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Sample records for survival secondary endpoints

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

    OpenAIRE

    Bonnetain Franck; Bedenne Laurent; Methy Nicolas

    2010-01-01

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

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

    Science.gov (United States)

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

    2010-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Bonnetain Franck

    2010-06-01

    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

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

    International Nuclear Information System (INIS)

    Methy, Nicolas; Bedenne, Laurent; Bonnetain, Franck

    2010-01-01

    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

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

    Science.gov (United States)

    Methy, Nicolas; Bedenne, Laurent; Bonnetain, Franck

    2010-06-10

    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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2012-11-15

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

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

    Science.gov (United States)

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

    2012-04-27

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

  8. 21 CFR 314.510 - Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival...

    Science.gov (United States)

    2010-04-01

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

  9. Addressing issues associated with evaluating prediction models for survival endpoints based on the concordance statistic.

    Science.gov (United States)

    Wang, Ming; Long, Qi

    2016-09-01

    Prediction models for disease risk and prognosis play an important role in biomedical research, and evaluating their predictive accuracy in the presence of censored data is of substantial interest. The standard concordance (c) statistic has been extended to provide a summary measure of predictive accuracy for survival models. Motivated by a prostate cancer study, we address several issues associated with evaluating survival prediction models based on c-statistic with a focus on estimators using the technique of inverse probability of censoring weighting (IPCW). Compared to the existing work, we provide complete results on the asymptotic properties of the IPCW estimators under the assumption of coarsening at random (CAR), and propose a sensitivity analysis under the mechanism of noncoarsening at random (NCAR). In addition, we extend the IPCW approach as well as the sensitivity analysis to high-dimensional settings. The predictive accuracy of prediction models for cancer recurrence after prostatectomy is assessed by applying the proposed approaches. We find that the estimated predictive accuracy for the models in consideration is sensitive to NCAR assumption, and thus identify the best predictive model. Finally, we further evaluate the performance of the proposed methods in both settings of low-dimensional and high-dimensional data under CAR and NCAR through simulations. © 2016, The International Biometric Society.

  10. Predicting treatment effect from surrogate endpoints and historical trials: an extrapolation involving probabilities of a binary outcome or survival to a specific time.

    Science.gov (United States)

    Baker, Stuart G; Sargent, Daniel J; Buyse, Marc; Burzykowski, Tomasz

    2012-03-01

    Using multiple historical trials with surrogate and true endpoints, we consider various models to predict the effect of treatment on a true endpoint in a target trial in which only a surrogate endpoint is observed. This predicted result is computed using (1) a prediction model (mixture, linear, or principal stratification) estimated from historical trials and the surrogate endpoint of the target trial and (2) a random extrapolation error estimated from successively leaving out each trial among the historical trials. The method applies to either binary outcomes or survival to a particular time that is computed from censored survival data. We compute a 95% confidence interval for the predicted result and validate its coverage using simulation. To summarize the additional uncertainty from using a predicted instead of true result for the estimated treatment effect, we compute its multiplier of standard error. Software is available for download. © 2011, The International Biometric Society No claim to original US government works.

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

    Science.gov (United States)

    Guilbaud, Olivier

    2011-11-01

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

  12. Improved Survival Endpoints With Adjuvant Radiation Treatment in Patients With High-Risk Early-Stage Endometrial Carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Elshaikh, Mohamed A., E-mail: melshai1@hfhs.org [Department of Radiation Oncology, Henry Ford Hospital, Detroit, Michigan (United States); Vance, Sean; Suri, Jaipreet S. [Department of Radiation Oncology, Henry Ford Hospital, Detroit, Michigan (United States); Mahan, Meredith [Public Health Science, Henry Ford Hospital, Detroit, Michigan (United States); Munkarah, Adnan [Division of Gynecologic Oncology, Department of Women' s Health Services, Henry Ford Hospital, Detroit, Michigan (United States)

