000 IU every 3 months, once at baseline and once at 3 months (intermittent D(3) group) or cholecalciferol 1,000 IU/day (daily D(3) group). Serum PTH, 25(OH)D, calcium, bone-specific alkaline phosphatase, β-C-terminal telopeptide of type I collagen, phosphate, 24-hour urinary calcium excretion. The two groups had similar baseline characteristics. All participants had vitamin D deficiency [25(OH)DD(3) group, n=18; daily D(3) group, n=18). After 3 and 6 months, both groups had a significant increase in 25(OH)D and a reduction in PTH. Mean absolute increase ± standard deviation of 25(OH)D at 6 months was higher in the intermittent D(3) group (22.7±11.8 ng/mL) than in the daily D(3) group (13.7±6.7 ng/mL, PD(3) group reaching desirable serum concentration of 25(OH)D≥30 ng/mL (55% in the intermittent D(3) group vs 20% in the daily D(3) group, PD response to cholecalciferol showed a wide variability. In a logistic regression analysis, body mass index and type of treatment appeared to be significantly associated with normalization of 25(OH)D values. Cholecalciferol 300,000 IU every 3 months was more effective than 1,000 IU daily in correcting vitamin D deficiency, although the two groups achieved similar effects on PTH at 6 months. Only 55% of the higher-dose intermittent group reached desirable concentrations of 25(OH)D, suggesting that yet-higher doses will be required for

  1. Some thoughts on the nature of chromosomal aberrations and their use as a quantitative end-point for radiobiological studies

    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

  2. Comparison between the radiosensitivity of human, mouse and chicken fibroblast-like cells using short-term endpoints

    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)

  3. MARIJUANA SMOKING AMONG SECONDARY SCHOOL ...

    MARIJUANA SMOKING AMONG SECONDARY SCHOOL STUDENTS IN ZARIA, NIGERIA: FACTORS RESPONSIBLE AND ... Its medico-social effects could ruin the life and future of our youths. ... A comprehensive school health education

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

    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.

  5. Secondary osteoporosis.

    Gennari, C; Martini, G; Nuti, R

    1998-06-01

    Generalized osteoporosis currently represents a heterogeneous group of conditions with many different causes and pathogenetic mechanisms, that often are variably associated. The term "secondary" is applied to all patients with osteoporosis in whom the identifiable causal factors are other than menopause and aging. In this heterogeneous group of conditions, produced by many different pathogenetic mechanisms, a negative bone balance may be variably associated with low, normal or increased bone remodeling states. A consistent group of secondary osteoporosis is related to endocrinological or iatrogenic causes. Exogenous hypercortisolism may be considered an important risk factor for secondary osteoporosis in the community, and probably glucocorticoid-induced osteoporosis is the most common type of secondary osteoporosis. Supraphysiological doses of corticosteroids cause two abnormalities in bone metabolism: a relative increase in bone resorption, and a relative reduction in bone formation. Bone loss, mostly of trabecular bone, with its resultant fractures is the most incapacitating consequence of osteoporosis. The estimated incidence of fractures in patients prescribed corticosteroid is 30% to 50%. Osteoporosis is considered one of the potentially serious side effects of heparin therapy. The occurrence of heparin-induced osteoporosis appeared to be strictly related to the length of treatment (over 4-5 months), and the dosage (15,000 U or more daily), but the pathogenesis is poorly understood. It has been suggested that heparin could cause an increase in bone resorption by increasing the number of differentiated osteoclasts, and by enhancing the activity of individual osteoclasts. Hyperthyroidism is frequently associated with loss of trabecular and cortical bone; the enhanced bone turnover that develops in thyrotoxicosis is characterized by an increase in the number of osteoclasts and resorption sites, and an increase in the ratio of resorptive to formative bone

  6. Secondary osteoporosis.

    Boyle, I T

    1993-10-01

    Osteoporosis with attendant increased fracture risk is a common complication of many other diseases. Indeed, almost all chronic diseases make some impact on life-style, usually by restricting physical activity and hence reducing the anabolic effect of exercise and gravitational strains on the skeleton. Restricted appetite and modified gastrointestinal tract function is another commonplace finding that has an impact on bone nutrition and synthesis, as on other systems. Sex hormone status is of particular importance for the maintenance of the normal skeleton, and the postmenopausal woman is at particular risk for most causes of secondary osteoporosis. In dealing with secondary osteoporosis in the hypo-oestrogenic woman, the question of giving hormone replacement therapy in addition to other disease-specific therapy should always be considered, as, for example, in a young amenorrhoeic woman with Crohn's disease. Similarly, in hypogonadal men the administration of testosterone is useful for bone conservation. The wider availability of bone densitometry ought to make us more aware of the presence of osteoporosis in the many disease states discussed above. This is particularly important as the life span of such patients is now increased by improved management of the underlying disease process in many instances. Even in steroid-induced osteoporosis--one of the commonest and most severe forms of osteoporosis--we now have some effective therapy in the form of the bisphosphonates and other anti-bone-resorbing drug classes. The possibility of prophylaxis against secondary osteoporosis has therefore become a possibility, although the very long-term effects of such drug regimens are still unknown. In some situations, such as thyrotoxicosis, Cushing's syndrome and immobilization, spontaneous resolution of at least part of the osteoporosis is possible after cure of the underlying problem. The shorter the existence of the basic problem, the more successful the restoration of the

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

    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.

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

    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)

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

    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.

    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. Modulation of adipocytokines response and weight loss secondary to a hypocaloric diet in obese patients by -55CT polymorphism of UCP3 gene.

    de Luis, D A; Aller, R; Izaola, O; Sagrado, M G; Conde, R

    2008-03-01

    Decreased expression or function of UCP3 (uncoupling protein 3) could reduce energy expenditure and increase the storage of energy as fat. Some studies have pointed to a role of UCP3 in the regulation of whole body energy homeostasis, diet induced obesity, and regulation of lipids as metabolic substrates. The C/C genotype of a polymorphism in the UCP3 promoter (-55C-->T) is associated with an increased expression of UCP3 mRNA in muscle. The aim of our study was to investigate the influence of -55CT polymorphism of UCP3 gene on adipocytokines response and weight loss secondary to a hypocaloric diet in obese patients. A population of 107 obese (body mass index >30) nondiabetic outpatients was analyzed in a prospective way. Before and after three months of a hypocaloric diet, an indirect calorimetry, tetrapolar electrical bioimpedance, blood pressure, a serial assessment of nutritional intake with 3-day written food records, and biochemical analysis were performed. The lifestyle modification program consisted of a hypocaloric diet (1520 kcal, 52% of carbohydrates, 25% of lipids and 23% of proteins). The exercise program consisted of aerobic exercise for at least 3 times per week (60 minutes each). The mean age was 49.5+/-34.5 years and the mean BMI 34.5+/-4.8, with 27 males (25.3%) and 80 females (74.7%). Ninety patients (25 males/65 females) (83.6%) had the genotype 55CC (wild group) and 17 patients (2 male/15 females) (16.4%) 55CT (mutant group). The percentage of responders (weight loss) was similar in both groups (wild group: 84.7% vs. mutant group: 81.8%). BMI, weight, fat mass, systolic blood pressure, LDL cholesterol, waist circumference, and waist-to-hip ratio decreased in the wild group and RMR and VO (2) were increased. In the mutant group, BMI and weight decreased. Leptin and IL-6 levels have a significant decrease in the wild group (9.6%: p<0.05) and (30.5%: p<0.05), respectively. Patients with -55CC genotype have a significant decrease in leptin

  12. Tumor lymphocyte immune response to preoperative radiotherapy in locally advanced rectal cancer: The LYMPHOREC study.

    Mirjolet, C; Charon-Barra, C; Ladoire, S; Arbez-Gindre, F; Bertaut, A; Ghiringhelli, F; Leroux, A; Peiffert, D; Borg, C; Bosset, J F; Créhange, G

    2018-01-01

    Introduction : Some studies have suggested that baseline tumor-infiltrating-lymphocytes (TILs), such as CD8+ and FoxP3+ T-cells, may be associated with a better prognosis in colorectal cancer. We sought to investigate modulation of the immune response by preoperative radiotherapy (preopRT) and its impact on survival in locally advanced rectal cancer (LARC). Materials & Methods : We analyzed data for 237 patients with LARC who received RT. Density of TILS (CD8+ and FoxP3+) in intraepithelial (iTILs) and stromal compartments (sTILs) were evaluated from surgery pathological specimens and biopsies performed at baseline. The primary endpoint was to assess the impact of infiltration of the tumor or tumor site after preopRT on progression-free survival (PFS) and overall survival (OS). Secondary endpoints were the impact of dose fractionation scheme on TILs. Results : In univariate analysis, several factors significantly correlated (pguide physicians in adjuvant treatment decision-making.

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

    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....

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

    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

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

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

    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.

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

    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.

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

    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.

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

    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)

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

    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.

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

    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

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

    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. Multiple-endpoints gene alteration-based (MEGA) assay: A toxicogenomics approach for water quality assessment of wastewater effluents.

    Fukushima, Toshikazu; Hara-Yamamura, Hiroe; Nakashima, Koji; Tan, Lea Chua; Okabe, Satoshi

    2017-12-01

    Wastewater effluents contain a significant number of toxic contaminants, which, even at low concentrations, display a wide variety of toxic actions. In this study, we developed a multiple-endpoints gene alteration-based (MEGA) assay, a real-time PCR-based transcriptomic analysis, to assess the water quality of wastewater effluents for human health risk assessment and management. Twenty-one genes from the human hepatoblastoma cell line (HepG2), covering the basic health-relevant stress responses such as response to xenobiotics, genotoxicity, and cytotoxicity, were selected and incorporated into the MEGA assay. The genes related to the p53-mediated DNA damage response and cytochrome P450 were selected as markers for genotoxicity and response to xenobiotics, respectively. Additionally, the genes that were dose-dependently regulated by exposure to the wastewater effluents were chosen as markers for cytotoxicity. The alterations in the expression of an individual gene, induced by exposure to the wastewater effluents, were evaluated by real-time PCR and the results were validated by genotoxicity (e.g., comet assay) and cell-based cytotoxicity tests. In summary, the MEGA assay is a real-time PCR-based assay that targets cellular responses to contaminants present in wastewater effluents at the transcriptional level; it is rapid, cost-effective, and high-throughput and can thus complement any chemical analysis for water quality assessment and management. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. Kinetics of antibody responses after primary immunization with meningococcal serogroup C conjugate vaccine or secondary immunization with either conjugate or polysaccharide vaccine in adults

    de Voer, Richarda M.; van der Klis, Fiona R. M.; Engels, Carla W. A. M.; Schepp, Rutger M.; van de Kassteele, Jan; Sanders, Elisabeth A. M.; Rijkers, Ger T.; Berbers, Guy A. M.

    2009-01-01

    In the Netherlands the meningococcal serogroup C conjugate (MenCC) vaccine is administered as a single dose at 14 months. We evaluated the kinetics of isotype-specific antibodies in adults (n = 21) after primary immunization with MenCC or secondary immunization with MenCC or plain MenC

  5. Towards the Reform of Science Teaching in Spain: The Social and Personal Relevance of Junior Secondary School Science Projects for a Socially Responsible Understanding of Science.

    Membiela, Pedro

    1999-01-01

    Discusses aspects of more than a decade of research and implementation of cross-curriculum themes as part of the curriculum for secondary school students in Spain. Comments on theoretical and practical issues encountered in developing similar projects. Contains 45 references. (Author/WRM)

  6. Acute effects of a prooxidant herbicide on the microalga Chlamydomonas reinhardtii: Screening cytotoxicity and genotoxicity endpoints

    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

  7. Acute effects of a prooxidant herbicide on the microalga Chlamydomonas reinhardtii: Screening cytotoxicity and genotoxicity endpoints

    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

  8. Chloride and sulphate toxicity to Hydropsyche exocellata (Trichoptera, Hydropsychidae): Exploring intraspecific variation and sub-lethal endpoints.

    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

  9. Dynamic decoupling of secondary systems

    Gupta, A.K.; Tembulkar, J.M.

    1984-01-01

    The dynamic analysis of primary systems must often be performed decoupled from the secondary system. In doing so, one should assure that the decoupling does not significantly affect the frequencies and the response of the primary systems. The practice consists of heuristic algorithms intended to limit changes in the frequencies. The change in response is not considered. In this paper, changes in both the frequencies and the response are considered. Rational, but simple algorithms are derived to make accurate predictions. Material up to MDOF primary-SDOF secondary system is presented in this paper. MDOF-MDOF systems are treated in a companion paper. (orig.)

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

    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...

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

    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)

    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.

    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

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

    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.)

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

    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

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

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

    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)

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

    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)

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

    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)

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

    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)

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

    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...

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

    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

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

    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...

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

    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.

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

    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.

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

    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

  8. Bayesian enhancement two-stage design for single-arm phase II clinical trials with binary and time-to-event endpoints.

    Shi, Haolun; Yin, Guosheng

    2018-02-21

    Simon's two-stage design is one of the most commonly used methods in phase II clinical trials with binary endpoints. The design tests the null hypothesis that the response rate is less than an uninteresting level, versus the alternative hypothesis that the response rate is greater than a desirable target level. From a Bayesian perspective, we compute the posterior probabilities of the null and alternative hypotheses given that a promising result is declared in Simon's design. Our study reveals that because the frequentist hypothesis testing framework places its focus on the null hypothesis, a potentially efficacious treatment identified by rejecting the null under Simon's design could have only less than 10% posterior probability of attaining the desirable target level. Due to the indifference region between the null and alternative, rejecting the null does not necessarily mean that the drug achieves the desirable response level. To clarify such ambiguity, we propose a Bayesian enhancement two-stage (BET) design, which guarantees a high posterior probability of the response rate reaching the target level, while allowing for early termination and sample size saving in case that the drug's response rate is smaller than the clinically uninteresting level. Moreover, the BET design can be naturally adapted to accommodate survival endpoints. We conduct extensive simulation studies to examine the empirical performance of our design and present two trial examples as applications. © 2018, The International Biometric Society.

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

    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.

  10. Effects of short- and long-term exposures to copper on lethal and reproductive endpoints of the harpacticoid copepod Tigriopus fulvus.

    Biandolino, Francesca; Parlapiano, Isabella; Faraponova, Olga; Prato, Ermelinda

    2018-01-01

    The long-term exposure provides a realistic measurement of the effects of toxicants on aquatic organisms. The harpacticoid copepod Tigriopus fulvus has a wide geographical distribution and is considered as an ideal model organism for ecotoxicological studies for its good sensitivity to different toxicants. In this study, acute, sub-chronic and chronic toxicity tests based on lethal and reproductive responses of Tigriopus fulvus to copper were performed. The number of moults during larval development was chosen as an endpoint for sub-chronic test. Sex ratio, inhibitory effect on larval development, hatching time, fecundity, brood number, nauplii/brood, total newborn production, etc, were calculated in the chronic test (28d). Lethal effect of copper to nauplii showed the LC50-48h of 310 ± 72µgCu/L (mean ± sd). It was observed a significant inhibition of larval development at sublethal copper concentrations, after 4 and 7 d. After 4d, the EC50 value obtained for the endpoint in "moult naupliar reduction" was of 55.8 ± 2.5µgCu/L (mean ± sd). The EC50 for the inhibition of naupliar development into copepodite stage, was of 21.7 ± 4.4µgCu/L (mean ± sd), after 7 days. Among the different traits tested, copper did not affect sex ratio and growth, while fecundity and total nauplii production were the most sensitive endpoints. The reproductive endpoints offer the advantage of being detectable at very low pollutant concentrations. Copyright © 2017 Elsevier Inc. All rights reserved.

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

    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

  12. 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)

    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

  13. Compliance of secondary production and eco-exergy as indicators of benthic macroinvertebrates assemblages' response to canopy cover conditions in Neotropical headwater streams.

    Linares, Marden Seabra; Callisto, Marcos; Marques, João Carlos

    2018-02-01

    Riparian vegetation cover influences benthic assemblages structure and functioning in headwater streams, as it regulates light availability and autochthonous primary production in these ecosystems.Secondary production, diversity, and exergy-based indicators were applied in capturing how riparian cover influences the structure and functioning of benthic macroinvertebrate assemblages in tropical headwater streams. Four hypotheses were tested: (1) open canopy will determine the occurrence of higher diversity in benthic macroinvertebrate assemblages; (2) streams with open canopy will exhibit more complex benthic macroinvertebrate communities (in terms of information embedded in the organisms' biomass); (3) in streams with open canopy benthic macroinvertebrate assemblages will be more efficient in using the available resources to build structure, which will be reflected by higher eco-exergy values; (4) benthic assemblages in streams with open canopy will exhibit more secondary productivity. We selected eight non-impacted headwater streams, four shaded and four with open canopy, all located in the Neotropical savannah (Cerrado) of southeastern Brazil. Open canopy streams consistently exhibited significantly higher eco-exergy and instant secondary production values, exemplifying that these streams may support more complex and productive benthic macroinvertebrate assemblages. Nevertheless, diversity indices and specific eco-exergy were not significantly different in shaded and open canopy streams. Since all the studied streams were selected for being considered as non-impacted, this suggests that the potential represented by more available food resources was not used to build a more complex dissipative structure. These results illustrate the role and importance of the canopy cover characteristics on the structure and functioning of benthic macroinvertebrate assemblages in tropical headwater streams, while autochthonous production appears to play a crucial role as food

  14. Adaptive responses to cefotaxime treatment in ESBL-producing Escherichia coli and the possible use of significantly regulated pathways as novel secondary targets

    Møller, Thea S. B.; Rau, Martin Holm; Bonde, Charlotte S

    2016-01-01

    The aim of the study was to determine how ESBL-producing Escherichia coli change the expression of metabolic and biosynthesis genes when adapting to inhibitory concentrations of cefotaxime. Secondly, it was investigated whether significantly regulated pathways constitute putative secondary targets......-fold). Inhibition and/or mutations in other genes that were significantly regulated, belonging to energy synthesis, purine synthesis, proline uptake or potassium uptake, also rendered the resistant bacteria more susceptible to cefotaxime. The results show that ESBL-producing E. coli adapt to treatment...

  15. Two Phase III randomised double-blind studies of fixed-dose TC-5214 (dexmecamylamine) adjunct to ongoing antidepressant therapy in patients with major depressive disorder and an inadequate response to prior antidepressant therapy.

    Möller, Hans-Jürgen; Demyttenaere, Koen; Olausson, Bengt; Szamosi, Johan; Wilson, Ellis; Hosford, David; Dunbar, Geoffrey; Tummala, Raj; Eriksson, Hans

    2015-10-01

    To evaluate the neuronal nicotinic channel modulator TC-5214 (dexmecamylamine) as adjunct therapy in patients with major depressive disorder (MDD) and inadequate response to prior antidepressant treatment. Study 004 (D4130C00004) and Study 005 (D4130C00005) comprised an 8-week open-label antidepressant (SSRI/SNRI) treatment period followed by an 8-week randomised, active treatment with twice-daily TC-5214 (0.5, 2 or 4 mg in Study 004; 0.1, 1 or 4 mg in Study 005) or placebo, adjunct to ongoing SSRI/SNRI. Primary efficacy endpoint was change in MADRS total score from randomisation (Week 8) to treatment end (Week 16). Secondary endpoints included MADRS response and remission, and changes in SDS and HAM-D-17-item scores. Safety and tolerability were monitored throughout. Studies 004 and 005 randomised 640 and 696 patients, respectively, to TC-5214 or placebo. No statistically significant improvements in MADRS total score or any secondary endpoints were seen with TC-5214 versus placebo in either study at treatment end. The most commonly reported adverse events (> 10%) with TC-5214 were constipation, dizziness and dry mouth. TC-5214 adjunct to antidepressant was generally well tolerated. However, the studies were not supportive of an antidepressant effect for TC-5214 in patients with MDD and inadequate response to prior antidepressant therapy.

  16. Characterization of the CD8(+)T cell responses directed against respiratory syncytial virus during primary and secondary infection in C57BL/6 mice

    Lukens, M.V.; Claassen, E.A.W.; Graaff, de P.M.A.; Dijk, van M.E.A.; Hoogerhout, P.; Toebes, M.; Schumacher, T.N.; Most, van der R.G.; Kimpen, J.L.L.; Bleek, van G.M.

    2006-01-01

    The BALB/c mouse model for human respiratory syncytial virus infection has contributed significantly to our understanding of the relative role for CD4+ and CD8+ T cells to immune protection and pathogenic immune responses. To enable comparison of RSV-specific T cell responses in different mouse

  17. Changes of Serum Total and Free Testosterone Concentrations in Male Chronic Hemodialysis Patients with Secondary Hyperparathyroidism in Response to Cinacalcet Treatment

    Piotr Kuczera

    2016-01-01

    Full Text Available Background/Aims: Calcium sensing receptor (CaSR is expressed, among others also in testis. Cinacalcet binds to the CaSR, increases sensitivity of CaSR to serum calcium and is used in the treatment of secondary hyperparathyroidism (sHPT in chronic hemodialysis patients (HDP. In most of male HDP, serum testosterone concentration is lower than in healthy males. The aim of this study was to assess the influence of six-month treatment with cinacalcet on the serum total and free testosterone concentration in male HDP with sHPT. Methods: 38 male, hemodialysed CKD patients with sHPT (PTH>300 pg/ml were enrolled into the study. In each patient serum PTH, total testosterone (TT and free testosterone (FT concentrations were assessed before the first dose of cinacalcet and then after 3 and 6 months of treatment. The results are presented as means with 95% confidence interval. Results: In 33 patients who completed the study cinacalcet treatment caused significant decrease of serum PTH from 1143 pg/ml (828 - 1458 pg/ml at the baseline, to 809 pg/ml (487 - 1132pg/ml after 3 month of treatment (p = 0.002, and to 607 pg/ml (281 - 934pg/ml; p Conclusion: Treatment with cinacalcet decreases serum total and free testosterone concentration in male hemodialysed patients with chronic kidney disease and secondary hyperparathyroidism.

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

    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.

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

    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

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

    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.

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

    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

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

    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

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

    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

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

    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

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

    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.

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

    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

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

    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.

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

    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.

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

    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.

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

    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.

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

    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.