    2014-02-01

    Purpose/Objective(s): To determine the impact of adjuvant radiation treatment (RT) on recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS) in patients with high-risk 2009 International Federation of Gynecology and Obstetrics stage I-II endometrial carcinoma. Methods and Materials: We identified 382 patients with high-risk EC who underwent hysterectomy. RFS, DSS, and OS were calculated from the date of hysterectomy by use of the Kaplan-Meier method. Cox regression modeling was used to explore the risks associated with various factors on survival endpoints. Results: The median follow-up time for the study cohort was 5.4 years. The median age was 71 years. All patients underwent hysterectomy and salpingo-oophorectomy, 93% had peritoneal cytology, and 85% underwent lymphadenectomy. Patients with endometrioid histology constituted 72% of the study cohort, serous in 16%, clear cell in 7%, and mixed histology in 4%. Twenty-three percent of patients had stage II disease. Adjuvant management included RT alone in 220 patients (57%), chemotherapy alone in 25 patients (7%), and chemoradiation therapy in 27 patients (7%); 110 patients (29%) were treated with close surveillance. The 5-year RFS, DSS, and OS were 76%, 88%, and 73%, respectively. On multivariate analysis, adjuvant RT was a significant predictor of RFS (P<.001) DSS (P<.001), and OS (P=.017). Lymphovascular space involvement was a significant predictor of RFS and DSS (P<.001). High tumor grade was a significant predictor for RFS (P=.038) and DSS (P=.025). Involvement of the lower uterine segment was also a predictor of RFS (P=.049). Age at diagnosis and lymphovascular space involvement were significant predictors of OS: P<.001 and P=.002, respectively. Conclusion: In the treatment of patients with high-risk features, our study suggests that adjuvant RT significantly improves recurrence-free, disease-specific, and overall survival in patients with early-stage endometrial carcinoma

  13. Surrogate endpoints for overall survival in chemotherapy and radiotherapy trials in operable and locally advanced lung cancer: a re-analysis of meta-analyses of individual patients' data

    NARCIS (Netherlands)

    Mauguen, Audrey; Pignon, Jean-Pierre; Burdett, Sarah; Domerg, Caroline; Fisher, David; Paulus, Rebecca; Mandrekar, Samithra J.; Belani, Chandra P.; Shepherd, Frances A.; Eisen, Tim; Pang, Herbert; Collette, Laurence; Sause, William T.; Dahlberg, Suzanne E.; Crawford, Jeffrey; O'Brien, Mary; Schild, Steven E.; Parmar, Mahesh; Tierney, Jayne F.; Le Pechoux, Cécile; Michiels, Stefan; Burdett, S.; Fisher, D.; Le Péchoux, C.; Mauguen, A.; Michiels, S.; Pignon, J. P.; Tierney, J. F.; Belani, C. P.; Collette, L.; Dahlberg, S.; Eisen, T.; Mandrekar, S.; O'Brien, M.; Parmar, M.; Pang, H.; Paulus, R.; Crawford, J.; Sause, W.; Schild, S. E.; Shepherd, F.; Arriagada, R.; Atagi, S.; Auperin, A.; Ball, D.; Baumann, M.; Behrendt, K.; Belderbos, J.; Koning, C. C. E.; Uitterhoeve, A.

    2013-01-01

    The gold standard endpoint in clinical trials of chemotherapy and radiotherapy for lung cancer is overall survival. Although reliable and simple to measure, this endpoint takes years to observe. Surrogate endpoints that would enable earlier assessments of treatment effects would be useful. We

  14. A two-stage model in a Bayesian framework to estimate a survival endpoint in the presence of confounding by indication.

    Science.gov (United States)

    Bellera, Carine; Proust-Lima, Cécile; Joseph, Lawrence; Richaud, Pierre; Taylor, Jeremy; Sandler, Howard; Hanley, James; Mathoulin-Pélissier, Simone

    2018-04-01

    Background Biomarker series can indicate disease progression and predict clinical endpoints. When a treatment is prescribed depending on the biomarker, confounding by indication might be introduced if the treatment modifies the marker profile and risk of failure. Objective Our aim was to highlight the flexibility of a two-stage model fitted within a Bayesian Markov Chain Monte Carlo framework. For this purpose, we monitored the prostate-specific antigens in prostate cancer patients treated with external beam radiation therapy. In the presence of rising prostate-specific antigens after external beam radiation therapy, salvage hormone therapy can be prescribed to reduce both the prostate-specific antigens concentration and the risk of clinical failure, an illustration of confounding by indication. We focused on the assessment of the prognostic value of hormone therapy and prostate-specific antigens trajectory on the risk of failure. Methods We used a two-stage model within a Bayesian framework to assess the role of the prostate-specific antigens profile on clinical failure while accounting for a secondary treatment prescribed by indication. We modeled prostate-specific antigens using a hierarchical piecewise linear trajectory with a random changepoint. Residual prostate-specific antigens variability was expressed as a function of prostate-specific antigens concentration. Covariates in the survival model included hormone therapy, baseline characteristics, and individual predictions of the prostate-specific antigens nadir and timing and prostate-specific antigens slopes before and after the nadir as provided by the longitudinal process. Results We showed positive associations between an increased prostate-specific antigens nadir, an earlier changepoint and a steeper post-nadir slope with an increased risk of failure. Importantly, we highlighted a significant benefit of hormone therapy, an effect that was not observed when the prostate-specific antigens trajectory was