  12. Response

    Higgins, Chris

    2012-01-01

    This article presents the author's response to the reviews of his book, "The Good Life of Teaching: An Ethics of Professional Practice." He begins by highlighting some of the main concerns of his book. He then offers a brief response, doing his best to address the main criticisms of his argument and noting where the four reviewers (Charlene…

  13. Cancer as secondary immunodeficiency. Review

    María Eugenia Vargas-Camaño

    2016-05-01

    Full Text Available The secondary immunodeficiency’s, previously presented in immunocompetent individuals. The lack of primary or secondary response to the presence of a foreign antigen, in the case of infections is a sentinel data in the diagnosis of immunodeficiency (can be primary or secondary, in the case of a self antigen may generate the presence of Cancer. Cancer has shown an increase in the prevalence and incidence globally. Most current medical treatments in cancer are focused primarily on immunomodulatory actions (immunosuppression / immune stimulation or both. Knowledge of key concepts from the perspective of innate and acquired immunity lead to cancer development, engaging immune surveillance and escape mechanisms of this that contribute to better understand the origin, behavior and treatment of neoplasm’s. These treatments can cause immunological disorders such as allergy, anaphylaxis, lack of response immunogenicity care fields specialist in Allergy and Clinical Immunology.

  14. Change in the terpenoid profile and secondary growth in declining stands of Pinus sylvestris L. under mediterranean influence as a response to local factors

    Sanz, M. A.

    2014-12-01

    Full Text Available The terpenoid profile could give information about the water status in Scots pine, especially for trees growing in the same geographical area but under contrasting local environmental conditions. Terpenes were analyzed by gas chromatography-mass spectrometry in needles, twigs and wood of ten affected and ten unaffected Scots pines in the southern “Sistema Ibérico” range (Teruel, Spain, where forest decline has been recently reported. Soil depth and secondary growth was also studied in both types of trees. Needles and twigs total resin acids were significantly higher in affected trees. The pimarane type resin acids were also higher in the twigs of affected trees. Secondary growth was lower in affected trees and it showed higher climate sensitivity. The use of the terpenoid profile may be used as an additional tool for the estimation of the water status, especially for situations inducing moderate but relatively prolonged stress conditions.El perfil terpénico podría dar información sobre el estado hídrico en el pino albar, especialmente cuando se comparen especímenes de una zona geográfica concreta afectados por factores ambientales locales. Los terpenos de acículas, brotes del año y madera fueron analizados en diez ejemplares afectados y otros tantos no afectados por el decaimiento mediante cromatografía de masas acoplada a espectrometría de masas. La serie de crecimiento secundario en ambos tipos de ejemplares fue también estudiada. La concentración total de ácidos resínicos aumentó de modo significativo en los árboles afectados tanto en brotes del año como en acículas. La cantidad de ácidos de tipo pimarano también aumentó en los brotes de los árboles afectados. La profundidad del suelo y el crecimiento secundario era menor en este tipo de ejemplares, que muestran una mayor sensibilidad en términos dendrocronológicos. El perfíl terpénico podría utilizarse como una herramienta adicional a la estimación del estado

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

    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.

  16. The efficiency of therapeutic erythrocytapheresis compared to phlebotomy: a mathematical tool for predicting response in hereditary hemochromatosis, polycythemia vera, and secondary erythrocytosis.

    Evers, Dorothea; Kerkhoffs, Jean-Louis; Van Egmond, Liane; Schipperus, Martin R; Wijermans, Pierre W

    2014-06-01

    Recently, therapeutic erythrocytapheresis (TE) was suggested to be more efficient in depletion of red blood cells (RBC) compared to manual phlebotomy in the treatment of hereditary hemochromatosis (HH), polycythemia vera (PV), and secondary erythrocytosis (SE). The efficiency rate (ER) of TE, that is, the increase in RBC depletion achieved with one TE cycle compared to one phlebotomy procedure, can be calculated based on estimated blood volume (BV), preprocedural hematocrit (Hct(B)), and delta-hematocrit (ΔHct). In a retrospective evaluation of 843 TE procedures (in 45 HH, 33 PV, and 40 SE patients) the mean ER was 1.86 ± 0.62 with the highest rates achieved in HH patients. An ER of 1.5 was not reached in 37.9% of all procedures mainly concerning patients with a BV below 4,500 ml. In 12 newly diagnosed homozygous HH patients, the induction phase duration was medially 38.4 weeks (medially 10.5 procedures). During the maintenance treatment of HH, PV, and SE, the interval between TE procedures was medially 13.4 weeks. This mathematical model can help select the proper treatment modality for the individual patient. Especially for patients with a large BV and high achievable ΔHct, TE appears to be more efficient than manual phlebotomy in RBC depletion thereby potentially reducing the numbers of procedures and expanding the interprocedural time period for HH, PV, and SE. © 2013 Wiley Periodicals, Inc.

  17. Pilot study: Exposure and materiality of the secondary room and its impact in the impulse response of coupled-volume concert halls

    Ermann, Michael; Johnson, Marty E.

    2002-05-01

    What does one room sound like when it is partially exposed to another (acoustically coupled)? More specifically, this research aims to quantify how operational and design decisions impact aural impressions in the design of concert halls with acoustical coupling. By adding a second room to a concert hall, and designing doors to control the sonic transparency between the two rooms, designers can create a new, coupled acoustic. Concert halls use coupling to achieve a variable, longer, and distinct reverberant quality for their musicians and listeners. For this study, a coupled-volume shoebox concert hall was conceived with a fixed geometric volume, form, and primary-room sound absorption. Aperture size and secondary-room sound-absorption levels were established as variables. Statistical analysis of sound decay in this simulated hall suggests a highly sensitive relationship between the double-sloped condition and (1) Architectural composition, as defined by the aperture size exposing the chamber and (2) Materiality, as defined by the sound absorbance in the coupled volume. Preliminary calculations indicate that the double-sloped sound decay condition only appears when the total aperture area is less than 1.5% of the total shoebox surface area and the average absorption coefficient of the coupled volume is less than 0.07.

  18. Secondary emission electron gun using external primaries

    Srinivasan-Rao, Triveni [Shoreham, NY; Ben-Zvi, Ilan [Setauket, NY

    2009-10-13

    An electron gun for generating an electron beam is provided, which includes a secondary emitter. The secondary emitter includes a non-contaminating negative-electron-affinity (NEA) material and emitting surface. The gun includes an accelerating region which accelerates the secondaries from the emitting surface. The secondaries are emitted in response to a primary beam generated external to the accelerating region. The accelerating region may include a superconducting radio frequency (RF) cavity, and the gun may be operated in a continuous wave (CW) mode. The secondary emitter includes hydrogenated diamond. A uniform electrically conductive layer is superposed on the emitter to replenish the extracted current, preventing charging of the emitter. An encapsulated secondary emission enhanced cathode device, useful in a superconducting RF cavity, includes a housing for maintaining vacuum, a cathode, e.g., a photocathode, and the non-contaminating NEA secondary emitter with the uniform electrically conductive layer superposed thereon.

  19. Does Response to Induction Chemotherapy Predict Survival for Locally Advanced Non-Small-Cell Lung Cancer? Secondary Analysis of RTOG 8804/8808

    McAleer, Mary Frances; Moughan, Jennifer M.S.; Byhardt, Roger W.; Cox, James D.; Sause, William T.; Komaki, Ritsuko

    2010-01-01

    Purpose: Induction chemotherapy (ICT) improves survival compared with radiotherapy (RT) alone in locally advanced non-small-cell lung cancer (LANSCLC) patients with good prognostic factors. Concurrent chemoradiotherapy (CCRT) is superior to ICT followed by RT. The question arises whether ICT response predicts the outcome of patients subsequently treated with CCRT or RT. Methods and Materials: Between 1988 and 1992, 194 LANSCLC patients were treated prospectively with ICT (two cycles of vinblastine and cisplatin) and then CCRT (cisplatin plus 63 Gy for 7 weeks) in the Radiation Therapy Oncology Group 8804 trial (n = 30) or ICT and then RT (60 Gy/6 wk) on Radiation Therapy Oncology Group 8808 trial (n = 164). Of the 194 patients, 183 were evaluable and 141 had undergone a postinduction assessment. The overall survival (OS) of those with complete remission (CR) or partial remission (PR) was compared with that of patients with stable disease (SD) or progressive disease (PD) after ICT. Results: Of the 141 patients, 6, 30, 99, and 6 had CR, PR, SD, and PD, respectively. The log-rank test showed a significant difference (p <0.0001) in OS when the response groups were compared (CR/PR vs. SD/PD). On univariate and multivariate analyses, a trend was seen toward a response to ICT with OS (p = 0.097 and p = 0.06, respectively). A squamous histologic type was associated with worse OS on univariate and multivariate analyses (p = 0.031 and p = 0.018, respectively). SD/PD plus a squamous histologic type had a hazard ratio of 2.25 vs. CR/PR plus a nonsquamous histologic type (p = 0.007) on covariate analysis. Conclusion: The response to ICT was associated with a significant survival difference when the response groups were compared. A response to ICT showed a trend toward, but was not predictive of, improved OS in LANSCLC patients. Patients with SD/PD after ICT and a squamous histologic type had the poorest OS. These data suggest that patients with squamous LANSCLC might benefit

  20. Ceiling-mounted personalized ventilation system integrated with a secondary air distribution system--a human response study in hot and humid climate.

    Yang, B; Sekhar, S C; Melikov, A K

    2010-08-01

    The benefits of thermal comfort and indoor air quality with personalized ventilation (PV) systems have been demonstrated in recent studies. One of the barriers for wide spread acceptance by architects and HVAC designers has been attributed to challenges and constraints faced in the integration of PV systems with the work station. A newly developed ceiling-mounted PV system addresses these challenges and provides a practical solution while retaining much of the apparent benefits of PV systems. Assessments of thermal environment, air movement, and air quality for ceiling-mounted PV system were performed with tropically acclimatized subjects in a Field Environmental Chamber. Thirty-two subjects performed normal office work and could choose to be exposed to four different PV airflow rates (4, 8, 12, and 16 L/s), thus offering themselves a reasonable degree of individual control. Ambient temperatures of 26 and 23.5 degrees C and PV air temperatures of 26, 23.5, and 21 degrees C were employed. The local and whole body thermal sensations were reduced when PV airflow rates were increased. Inhaled air temperature was perceived cooler and perceived air quality and air freshness improved when PV airflow rate was increased or temperature was reduced. The newly developed ceiling-mounted PV system offers a practical solution to the integration of PV air terminal devices (ATDs) in the vicinity of the workstation. By remotely locating the PV ATDs on the ceiling directly above the occupants and under their control, the conditioned outdoor air is now provided to the occupants through the downward momentum of the air. A secondary air-conditioning and air distribution system offers additional cooling in the room and maintains a higher ambient temperature, thus offering significant benefits in conserving energy. The results of this study provide designers and consultants with needed knowledge for design of PV systems.

  1. Decreased Secondary Lesion Growth and Attenuated Immune Response after Traumatic Brain Injury in Tlr2/4−/− Mice

    Sandro M. Krieg

    2017-08-01

    Full Text Available Danger-associated molecular patterns are released by damaged cells and trigger neuroinflammation through activation of non-specific pattern recognition receptors, e.g., toll-like receptors (TLRs. Since the role of TLR2 and 4 after traumatic brain injury (TBI is still unclear, we examined the outcome and the expression of pro-inflammatory mediators after experimental TBI in Tlr2/4−/− and wild-type (WT mice. Tlr2/4−/− and WT mice were subjected to controlled cortical injury and contusion volume and brain edema formation were assessed 24 h thereafter. Expression of inflammatory markers in brain tissue was measured by quantitative PCR 15 min, 3 h, 6 h, 12 h, and 24 h after controlled cortical impact (CCI. Contusion volume was significantly attenuated in Tlr2/4−/− mice (29.7 ± 0.7 mm3 as compared to 33.5 ± 0.8 mm3 in WT; p < 0.05 after CCI while brain edema was not affected. Only interleukin (IL-1β gene expression was increased after CCI in the Tlr2/4−/− relative to WT mice. Inducible nitric oxide synthetase, TNF, IL-6, and COX-2 were similar in injured WT and Tlr2/4−/− mice, while the increase in high-mobility group box 1 was attenuated at 6 h. TLR2 and 4 are consequently shown to potentially promote secondary brain injury after experimental CCI via neuroinflammation and may therefore represent a novel therapeutic target for the treatment of TBI.

  2. Safety and efficacy of transarterial chemoembolization with degradable starch microspheres (DSM-TACE) in the treatment of secondary liver malignancies.

    Schicho, Andreas; Pereira, Philippe L; Michalik, Katharina; Beyer, Lukas P; Stroszczynski, Christian; Wiggermann, Philipp

    2018-01-01

    To evaluate the safety and efficacy of degradable starch microspheres (DSM) as embolic agents in transarterial chemoembolization (TACE) in the treatment of secondary liver metastases. This was a national, multicenter observational study. Primary endpoints were safety and treatment response according to Modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria. A total of 77 DSM-TACE procedures were performed in 20 patients. Minor immediate adverse events (AEs) were epigastric pain with an incidence of 45.5% (35/77), and nausea and vomiting at an incidence of 23.4% (18/77). Delayed minor AEs were epigastric pain in 13/77 (16.9%) treatments and nausea and vomiting in 10 (13.0%) treatments. No severe AEs were documented. Therapeutic efficacy of DSM-TACE procedures according to mRECIST was as follows: complete response 0/77, partial response 17/77, stable disease 33/77 and progressive disease 6/77, no data was available for 21/77 treatments. Overall, objective response was achieved in 8 of 20 patients (40.0%). DSM as embolic agent for TACE is safe in the treatment of liver metastases. An objective response in 40.0% of patients and disease control in 64.9% of procedures was achieved, and this should lead to further evaluation of DSM-TACE as treatment option for nonresectable liver metastases.

  3. 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).

    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.

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

    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.

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

    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

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

    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

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

    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.

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

    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.

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

    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

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

    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.

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

    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.

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

    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.

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

    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...

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

    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.

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

    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...

  16. Dose and dose rate extrapolation factors for malignant and non-malignant health endpoints after exposure to gamma and neutron radiation

    Tran, Van; Little, Mark P. [National Cancer Institute, Radiation Epidemiology Branch, Rockville, MD (United States)

    2017-11-15

    non-malignant, show downward curvature in the dose response, and for most endpoints this is statistically significant (p < 0.05). Associated with this, the low-dose extrapolation factor associated with neutron exposure is generally statistically significantly less than 1 for most malignant and non-malignant endpoints, with central estimates mostly in the range 0.1-0.9. In contrast to the situation at higher dose rates, there are statistically non-significant decreases of risk per unit dose at gamma dose rates of less than or equal to 5 mGy/h for most malignant endpoints, and generally non-significant increases in risk per unit dose at gamma dose rates ≤5 mGy/h for most non-malignant endpoints. Associated with this, the dose-rate extrapolation factor, the ratio of high dose-rate to low dose-rate (≤5 mGy/h) gamma dose response slopes, for many tumour sites is in the range 1.2-2.3, albeit not statistically significantly elevated from 1, while for most non-malignant endpoints the gamma dose-rate extrapolation factor is less than 1, with most estimates in the range 0.2-0.8. After neutron exposure there are non-significant indications of lower risk per unit dose at dose rates ≤5 mGy/h compared to higher dose rates for most malignant endpoints, and for all tumours (p = 0.001), and respiratory tumours (p = 0.007) this reduction is conventionally statistically significant; for most non-malignant outcomes risks per unit dose non-significantly increase at lower dose rates. Associated with this, the neutron dose-rate extrapolation factor is less than 1 for most malignant and non-malignant endpoints, in many cases statistically significantly so, with central estimates mostly in the range 0.0-0.2. (orig.)

  17. Secondary School Science Department Chairs Leading Change

    Gaubatz, Julie A.

    2012-01-01

    Secondary school department chairs are content area specialists in their schools and are responsible for providing students with the most appropriate curricula. However, most secondary school department chairs have limited authority to institute change unilaterally (Gmelch, 1993; Hannay & Erb, 1999). To explore how these educational leaders…

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

    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.

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

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

    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.

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

    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)

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

    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.

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

    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.

  4. An overview of techniques for linking high-dimensional molecular data to time-to-event endpoints by risk prediction models.

    Binder, Harald; Porzelius, Christine; Schumacher, Martin

    2011-03-01

    Analysis of molecular data promises identification of biomarkers for improving prognostic models, thus potentially enabling better patient management. For identifying such biomarkers, risk prediction models can be employed that link high-dimensional molecular covariate data to a clinical endpoint. In low-dimensional settings, a multitude of statistical techniques already exists for building such models, e.g. allowing for variable selection or for quantifying the added value of a new biomarker. We provide an overview of techniques for regularized estimation that transfer this toward high-dimensional settings, with a focus on models for time-to-event endpoints. Techniques for incorporating specific covariate structure are discussed, as well as techniques for dealing with more complex endpoints. Employing gene expression data from patients with diffuse large B-cell lymphoma, some typical modeling issues from low-dimensional settings are illustrated in a high-dimensional application. First, the performance of classical stepwise regression is compared to stage-wise regression, as implemented by a component-wise likelihood-based boosting approach. A second issues arises, when artificially transforming the response into a binary variable. The effects of the resulting loss of efficiency and potential bias in a high-dimensional setting are illustrated, and a link to competing risks models is provided. Finally, we discuss conditions for adequately quantifying the added value of high-dimensional gene expression measurements, both at the stage of model fitting and when performing evaluation. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. Time to second prostate specific antigen (PSA) failure is a surrogate endpoint for prostate cancer death in prospective trials of therapy for localized disease

    Zietman, A L; Dallow, K C; Shipley, W U; Heney, N M; McManus, P L

    1995-07-01

    Purpose In assessing the efficacy of the competing curative therapies for prostate cancer the most relevant endpoint is cancer specific death. Due to the long natural history of the disease and the use of salvage androgen suppression prospective trials need to mature for at least a decade to provide meaningful results. An endpoint that predicted for cancer death with high probability would allow more rapid completion of prospective studies, hopefully before the tested therapies become outdated. Materials and methods 202 patients entered into a single institution prospective randomized study for T3-4 prostate cancer between 1982 and 1992 were evaluated. All received radical irradiation to either a standard dose of 67.2Gy or a higher dose of 75.6Gy (the latter employing a proton beam boost). 76 men have received androgen suppression or orchiectomy for salvage following relapse (median follow-up 6.9 years). Of this group 35 experienced a second relapse heralded by a rise in the serum PSA. Second failure was scored on the date that the serum PSA rose to greater than 10% above the post-androgen suppression nadir. Kaplan-Meier analysis was made of survival from the time of second PSA failure and the cause of death established in all patients who subsequently died. Results The median duration of response to hormone therapy following first failure was 27.2 months. The actuarial survival from the time of second biochemical relapse was 93%, 66%, 35%, and 0% at 1, 2, 3, and 4 years respectively (50% at 32 months). 16 patients have so far died after second failure all from causes related to their prostate cancer. Conclusion Second PSA failure appears to be a secure surrogate for impending prostate cancer death. Its use as an endpoint in prospective studies should allow earlier reporting by 2 - 3 years.

  6. 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.

    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.

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

    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

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

    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

  9. 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.

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

    2017-01-01

    responsiveness are important to help guide appropriate management. As new clinical trials and observational studies are conducted, it will be important to maintain universal endpoints so that health care providers, decision makers, and payers can better understand the value of targeted pharmacotherapies and combination therapies for the treatment of patients with PAH and CTEPH. Sponsorship for this review and article processing charges were funded by Bayer HealthCare Pharmaceuticals. Divers and Platt are employees of Bayer HealthCare Pharmaceuticals. Wang is an employee of Bayer HealthCare Pharmaceuticals and owns stock in the company. Lin and Lingohr-Smith are employees of Novosys Health, which received research funds from Bayer HealthCare Pharmaceuticals in connection with conducting this review and developing this manuscript. Mathai is a consultant to Bayer HealthCare Pharmaceuticals and also reports consulting fees from Actelion and Gilead. Study concept and design were contributed by Divers, Platt, Lin, and Mathai. Lin and Lingohr-Smith collected the data, and data interpretation was performed by Divers, Platt, Wang, and Matthai. The manuscript was written primarily by Lingohr-Smith, with assistance from the other authors, and revised by Divers, Platt, Wang, and Mathai.

  10. Responses of reactive oxygen scavenging enzymes, proline and malondialdehyde to water deficits among six secondary successional seral species in Loess Plateau.

    Feng Du

    Full Text Available Drought can impact local vegetation dynamics in a long term. In order to predict the possible successional pathway of local community under drought, the responses of some drought resistance indices of six successional seral species in the semi-arid Loss Hilly Region of China were illustrated and compared on three levels of soil water deficits along three growing months (7, 8 and 9. The results showed that: 1 the six species had significant differences in SOD, POD activities and MDA content. The rank correlations between SOD, POD activities and the successional niche positions of the six species were positive, and the correlation between MDA content and the niche positions was negative; 2 activities of SOD, CAT and POD, and content of proline and MDA had significant differences among the three months; 3 there existed significant interactions of SOD, CAT, POD activities and MDA content between months and species. With an exception, no interaction of proline was found. Proline in leaves had a general decline in reproductive month; 4 SOD, CAT, POD activities and proline content had negative correlations with MDA content. Among which, the correlation between SOD activity and MDA content was significant. The results implied that, in arid or semiarid region, the species at later successional stage tend to have strong drought resistance than those at early stage. Anti-drought indices can partially interpret the pathway of community succession in the drought impacted area. SOD activity is more distinct and important on the scope of protecting membrane damage through the scavenging of ROS on exposure to drought.

  11. Application of response surface methodology in optimization of performance and exhaust emissions of secondary butyl alcohol-gasoline blends in SI engine

    Yusri, I.M.; Mamat, R.; Azmi, W.H.; Omar, A.I.; Obed, M.A.; Shaiful, A.I.M.