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

    Science.gov (United States)

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

    2017-01-01

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

  16. Validation of Progression‐Free Survival as a Surrogate Endpoint for Overall Survival in Malignant Mesothelioma: Analysis of Cancer and Leukemia Group B and North Central Cancer Treatment Group (Alliance) Trials

    Science.gov (United States)

    Wang, Xiaoyi; Hodgson, Lydia; George, Stephen L.; Sargent, Daniel J.; Foster, Nate R.; Ganti, Apar Kishor; Stinchcombe, Thomas E.; Crawford, Jeffrey; Kratzke, Robert; Adjei, Alex A.; Kindler, Hedy L.; Vokes, Everett E.; Pang, Herbert

    2017-01-01

    Abstract Purpose. The aim of this study was to investigate whether progression‐free survival (PFS) can be considered a surrogate endpoint for overall survival (OS) in malignant mesothelioma. Materials and Methods. Individual data were collected from 15 Cancer and Leukemia Group B (615 patients) and 2 North Central Cancer Treatment Group (101 patients) phase II trials. The effects of 5 risk factors for OS and PFS, including age, histology, performance status (PS), white blood cell count, and European Organisation for Research and Treatment of Cancer (EORTC) risk score, were used in the analysis. Individual‐level surrogacy was assessed by Kendall's tau through a Clayton bivariate Copula survival (CBCS) model. Summary‐level surrogacy was evaluated via the association between logarithms of the hazard ratio (log HR)—log HROS and log HRPFS—measured in R2 from a weighted least‐square (WLS) regression model and the CBCS model. Results. The median PFS for all patients was 3.0 months (95% confidence interval [CI], 2.8–3.5 months) and the median OS was 7.2 months (95% CI, 6.5–8.0 months). Moderate correlations between PFS and OS were observed across all risk factors at the individual level, with Kendall's tau ranging from 0.46 to 0.47. The summary‐level surrogacy varied among risk factors. The Copula R2 ranged from 0.51 for PS to 0.78 for histology. The WLS R2 ranged from 0.26 for EORTC and PS to 0.67 for age. Conclusions. The analyses demonstrated low to moderate individual‐level surrogacy between PFS and OS. At the summary level, the surrogacy between PFS and OS varied significantly across different risk factors. With a short postprogression survival and a moderate correlation between PFS and OS, there is no evidence that PFS is a valid surrogate endpoint for OS in malignant mesothelioma. Implications for Practice. For better disease management and for more efficient clinical trial designs, it is important to know if progression‐free survival (PFS) is

  17. Enhanced secondary analysis of survival data: reconstructing the data from published Kaplan-Meier survival curves

    Directory of Open Access Journals (Sweden)

    Guyot Patricia

    2012-02-01

    Full Text Available Abstract Background The results of Randomized Controlled Trials (RCTs on time-to-event outcomes that are usually reported are median time to events and Cox Hazard Ratio. These do not constitute the sufficient statistics required for meta-analysis or cost-effectiveness analysis, and their use in secondary analyses requires strong assumptions that may not have been adequately tested. In order to enhance the quality of secondary data analyses, we propose a method which derives from the published Kaplan Meier survival curves a close approximation to the original individual patient time-to-event data from which they were generated. Methods We develop an algorithm that maps from digitised curves back to KM data by finding numerical solutions to the inverted KM equations, using where available information on number of events and numbers at risk. The reproducibility and accuracy of survival probabilities, median survival times and hazard ratios based on reconstructed KM data was assessed by comparing published statistics (survival probabilities, medians and hazard ratios with statistics based on repeated reconstructions by multiple observers. Results The validation exercise established there was no material systematic error and that there was a high degree of reproducibility for all statistics. Accuracy was excellent for survival probabilities and medians, for hazard ratios reasonable accuracy can only be obtained if at least numbers at risk or total number of events are reported. Conclusion The algorithm is a reliable tool for meta-analysis and cost-effectiveness analyses of RCTs reporting time-to-event data. It is recommended that all RCTs should report information on numbers at risk and total number of events alongside KM curves.