    2017-01-01

    Highlights: • Adding 2-butanol in gasoline fuel can improve engine performance. • 2-Butanol addition reduced NO x , CO, and HC but produced higher CO 2 . • RSM was applied to optimize the engine performance and exhaust emissions. - Abstract: Producing an optimal balance between engine performance and exhaust emissions has always been one of the main challenges in automotive technology. This paper examines the use of RSM (response surface methodology) to optimize the engine performance, and exhaust emissions of a spark-ignition (SI) engine which operates with 2-butanol–gasoline blends of 5%, 10%, and 15% called GBu5, GBu10, and GBu15. In the experiments, the engine ran at various speeds for each test fuel and 13 different conditions were constructed. The optimization of the independent variables was performed by means of a statistical tool known as DoE (design of experiments). The desirability approach by RSM was employed with the aim of minimizing emissions and maximizing of performance parameters. Based on the RSM model, performance characteristics revealed that increments of 2-butanol in the blended fuels lead to increasing trends of brake power, brake mean effective pressure and brake thermal efficiency. Nonetheless, marginal higher brake specific fuel consumption was observed. Furthermore, the RSM model suggests that the presence of 2-butanol exhibits a decreasing trend of nitrogen oxides, carbon monoxides, and unburnt hydrocarbon, however, a higher trend was observed for carbon dioxides exhaust emissions. It was established from the study that the GBu15 blend with an engine speed of 3205 rpm was found to be optimal to provide the best performance and emissions characteristics as compared to the other tested blends.

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

    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

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

    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.

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

    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.

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

    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

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

    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...

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

    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.

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

    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.

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

    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.

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

    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.

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

    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)

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

    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)

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

    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.

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

    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

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

    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

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

    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.

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

    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.

  8. Monoparesis secondary to herpes zoster.

    Bilal, S

    2011-06-01

    We describe a 90-year-old woman with right upper limb monoparesis secondary to varicella zoster virus infection as a result of extensive inflammatory involvement of the entire brachial plexus at root level. To our knowledge, this is the first report of entire brachial plexus involvement in a living patient of such advanced age. Despite a delay in presentation and thus initiation of treatment, a favourable clinical response was observed.

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

    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.

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

    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.

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

    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.

  12. The enrichment secondary market

    Einbund, D.R.

    1986-01-01

    This paper will addresses two topics: the background to the present status of the enrichment secondary market and the future outlook of the secondary market in enrichment services, and the viability of the nuclear fuel brokerage industry. These two topics are inevitably connected, as most secondary market activity, not only in enrichment but also in natural uranium, has traditionally been conducted with the participation of brokers. Therefore, the author interrelates these topics

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

    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.

  14. Quantitative secondary electron detection

    Agrawal, Jyoti; Joy, David C.; Nayak, Subuhadarshi

    2018-05-08

    Quantitative Secondary Electron Detection (QSED) using the array of solid state devices (SSD) based electron-counters enable critical dimension metrology measurements in materials such as semiconductors, nanomaterials, and biological samples (FIG. 3). Methods and devices effect a quantitative detection of secondary electrons with the array of solid state detectors comprising a number of solid state detectors. An array senses the number of secondary electrons with a plurality of solid state detectors, counting the number of secondary electrons with a time to digital converter circuit in counter mode.

  15. 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.

    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.

  16. [Secondary Arterial Hypertension: Uncertainties in Diagnosis].

    Dinis, Paulo Gomes; Cachulo, Maria Carmo; Fernandes, Andreia; Paiva, Luis; Gonçalves, Lino

    2017-06-30

    Arterial hypertension is regarded today as a global public health problem, and the prevalence rate in Portugal is 26.9%. According to the etiology, is classified into primary or secondary arterial hypertension. In about 90% of cases it is not possible to establish a cause, so is called primary arterial hypertension. In the remaining 5 to 10%, it can be identified secondary causes, which are potentially treatable. For secondary arterial hypertension study to be cost-effective, it is essential to understand which patients investigate, and evaluate the best strategy to adopt. The main causes identified as responsible for secondary arterial hypertension are: kidney disease; endocrine and vascular diseases and obstructive sleep apnea. Among these some are consensual, and others more controversial in the literature. In this regard we present two cases of arterial hypertension, which are potentially secondary in etiology, but still focus of debate.

  17. Peninsula Humane Society Teacher's Packet. Secondary Level.

    Peninsula Humane Society, San Mateo, CA.

    Activities in this teacher's packet are designed to familiarize secondary school students with the responsibilities involved in pet ownership. Teaching plans are provided for a total of 12 lessons grouped under social studies, language arts, math, and health sciences. Activities focus on pet overpopulation, expressions of social responses in…

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

    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.

  19. Secondary acute pneumonias

    Rozenshtraukh, L.C.; Rybakova, N.I.; Vinner, M.G.

    1987-01-01

    Pathological changes, promoting the development of secondary pneumonias, are investigated. To this group belong: blood circulation disturbance in small circle, bronchial passability disturbance, aspiration of liquids, gases and vapors, infections and purulent processes, intoxications, injuries, operative interference. Roetgenologic symptomatics of each secondary acute pneumonia form is presented in detail

  20. Building a secondary containment system

    Broder, M.F.

    1994-10-01

    Retail fertilizer and pesticide dealers across the United States are installing secondary containment at their facilities or are seriously considering it. Much of this work is in response to new state regulations; however, many dealers not facing new regulations are upgrading their facilities to reduce their liability, lower their insurance costs, or comply with anticipated regulations. The Tennessee Valley Authority`s (TVA) National Fertilizer and Environmental Research Center (NFERC) has assisted dealers in 22 states in retrofitting containment to their facilities. Simultaneous improvements in the operational efficiency of the facilities have been achieved at many of the sites. This paper is based on experience gained in that work and details the rationale used in planning secondary containment and facility modifications.

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

    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

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

    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.

  3. Elimination of endpoint-discontinuity artifacts in the analysis of spectra in reciprocal space

    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

  4. Center-Within-Trial Versus Trial-Level Evaluation of Surrogate Endpoints

    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

  5. End-Point Immobilization of Recombinant Thrombomodulin via Sortase-Mediated Ligation

    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

  6. The interpolation method based on endpoint coordinate for CT three-dimensional image

    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)

  7. Speech endpoint detection with non-language speech sounds for generic speech processing applications

    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.

  8. End-point detection in potentiometric titration by continuous wavelet transform.

    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.

  9. Analysing data from patient-reported outcome and quality of life endpoints for cancer clinical trials

    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...

  10. CaFE: a tool for binding affinity prediction using end-point free energy methods.

    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.

  11. Secondary fuel delivery system

    Parker, David M.; Cai, Weidong; Garan, Daniel W.; Harris, Arthur J.

    2010-02-23

    A secondary fuel delivery system for delivering a secondary stream of fuel and/or diluent to a secondary combustion zone located in the transition piece of a combustion engine, downstream of the engine primary combustion region is disclosed. The system includes a manifold formed integral to, and surrounding a portion of, the transition piece, a manifold inlet port, and a collection of injection nozzles. A flowsleeve augments fuel/diluent flow velocity and improves the system cooling effectiveness. Passive cooling elements, including effusion cooling holes located within the transition boundary and thermal-stress-dissipating gaps that resist thermal stress accumulation, provide supplemental heat dissipation in key areas. The system delivers a secondary fuel/diluent mixture to a secondary combustion zone located along the length of the transition piece, while reducing the impact of elevated vibration levels found within the transition piece and avoiding the heat dissipation difficulties often associated with traditional vibration reduction methods.

  12. Uncertainty analysis for secondary energy distributions

    Gerstl, S.A.W.

    1978-01-01

    In many transport calculations the integral design parameter of interest (response) is determined mainly by secondary particles such as gamma rays from (n,γ) reactions or secondary neutrons from inelastic scattering events or (n,2n) reactions. Standard sensitivity analysis usually allows to calculate the sensitivities to the production cross sections of such secondaries, but an extended formalism is needed to also obtain the sensitivities to the energy distribution of the generated secondary particles. For a 30-group standard cross-section set 84% of all non-zero table positions pertain to the description of secondary energy distributions (SED's) and only 16% to the actual reaction cross sections. Therefore, any sensitivity/uncertainty analysis which does not consider the effects of SED's is incomplete and neglects most of the input data. This paper describes the methods of how sensitivity profiles for SED's are obtained and used to estimate the uncertainty of an integral response due to uncertainties in these SED's. The detailed theory is documented elsewhere and implemented in the LASL sensitivity code SENSIT. SED sensitivity profiles have proven particularly valuable in cross-section uncertainty analyses for fusion reactors. Even when the production cross sections for secondary neutrons were assumed to be without error, the uncertainties in the energy distribution of these secondaries produced appreciable uncertainties in the calculated tritium breeding rate. However, complete error files for SED's are presently nonexistent. Therefore, methods will be described that allow rough error estimates due to estimated SED uncertainties based on integral SED sensitivities

  13. Fourier-transform infrared spectroscopy as a novel approach to providing effect-based endpoints in duckweed toxicity testing.

    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.

  14. Updated standardized endpoint definitions for transcatheter aortic valve implantation: The Valve Academic Research Consortium-2 consensus document

    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.

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

    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

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

    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

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

    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.

  18. The Impact of Multiple Endpoint Dependency on "Q" and "I"[superscript 2] in Meta-Analysis

    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…

  19. Pressure Injury Progression and Factors Associated With Different End-Points in a Home Palliative Care Setting: A Retrospective Chart Review Study.

    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.

  20. need for adequate funding in the administration of secondary

    PROF. BARTH EKWEME

    their corporate social responsibility. ... This is because such funding strategy will assist in .... social corporate responsibilities of contributing to the .... Exploring funding sources will therefore help to reduce the burden of funding secondary ...

  1. Teaching secondary mathematics

    Rock, David

    2013-01-01

    Solidly grounded in up-to-date research, theory and technology,?Teaching Secondary Mathematics?is a practical, student-friendly, and popular text for secondary mathematics methods courses. It provides clear and useful approaches for mathematics teachers, and shows how concepts typically found in a secondary mathematics curriculum can be taught in a positive and encouraging way. The thoroughly revised fourth edition combines this pragmatic approach with truly innovative and integrated technology content throughout. Synthesized content between the book and comprehensive companion websi

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

    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

  3. Novel joint selection methods can reduce sample size for rheumatoid arthritis clinical trials with ultrasound endpoints.

    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.

  4. First observation of bald patches in a filament channel and at a barb endpoint

    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

  5. Comparison of the sensitivity of different toxicological endpoints in Caco-2 cells after cadmium chloride treatment

    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.)

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

    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

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

    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.

  8. NPP Krsko secondary side analysis

    Fabijan, Lj.

    1987-01-01

    The purpose of this work is to analyze secondary side thermohydraulics response on steam generator tube plugging in order to ensure nominal NPP power. We had established that the additional opening of the governing valve No. 3 and 4 can compensate pressure drop caused by steam generator tube plugging. Two main steam flows with four governing valves were simulated. Steam expansion in turbine and feed water system was modeled separately. All important process point and steam moisture changes impact on nominal NPP power were analysed. (author)

  9. Protein kinase FgSch9 serves as a mediator of the target of rapamycin and high osmolarity glycerol pathways and regulates multiple stress responses and secondary metabolism in Fusarium graminearum.

    Gu, Qin; Zhang, Chengqi; Yu, Fangwei; Yin, Yanni; Shim, Won-Bo; Ma, Zhonghua

    2015-08-01

    Saccharomyces cerevisiae protein kinase Sch9 is one of the downstream effectors of the target of rapamycin (TOR) complex 1 and plays multiple roles in stress resistance, longevity and nutrient sensing. However, the functions of Sch9 orthologs in filamentous fungi, particularly in pathogenic species, have not been characterized to date. Here, we investigated biological and genetic functions of FgSch9 in Fusarium graminearum. The FgSCH9 deletion mutant (ΔFgSch9) was defective in aerial hyphal growth, hyphal branching and conidial germination. The mutant exhibited increased sensitivity to osmotic and oxidative stresses, cell wall-damaging agents, and to rapamycin, while showing increased thermal tolerance. We identified FgMaf1 as one of the FgSch9-interacting proteins that plays an important role in regulating mycotoxin biosynthesis and virulence of F. graminearum. Co-immunoprecipitation and affinity capture-mass spectrometry assays showed that FgSch9 also interacts with FgTor and FgHog1. More importantly, both ΔFgSch9 and FgHog1 null mutant (ΔFgHog1) exhibited increased sensitivity to osmotic and oxidative stresses. This defect was more severe in the FgSch9/FgHog1 double mutant. Taken together, we propose that FgSch9 serves as a mediator of the TOR and high osmolarity glycerol pathways, and regulates vegetative differentiation, multiple stress responses and secondary metabolism in F. graminearum. © 2014 Society for Applied Microbiology and John Wiley & Sons Ltd.

  10. Secondary amenorrhea (image)

    Secondary amenorrhea is the cessation of menstrual flow for a period of 6 months or more in the absence ... as anxiety can be the root cause of amenorrhea. Treatment can range from behavior modification for excessive ...

  11. Towards secondary fingerprint classification

    Msiza, IS

    2011-07-01

    Full Text Available an accuracy figure of 76.8%. This small difference between the two figures is indicative of the validity of the proposed secondary classification module. Keywords?fingerprint core; fingerprint delta; primary classifi- cation; secondary classification I..., namely, the fingerprint core and the fingerprint delta. Forensically, a fingerprint core is defined as the innermost turning point where the fingerprint ridges form a loop, while the fingerprint delta is defined as the point where these ridges form a...

  12. Secondary Fire Analysis.

    1981-09-01

    Megaton Weapons and Secondary Ignition There are very few well documented data on fires initiated by physical damage (i.e., secondary ignitions). Those data...where significant physical damage to buildings and/or contents can occur. Where this outer bound is located relative to the primary ignition range is...maintenance 7.9 Busline facilities, including shops 3.0 Convalescent homes8 3.1 Hospitals 8.0 Radio and television transmitters Collges and universities

  13. 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

    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

  14. 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

    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

  15. Ruling out secondary causes of hypertension.

    Ott, Christian; Schneider, Markus P; Schmieder, Roland E

    2013-05-01

    In the majority of hypertensive patients, no particular cause for abnormal blood pressure is evident (primary or essential hypertension). In contrast, in the minority of patients with secondary hypertension a specific underlying cause is responsible for the elevated blood pressure. The prevalence of secondary hypertension is higher in patients with resistant hypertension than in the general hypertensive population and increases with age. The list of secondary forms of hypertension is long and prevalence of the individual causes of secondary hypertension varies. Hence, this review divides them into two categories: common causes and rare causes. If appropriately diagnosed and treated, patients with a secondary form of hypertension might be cured, or at least show an improvement in their blood pressure control. Consequently, screening for secondary causes of hypertension plays an essential part in the care of patients with arterial hypertension. If the basal work-up raises the suspicion of a secondary cause of hypertension, specific diagnostic procedures become necessary, some of which can be performed by primary care physicians, while others require specialist input.

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

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

    2017-05-01

    medical challenge with a prevalence rate ranging from 8% to 50%. Many clinicians and researchers across the globe are searching for better answers to understand the mechanisms related to the development and chronicity of DED. Though there have been many clinical trials for DED, few new treatments have emerged over the last decade. Biomarkers may provide the needed breakthrough to propel our understanding of DED to the next level and the potential to realize our goal of truly personalized medicine based on scientific evidence. Clinical trials and research on DED have suffered from the lack of validated biomarkers and less than objective and reproducible endpoints. Current work on biomarkers has provided the groundwork to move forward. This review highlights primarily ocular biomarkers that have been investigated for use in DED, discusses the methodologic outcomes in providing objective metrics for clinical research, and suggests recommendations for further work.

  17. Lethal and sublethal endpoints observed for Artemia exposed to two reference toxicants and an ecotoxicological concern organic compound.

    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.

  18. New drugs and patient-centred end-points in old age: setting the wheels in motion.

    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.

  19. Optimal descriptor as a translator of eclectic data into endpoint prediction: mutagenicity of fullerene as a mathematical function of conditions.

    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.

  20. QED contribution to the color-singlet J/ψ production in Υ decay near the endpoint

    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.

  1. How "humane" is your endpoint? Refining the science-driven approach for termination of animal studies of chronic infection.

    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...

  2. Secondary metabolites from Ganoderma.

    Baby, Sabulal; Johnson, Anil John; Govindan, Balaji

    2015-06-01

    Ganoderma is a genus of medicinal mushrooms. This review deals with secondary metabolites isolated from Ganoderma and their biological significance. Phytochemical studies over the last 40years led to the isolation of 431 secondary metabolites from various Ganoderma species. The major secondary compounds isolated are (a) C30 lanostanes (ganoderic acids), (b) C30 lanostanes (aldehydes, alcohols, esters, glycosides, lactones, ketones), (c) C27 lanostanes (lucidenic acids), (d) C27 lanostanes (alcohols, lactones, esters), (e) C24, C25 lanostanes (f) C30 pentacyclic triterpenes, (g) meroterpenoids, (h) farnesyl hydroquinones (meroterpenoids), (i) C15 sesquiterpenoids, (j) steroids, (k) alkaloids, (l) prenyl hydroquinone (m) benzofurans, (n) benzopyran-4-one derivatives and (o) benzenoid derivatives. Ganoderma lucidum is the species extensively studied for its secondary metabolites and biological activities. Ganoderma applanatum, Ganoderma colossum, Ganoderma sinense, Ganoderma cochlear, Ganoderma tsugae, Ganoderma amboinense, Ganoderma orbiforme, Ganoderma resinaceum, Ganoderma hainanense, Ganoderma concinna, Ganoderma pfeifferi, Ganoderma neo-japonicum, Ganoderma tropicum, Ganoderma australe, Ganoderma carnosum, Ganoderma fornicatum, Ganoderma lipsiense (synonym G. applanatum), Ganoderma mastoporum, Ganoderma theaecolum, Ganoderma boninense, Ganoderma capense and Ganoderma annulare are the other Ganoderma species subjected to phytochemical studies. Further phytochemical studies on Ganoderma could lead to the discovery of hitherto unknown biologically active secondary metabolites. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. Pharmaceutics, Drug Delivery and Pharmaceutical Technology: A New Test Unit for Disintegration End-Point Determination of Orodispersible Films.

    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.

  4. The role of categorization and scale endpoint comparisons in numerical information processing: A two-process model.

    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).

  5. Investigation of allergenicity of some cosmetic mixtures by using ex vivo local lymph node assay-BrdU endpoints.

    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.

  6. A Comparison of Real-Time and Endpoint Cell Viability Assays for Improved Synthetic Lethal Drug Validation.

    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.

  7. 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.

    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.

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

    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

  9. Linkage of genomic biomarkers to whole organism endpoints in a Toxicity Identification Evaluation (TIE).

    Aquatic organisms are exposed to many toxic chemicals and interpreting the cause and effect relationships between occurrence and impairment is difficult. Toxicity Identification Evaluation (TIE) provides a systematic approach for identifying responsible toxicants. TIE relies on ...

  10. PSR 1913 + 16: endpoints of speculation. A critical discussion of possible companions and progenitors

    Webbink, R F [Cambridge Univ. (UK). Inst. of Astronomy

    1975-01-01

    We attempt a comprehensive discussion of the nature and origin of the binary pulsar PSR 1913 + 16. It is shown that the system must have been binary before the creation of the pulsar. Main-sequence stars, white dwarfs, helium stars, neutron stars and black holes are considered as possible secondaries. It is shown that the pulsar component must have been a helium star before collapse. The companion is probably a neutron star, although a helium star or black hole cannot be excluded. We suggest that the pulsar was formed when a moderately massive (2 to 8 M(S)) helium star overfilled its Roche lobe and was stripped of its helium-rich envelope. Core collapse and carbon ignition followed rapidly, creating the neutron star we observe.

  11. Dynamics of secondary forests

    Breugel, van M.

    2007-01-01

    The succession of tropical secondary forests on abandoned agricultural fields has been studied since long, most often by comparing stands of different age since abandonment. These so-called chronosequence studies have yielded much insight in general patterns of succession and the constraints and

  12. Two secondary drops

    Figure shows formation of two secondary drops of unequal size and their merger. The process is same as the earlier process until t= 0.039 Tc with necking occurring at two places, one at the bottom of the column and the other at the middle. The necking at the middle of the liquid column is due to Raleigh instability.

  13. [Primary and secondary encopresis].

    Lang-Langer, Ellen

    2007-01-01

    While the difficulty of the child to part with its faeces in primary encopresis is linked to the incapability to experience the object as separated and independent from himself, secondary encopresis is a progressed psychical state of development. In this case we have to deal with regression caused by conflict. Two case-studies show clearly the differences.

  14. [Secondary thrombotic microangiopathies].

    Coppo, P

    2017-11-01

    Thrombotic microangiopathies (TMA) are termed secondary when associated to a specific context favouring their occurrence. They encompass mainly TMA associated with pregnancy, allogeneic hematopoietic stem cell transplantation, cancer, drugs, or HIV infection. Secondary TMA represent a heterogeneous group of diseases which clinical presentation largely depends on the associated context. It is therefore mandatory to recognize these conditions since they have a significant impact in TMA management and prognosis. A successful management still represents a challenge in secondary TMA. Significant progresses have been made in the understanding of pregnancy-associated TMA, allowing an improvement of prognosis; on the opposite, other forms of secondary TMA such as hematopoietic stem cell transplantation-associated TMA or TMA associated with chemotherapy remain of dismal prognosis. A better understanding of pathophysiology in these forms of TMA, in association with a more empirical approach through the use of new therapeutic agents that can also help in the understanding on new mechanisms a posteriori, should improve their prognosis. The preliminary encouraging results reported with complement blockers in this field could represent a convincing example. Copyright © 2017 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier SAS. All rights reserved.

  15. Secondary coolant purification system

    Stiteler, F.Z.; Donohue, J.P.

    1978-01-01

    The present invention combines the attributes of volatile chemical addition, continuous blowdown, and full flow condensate demineralization. During normal plant operation (defined as no primary to secondary leakage) condensate from the condenser is pumped through a full flow condensate demineralizer system by the condensate pumps. Volatile chemical additions are made. Dissolved and suspended solids are removed in the condensate polishers by ion exchange and/or filtration. At the same time a continuous blowdown of approximately 1 percent of the main steaming rate of the steam generators is maintained. Radiation detectors monitor the secondary coolant. If these monitors indicate no primary to secondary leakage, the blowdown is cooled and returned directly to the condensate pump discharge. If one of the radiation monitors should indicate a primary to secondary leak, when the temperature of the effluent exiting from the blowdown heat exchanger is compatible with the resin specifications of the ion exchangers, the bypass valve causes the blowdown flow to pass through the blowdown ion exchangers

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

    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.