  18. Enhanced secondary analysis of survival data: reconstructing the data from published Kaplan-Meier survival curves.

    Science.gov (United States)

    Guyot, Patricia; Ades, A E; Ouwens, Mario J N M; Welton, Nicky J

    2012-02-01

    The results of Randomized Controlled Trials (RCTs) on time-to-event outcomes that are usually reported are median time to events and Cox Hazard Ratio. These do not constitute the sufficient statistics required for meta-analysis or cost-effectiveness analysis, and their use in secondary analyses requires strong assumptions that may not have been adequately tested. In order to enhance the quality of secondary data analyses, we propose a method which derives from the published Kaplan Meier survival curves a close approximation to the original individual patient time-to-event data from which they were generated. We develop an algorithm that maps from digitised curves back to KM data by finding numerical solutions to the inverted KM equations, using where available information on number of events and numbers at risk. The reproducibility and accuracy of survival probabilities, median survival times and hazard ratios based on reconstructed KM data was assessed by comparing published statistics (survival probabilities, medians and hazard ratios) with statistics based on repeated reconstructions by multiple observers. The validation exercise established there was no material systematic error and that there was a high degree of reproducibility for all statistics. Accuracy was excellent for survival probabilities and medians, for hazard ratios reasonable accuracy can only be obtained if at least numbers at risk or total number of events are reported. The algorithm is a reliable tool for meta-analysis and cost-effectiveness analyses of RCTs reporting time-to-event data. It is recommended that all RCTs should report information on numbers at risk and total number of events alongside KM curves.

  19. The effect of parathyroidectomy on patient survival in secondary hyperparathyroidism.

    Science.gov (United States)

    Ivarsson, Kerstin M; Akaberi, Shahriar; Isaksson, Elin; Reihnér, Eva; Rylance, Rebecca; Prütz, Karl-Göran; Clyne, Naomi; Almquist, Martin

    2015-12-01

    Secondary hyperparathyroidism is a common condition in patients with end-stage renal disease and is associated with osteoporosis and cardiovascular disease. Despite improved medical treatment, parathyroidectomy (PTX) is still necessary for many patients on renal replacement therapy. The aim of this study was to evaluate the effect of PTX on patient survival. A nested index-referent study was performed within the Swedish Renal Registry (SRR). Patients on maintenance dialysis and transplantation at the time of PTX were analysed separately. The PTX patients in each of these strata were matched for age, sex and underlying renal diseases with up to five referent patients who had not undergone PTX. To calculate survival time and hazard ratios, indexes and referents were assigned the calendar date (d) of the PTX of the index patient. The risk of death after PTX was calculated using crude and adjusted Cox proportional hazards regressions. There were 20 056 patients in the SRR between 1991 and 2009. Of these, 579 (423 on dialysis and 156 with a renal transplant at d) incident patients with PTX were matched with 1234/892 non-PTX patients. The adjusted relative risk of death was a hazard ratio (HR) of 0.80 [95% confidence interval (CI) 0.65-0.99] for dialysis patients at d who had undergone PTX compared with matched patients who had not. Corresponding results for the patients with a renal allograft at d were an HR of 1.10 (95% CI 0.71-1.70). PTX was associated with improved survival in patients on maintenance dialysis but not in patients with renal allograft. © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

  20. Instrumental variables estimation of exposure effects on a time-to-event endpoint using structural cumulative survival models.

    Science.gov (United States)

    Martinussen, Torben; Vansteelandt, Stijn; Tchetgen Tchetgen, Eric J; Zucker, David M

    2017-12-01

    The use of instrumental variables for estimating the effect of an exposure on an outcome is popular in econometrics, and increasingly so in epidemiology. This increasing popularity may be attributed to the natural occurrence of instrumental variables in observational studies that incorporate elements of randomization, either by design or by nature (e.g., random inheritance of genes). Instrumental variables estimation of exposure effects is well established for continuous outcomes and to some extent for binary outcomes. It is, however, largely lacking for time-to-event outcomes because of complications due to censoring and survivorship bias. In this article, we make a novel proposal under a class of structural cumulative survival models which parameterize time-varying effects of a point exposure directly on the scale of the survival function; these models are essentially equivalent with a semi-parametric variant of the instrumental variables additive hazards model. We propose a class of recursive instrumental variable estimators for these exposure effects, and derive their large sample properties along with inferential tools. We examine the performance of the proposed method in simulation studies and illustrate it in a Mendelian randomization study to evaluate the effect of diabetes on mortality using data from the Health and Retirement Study. We further use the proposed method to investigate potential benefit from breast cancer screening on subsequent breast cancer mortality based on the HIP-study. © 2017, The International Biometric Society.

  1. 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.

    Science.gov (United States)

    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.