  17. Secondary metabolites in fungus-plant interactions

    Pusztahelyi, Tünde; Holb, Imre J.; Pócsi, István

    2015-01-01

    Fungi and plants are rich sources of thousands of secondary metabolites. The genetically coded possibilities for secondary metabolite production, the stimuli of the production, and the special phytotoxins basically determine the microscopic fungi-host plant interactions and the pathogenic lifestyle of fungi. The review introduces plant secondary metabolites usually with antifungal effect as well as the importance of signaling molecules in induced systemic resistance and systemic acquired resistance processes. The review also concerns the mimicking of plant effector molecules like auxins, gibberellins and abscisic acid by fungal secondary metabolites that modulate plant growth or even can subvert the plant defense responses such as programmed cell death to gain nutrients for fungal growth and colonization. It also looks through the special secondary metabolite production and host selective toxins of some significant fungal pathogens and the plant response in form of phytoalexin production. New results coming from genome and transcriptional analyses in context of selected fungal pathogens and their hosts are also discussed. PMID:26300892

  18. Influence of Carbohydrates on Secondary Metabolism in Fusarium avenaceum

    Jens Laurids Sørensen; Henriette Giese

    2013-01-01

    Fusarium avenaceum is a widespread pathogen of important crops in the temperate climate zones that can produce many bioactive secondary metabolites, including moniliformin, fusarin C, antibiotic Y, 2-amino-14,16-dimethyloctadecan-3-ol (2-AOD-3-ol), chlamydosporol, aurofusarin and enniatins. Here, we examine the production of these secondary metabolites in response to cultivation on different carbon sources in order to gain insight into the regulation and production of secondary metabolites in...

  19. Stem secondary growth of tundra shrubs

    Campioli, Matteo; Leblans, Niki; Michelsen, Anders

    2012-01-01

    Our knowledge of stem secondary growth of arctic shrubs (a key component of tundra net primary production, NPP) is very limited. Here, we investigated the impact of the physical elements of the environment on shrub secondary growth by comparing annual growth rates of model species from similar...... growth (stem apical growth, stem length, and apical growth of stem plus leaves), in some cases even with opposite responses. Thus caution should be taken when estimating the impact of the environment on shrub growth from apical growth only. Integration of our data set with the (very limited) previously...

  20. The Factors Influencing Depression Endpoints Research (FINDER study: final results of Italian patients with depression

    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

  1. The effect of adherence to statin therapy on cardiovascular mortality: quantification of unmeasured bias using falsification end-points

    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.

  2. A comparison of height and weight velocity as a part of the composite endpoint in pediatric HIV.

    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.

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

    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.

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

    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

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

    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.

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

    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.

  7. Secondary Emission Calorimeter Sensor Development

    Winn, David R.; Onel, Yasar

    2012-12-01

    In a Secondary Emission electron(SEe) detector module, Secondary Emission electrons (SEe) are generated from an SE surface/cathode, when charged hadronic or electromagnetic particles, particularly shower particles, penetrate an SE sampling module placed between absorber materials (Fe, Cu, Pb, W etc) in calorimeters. The SE cathode is a thin (10-50 nm thick) film (simple metal-oxides, or other higher yield materials) on the surface of a metal plate, which serves as the entrance “window” to a compact vacuum vessel (metal or metal-ceramic); this SE film cathode is analogous to a photocathode, and the SEe are similar to p.e., which are then amplified by dynodes, also is in a PMT. SE sensor modules can make use of electrochemically etched/machined or laser-cut metal mesh dynode sheets, as large as ~30 cm square, to amplify the Secondary Emission Electrons (SEe), much like those that compact metal mesh or mesh dynode PMT's use to amplify p.e.'s. The construction requirements easier than a PMT, since the entire final assembly can be done in air; there are no critical controlled thin film depositions, cesiation or other oxygen-excluded processes or other required vacuum activation, and consequently bake-out can be a refractory temperatures; the module is sealed by normal vacuum techniques (welding or brazing or other high temperature joinings), with a simple final heated vacuum pump-out and tip-off. The modules envisioned are compact, high gain, high speed, exceptionally radiation damage resistant, rugged, and cost effective, and can be fabricated in arbitrary tileable shapes. The SE sensor module anodes can be segmented transversely to sizes appropriate to reconstruct electromagnetic cores with high precision. The GEANT4 and existing calorimeter data estimated calorimeter response performance is between 35-50 Secondary Emission electrons per GeV, in a 1 cm thick Cu absorber calorimeter, with a gain per SEe > 105 per SEe, and an e/pi<1.2. The calorimeter pulse width is

  8. Identifying and Addressing Themes of Job Dissatisfaction for Secondary Principals

    De Jong, David; Grundmeyer, Trent; Yankey, Julie

    2017-01-01

    Secondary principals serve in important roles that are complex, high-stress, and include demanding job responsibilities. Key stakeholders such as superintendents, school board members, and legislators must understand the challenges facing secondary principals in order to address the current themes of job dissatisfaction. Using new survey data…

  9. Secondary syphilis in HIV infection - a diagnostic dilemma

    Panvelker V

    1997-01-01

    Full Text Available A case of secondary syphilis in HIV infection is being reported. The patient presented with skin rash only. VDRL was found to be negative and HIV testing was positive. He was treated for secondary syphilis with clinical response. Blood VDRL test was subsequently reported as reactive.

  10. Are Haemopoietic Stem Cells Precursor Cells in Secondary Disease?

    Chertkov, J. L. [Central Institute of Haematology and Blood Transfusion, Moscow, USSR (Russian Federation)

    1969-07-15

    The paper gives data on acute secondary disease developing in supra-lethally irradiated dogs and monkeys after transplantation of allogenic bone marrow. On the basis of the experimental data obtained, the author discusses the question whether haemopoietic stem cells play a role as first links in the histogenesis of the lymphoid elements responsible for acute secondary disease. (author)

  11. Secondary Special Education Teachers as Teacher Leaders: Redefining Their Role

    Mulrine, Christopher F.; Huckvale, Manina Urgolo

    2014-01-01

    As the responsibilities and challenges of special education teachers at the secondary level increase, their roles are expanding to include mentor, coach, and facilitator for other teachers. In these roles, they lend their expertise and skills to become the new teacher leaders for today's inclusive secondary classroom settings.

  12. Just Do It! Reducing Academic Procrastination of Secondary Students

    Xu, Ziwei

    2016-01-01

    Academic procrastination is a common problem among secondary students. This paper provides secondary teachers with evidence-based strategies to reduce or prevent academic procrastination in their classrooms. Given that reducing academic procrastination is a responsibility for teachers as well as students, the paper describes teacher-administered…

  13. Secondary hypertension in adults.

    Puar, Troy Hai Kiat; Mok, Yingjuan; Debajyoti, Roy; Khoo, Joan; How, Choon How; Ng, Alvin Kok Heong

    2016-05-01

    Secondary hypertension occurs in a significant proportion of adult patients (~10%). In young patients, renal causes (glomerulonephritis) and coarctation of the aorta should be considered. In older patients, primary aldosteronism, obstructive sleep apnoea and renal artery stenosis are more prevalent than previously thought. Primary aldosteronism can be screened by taking morning aldosterone and renin levels, and should be considered in patients with severe, resistant or hypokalaemia-associated hypertension. Symptoms of obstructive sleep apnoea should be sought. Worsening of renal function after starting an angiotensin-converting enzyme inhibitor suggests the possibility of renal artery stenosis. Recognition, diagnosis and treatment of secondary causes of hypertension lead to good clinical outcomes and the possible reversal of end-organ damage, in addition to blood pressure control. As most patients with hypertension are managed at the primary care level, it is important for primary care physicians to recognise these conditions and refer patients appropriately. Copyright: © Singapore Medical Association.

  14. Secondary combined suicide pact.

    Jayanth, S H; Girish Chandra, Y P; Hugar, Basappa S; Kainoor, Sunilkumar

    2014-03-01

    This article reports a combined suicide pact, where in a young couple; a 26 year old male and a 20 year old female committed suicide by using two methods. The couple had resorted to hanging and self-immolation to prevent failure of single method alone. In secondary combined suicides, several other methods of suicide are tried after the first method chosen has failed. It is primary combined suicide only when two or more methods are used simultaneously. Both types of combined suicide by one individual is well reported in the literature whereas the same by two persons together is rare. In this report, the deceased were disappointed lovers, poor and the family members were against their marriage. The investigation of scene, methods employed to commit suicide, autopsy findings and the interview with their relatives altogether suggested that it was a secondary combined suicide pact. Copyright © 2014 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.

  15. THE SECONDARY EXTINCTION CORRECTION

    Zachariasen, W. H.

    1963-03-15

    It is shown that Darwin's formula for the secondary extinction correction, which has been universally accepted and extensively used, contains an appreciable error in the x-ray diffraction case. The correct formula is derived. As a first order correction for secondary extinction, Darwin showed that one should use an effective absorption coefficient mu + gQ where an unpolarized incident beam is presumed. The new derivation shows that the effective absorption coefficient is mu + 2gQ(1 + cos/sup 4/2 theta )/(1 plus or minus cos/sup 2/2 theta )/s up 2/, which gives mu + gQ at theta =0 deg and theta = 90 deg , but mu + 2gQ at theta = 45 deg . Darwin's theory remains valid when applied to neutron diffraction. (auth)

  16. Secondary Breast Augmentation.

    Brown, Mitchell H; Somogyi, Ron B; Aggarwal, Shagun

    2016-07-01

    After studying this article, the participant should be able to: 1. Assess common clinical problems in the secondary breast augmentation patient. 2. Describe a treatment plan to correct the most common complications of breast augmentation. 3. Provide surgical and nonsurgical options for managing complications of breast augmentation. 4. Decrease the incidence of future complications through accurate assessment, preoperative planning, and precise surgical technique. Breast augmentation has been increasing steadily in popularity over the past three decades. Many of these patients present with secondary problems or complications following their primary breast augmentation. Two of the most common complications are capsular contracture and implant malposition. Familiarity and comfort with the assessment and management of these complications is necessary for all plastic surgeons. An up-to-date understanding of current devices and techniques may decrease the need to manage future complications from the current cohort of breast augmentation patients.

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

    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

  18. Simulation from endpoint-conditioned, continuous-time Markov chains on a finite state space, with applications to molecular evolution

    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....

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

    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

    Ammonia is known to be an important toxicant in aquatic environments. Although ammonia toxicity has been well studied in many fish species, effects of chronic exposure on slimy sculpin (Cottus cognatus), a critical biomonitoring species for northern aquatic habitats, are not well known. Further, with increasing mining development in Canada's north, this information is critical to better predict potential effects of mine effluent discharges on northern fish species. Slimy sculpin were exposed to six concentrations of un-ionized ammonia (NH{sub 3}) relevant to concentrations found in northern mining effluents: control (0 ppm), 0.278 ppm, 0.556 ppm, 0.834 ppm, 1.112 ppm, and 1.668 ppm. An LC{sub 50} of 1.529 ppm was calculated from mortality data. Histopathological examination of gills indicated significant tissue damage, measured as lamellar fusion and epithelial lifting, at 0.834 ppm, 1.112 ppm, and 1.668 ppm. Using gill endpoints, NOEC and LOEC were calculated as 0.556 ppm and 0.834 ppm, respectively. An EC{sub 50} of 0.775 ppm was determined for lamellar fusion and an EC{sub 50} of 0.842 ppm for epithelial lifting. Hemorrhage of gills was present in mortalities, which occurred at 1.668 ppm of un-ionized ammonia. A significant decrease in liver somatic index (LSI) was seen in both male and female fish at 0.834 ppm and 1.112 ppm, respectively. Gonadosomatic index (GSI) in female fish significantly increased at 1.668 ppm un-ionized ammonia with an associated significant increase in total wholebody testosterone concentrations. GSI in male fish also significantly increased at 1.668 ppm but no differences were seen in testosterone concentrations. No significant differences were seen in gonad histopathological assessments or condition factor. Gill histopathology endpoints may be a more sensitive indicator for detecting effects in slimy sculpin exposed to ammonia than traditional chronic endpoints. Results from this study indicate that ammonia concentrations commonly

  20. Secondary victims of rape

    Christiansen, Dorte Mølgaard; Bak, Rikke; Elklit, Ask

    2012-01-01

    secondary victims, including family members, partners, and friends of male and female rape victims. We found that many respondents found it difficult to support the PV and that their relationship with the PV was often affected by the assault. Furthermore, the sample showed significant levels...... of social support for the respondent, and feeling let down by others. The respondents were generally interested in friend-, family-, and partner-focused interventions, particularly in receiving education about how best to support a rape victim...

  1. Determination of plutonium by secondary coulometric titration with internally generated iron(II) Pt. 2

    Chitnis, R.T.; Talnikar, S.G.; Thakur, V.A.; Paranjape, A.H.

    1979-01-01

    Determination of plutonium by secondary coulometry involving the controlled potential technique for the generation of an iron(II) mediator, is reported in Part I. In this paper, the same determination is reported using constant current coulometry for the generation of the mediator, and zero current potentiometry for end-point detection. The factors affecting the current efficiency, viz. current density and supporting electrolyte composition have been checked in order to define the appropriate conditions for obtaining 100% current efficiency. The original method of Carson et al. suffers from the disadvantage that it involves complicated sample treatment. Introduction of perchloric acid treatment as a method for the oxidation of plutonium and the pretitration of the supporting electrolyte to the end-point potential prior to sample addition, have considerably helped to improve the precision and accuracy of the method. Exhaustive analytical data are reported covering plutonium quantities ranging from 25 micrograms to 5 milligrams, which establishes the scope of the method. (author)

  2. A PHYSIOLOGICALLY BASED COMPUTATIONAL MODEL OF THE BPG AXIS IN FATHEAD MINNOWS: PREDICTING EFFECTS OF ENDOCRINE DISRUPTING CHEMICAL EXPOSURE ON REPRODUCTIVE ENDPOINTS

    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

    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.

    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

    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. Is Forced Swimming Immobility a Good Endpoint for Modeling Negative Symptoms of Schizophrenia? - Study of Sub-Anesthetic Ketamine Repeated Administration Effects

    GILDA NEVES

    2017-08-01

    Full Text Available ABSTRACT Immobility time in the forced swimming has been described as analogous to emotional blunting or apathy and has been used for characterizing schizophrenia animal models. Several clinical studies support the use of NMDA receptor antagonists to model schizophrenia in rodents. Some works describe the effects of ketamine on immobility behavior but there is variability in the experimental design used leading to controversial results. In this study, we evaluated the effects of repeated administration of ketamine sub-anesthetic doses in forced swimming, locomotion in response to novelty and novel object recognition, aiming a broader evaluation of the usefulness of this experimental approach for modeling schizophrenia in mice. Ketamine (30 mg/kg/day i.p. for 14 days induced a not persistent decrease in immobility time, detected 24h but not 72h after treatment. This same administration protocol induced a deficit in novel object recognition. No change was observed in mice locomotion. Our results confirm that repeated administration of sub-anesthetic doses of ketamine is useful in modeling schizophrenia-related behavioral changes in mice. However, the immobility time during forced swimming does not seem to be a good endpoint to evaluate the modeling of negative symptoms in NMDAR antagonist animal models of schizophrenia.

  7. Is Forced Swimming Immobility a Good Endpoint for Modeling Negative Symptoms of Schizophrenia? - Study of Sub-Anesthetic Ketamine Repeated Administration Effects.

    Neves, Gilda; Borsoi, Milene; Antonio, Camila B; Pranke, Mariana A; Betti, Andresa H; Rates, Stela M K

    2017-01-01

    Immobility time in the forced swimming has been described as analogous to emotional blunting or apathy and has been used for characterizing schizophrenia animal models. Several clinical studies support the use of NMDA receptor antagonists to model schizophrenia in rodents. Some works describe the effects of ketamine on immobility behavior but there is variability in the experimental design used leading to controversial results. In this study, we evaluated the effects of repeated administration of ketamine sub-anesthetic doses in forced swimming, locomotion in response to novelty and novel object recognition, aiming a broader evaluation of the usefulness of this experimental approach for modeling schizophrenia in mice. Ketamine (30 mg/kg/day i.p. for 14 days) induced a not persistent decrease in immobility time, detected 24h but not 72h after treatment. This same administration protocol induced a deficit in novel object recognition. No change was observed in mice locomotion. Our results confirm that repeated administration of sub-anesthetic doses of ketamine is useful in modeling schizophrenia-related behavioral changes in mice. However, the immobility time during forced swimming does not seem to be a good endpoint to evaluate the modeling of negative symptoms in NMDAR antagonist animal models of schizophrenia.

  8. Radiation response of tumours

    Twentyman, P.R.

    1988-01-01

    In this chapter knowledge regarding cellular radiation response and the factors which modify it is related to the volume changes and probability of control of irradiated solid tumors. After a discussion of the different cell populations present within solid tumors the cell population kinetics of the neoplastic cells are considered in more detail. The influence of factors related to the three-dimensional geometry of the tumor, particularly hypoxia, are considered, and also the role of the tumor vasculature in radiation response. Repair of sublethal damage (SLD) and potentially lethal damage (PLD) is dealt with and finally the relationship between the various end-points of tumor radioresponsiveness is discussed

  9. 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.

    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

  10. Characteristics and generation of secondary jets and secondary gigantic jets

    Lee, Li-Jou; Huang, Sung-Ming; Chou, Jung-Kung; Kuo, Cheng-Ling; Chen, Alfred B.; Su, Han-Tzong; Hsu, Rue-Rou; Frey, Harald U.; Takahashi, Yukihiro; Lee, Lou-Chuang

    2012-06-01

    Secondary transient luminous events (TLEs) recorded by the ISUAL-FORMOSAT2 mission can either be secondary jets or secondary gigantic jets (GJs), depending on their terminal altitudes. The secondary jets emerge from the cloud top beneath the preceding sprites and extend upward to the base of the sprites at ˜50 km. The secondary jets likely are negative electric discharges with vertically straight luminous columns, morphologically resembling the trailing jet of the type-I GJs. The number of luminous columns in a secondary jet seems to be affected by the size of the effective capacitor plate formed near the base of the preceding sprites and the charge distribution left behind by the sprite-inducing positive cloud-to-ground discharges. The secondary GJs originate from the cloud top under the shielding area of the preceding sprites, and develop upward to reach the lower ionosphere at ˜90 km. The observed morphology of the secondary GJs can either be the curvy shifted secondary GJs extending outside the region occupied by the preceding sprites or the straight pop-through secondary GJs developing through the center of the preceding circular sprites. A key factor in determining the terminal height of the secondary TLEs appears to be the local ionosphere boundary height that established by the preceding sprites. The abundance and the distribution of the negative charge in the thundercloud following the sprite-inducing positive cloud-to-ground discharges may play important role in the generation of the secondary TLEs.

  11. Factors affecting Mathematics achievement of first-year secondary ...

    Hennie

    2015-08-14

    Aug 14, 2015 ... Faculty of Psychology and Educational Sciences, Campus Kulak Kortrijk, KU ... responses of 4,819 first-year secondary school students (Grade ... “its usefulness in science, mathematical and technological activities as well as.

  12. A Portable Automatic Endpoint Detection System for Amplicons of Loop Mediated Isothermal Amplification on Microfluidic Compact Disk Platform

    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.

    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?

    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

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

    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

  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

    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. Evaluation of an ex vivo murine local lymph node assay: multiple endpoint comparison.

    Piccotti, Joseph R; Knight, Stephanie A; Gillhouse, Kimberly; Lagattuta, Mark S; Bleavins, Michael R

    2006-01-01

    The local lymph node assay (LLNA) is used to assess the skin sensitization potential of chemicals. In the standard assay, mice are treated topically on the dorsum of both ears with test substance for 3 days. Following 2 days of rest, the initiation of the hypersensitivity response is evaluated by injecting (3)H-thymidine into a tail vein, and then measuring the levels of radioisotope incorporated into the DNA of lymph node cells draining the ears. In the current study, BALB/c mice were treated with the contact sensitizers hexylcinnamic aldehyde (HCA) and oxazolone, and the nonsensitizer methyl salicylate. The proliferative response of lymph node cells was evaluated in an ex vivo assay, in which isolated cells were cultured in vitro with (3)H-thymidine. Treatment of mice with HCA at 5-50% resulted in concentration-related increases in (3)H-thymidine incorporation, with stimulation indices ranging from 3 to 14. Low animal-to-animal variability was seen in three replicate assays testing HCA at 25%. As anticipated, the proliferative response induced by the potent sensitizer oxazolone at 0.25% was greater than HCA at all concentrations tested. Stimulation indices of 1.5 and 3 were seen in two independent experiments with methyl salicylate. These equivocal findings were likely due to the irritancy properties of the compound. Importantly, measuring ex vivo (3)H-thymidine incorporation was more sensitive than evaluating lymph node weight and cellularity, and in vitro bromodeoxyuridine incorporation. Furthermore, the results of the ex vivo LLNA were comparable to the standard assay. This study provided evidence that supports the use of an ex vivo LLNA for hazard assessment of contact hypersensitivity. Copyright 2006 John Wiley & Sons, Ltd.

  19. Causes of secondary headache (image)

    Temporomandibular joint, or TMJ, dysfunction, can be a cause of secondary headache. Secondary headaches result from underlying disorders which produce pain as a symptom. The TMJ may become painful and dysfunctional as a result ...

  20. Secondary beams at GANIL

    Doubre, H.

    1992-01-01

    GANIL, a user's facility since 1983, can deliver a broad spectrum of heavy-ion beams, from He to U, to well-equipped experimental areas. Their very large intensities are to be exploited to produce secondary beams, either using the fragmentation method (beams at energy per nucleon larger than 30 MeV/u), or the ISOL method. With the latter one, these ions have to be re-accelerated. The project of a cyclotron as a post-accelerator is described. (author) 11 refs.; 7 figs.; 3 tabs