  2. Impact of weight loss on survival after chemoradiation for locally advanced head and neck Cancer: secondary results of a randomized phase III trial (SAKK 10/94)

    International Nuclear Information System (INIS)

    Ghadjar, Pirus; Hayoz, Stefanie; Zimmermann, Frank; Bodis, Stephan; Kaul, David; Badakhshi, Harun; Bernier, Jacques; Studer, Gabriela; Plasswilm, Ludwig; Budach, Volker; Aebersold, Daniel M

    2015-01-01

    To analyze the impact of weight loss before and during chemoradiation on survival outcomes in patients with locally advanced head and neck cancer. From 07/1994-07/2000 a total of 224 patients with squamous cell carcinoma of the head and neck were randomized to either hyperfractionated radiation therapy alone or the same radiation therapy combined with two cycles of concomitant cisplatin. The primary endpoint was time to any treatment failure (TTF); secondary endpoints were locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS) and overall survival (OS). Patient weight was measured 6 months before treatment, at treatment start and treatment end. The proportion of patients with >5% weight loss was 32% before, and 51% during treatment, and the proportion of patients with >10% weight loss was 12% before, and 17% during treatment. After a median follow-up of 9.5 years (range, 0.1 – 15.4 years) weight loss before treatment was associated with decreased TTF, LRRFS, DMFS, cancer specific survival and OS in a multivariable analysis. However, weight loss during treatment was not associated with survival outcomes. Weight loss before and during chemoradiation was commonly observed. Weight loss before but not during treatment was associated with worse survival

  3. Is progression-free survival a more relevant endpoint than overall survival in first-line HR+/HER2− metastatic breast cancer?

    Directory of Open Access Journals (Sweden)

    Forsythe A

    2018-05-01

    Full Text Available Anna Forsythe,1 David Chandiwana,2 Janina Barth,3 Marroon Thabane,4 Johan Baeck,5 Anastasiya Shor,1 Gabriel Tremblay6 1Health Technology Assessment Evidence, Purple Squirrel Economics, New York, NY, USA; 2Global Value and Access, Novartis Pharmaceutical Corporation, East Hanover, NJ, USA; 3German Market Access, Novartis Pharma GmbH, Nuremberg, Germany; 4Health Policy and Patient Access, Novartis Pharmaceuticals Incorporated, Dorval, QC, Canada; 5Global Medical Affairs (Oncology Business Unit, Novartis Pharmaceutical Corporation, East Hanover, NJ, USA; 6Health Economics, Purple Squirrel Economics, New York, NY, USA Background: Hormone receptor-positive (HR+, human epidermal growth factor receptor 2- negative (HER2−, metastatic breast cancer (MBC accounts for 73% of all MBCs. Endocrine therapy (ET is the basis of first-line (1L therapy for patients with HR+/HER2− MBC. Novel therapies have demonstrated improvements in progression-free survival (PFS compared to ET. The clinical relevance of PFS is being debated, as there is no proven direct correlation with overall survival (OS benefit to date. We reviewed studies of HR+/HER2− MBC to assess PFS and other factors that influence OS and treatment response, and health-related quality of life (HRQoL. Methods: The Embase®, Medline®, and Cochrane databases were systematically searched to identify studies in adult women with HR+/HER2− MBC, published between January 2006 and January 2017, and written in English. Phase II and III randomized controlled trials (RCTs, observational, and retrospective studies were included. Results: Seventy-nine RCTs were identified: 58 (73% in the 1L+ setting and 21 (27% in second-line or greater settings. PFS hazard ratios (HRs were reported in 61 (77% studies; 31 (39% reported significant PFS improvements. OS was reported in 44 (41% studies; 12 (15% reported significant OS improvements. Significant improvements in both PFS and OS were reported in only 6 (8% studies

  4. Multi-Trial Evaluation of Progression-Free Survival (PFS) as a Surrogate Endpoint for Overall Survival (OS) in First-Line Extensive-Stage Small Cell Lung Cancer (ES-SCLC)

    Science.gov (United States)

    Foster, Nathan R.; Renfro, Lindsay A.; Schild, Steven E.; Redman, Mary W.; Wang, Xiaofei F.; Dahlberg, Suzanne E.; Ding, Keyue; Bradbury, Penelope A.; Ramalingam, Suresh S.; Gandara, David R.; Shibata, Taro; Saijo, Nagahiro; Vokes, Everett E.; Adjei, Alex A.; Mandrekar, Sumithra J.

    2015-01-01

    Introduction We previously reported that PFS may be a candidate surrogate endpoint for OS in first-line ES-SCLC using data from 3 randomized trials (Foster, Cancer 2011). In this validation study (N0424-Alliance), we assessed the patient- and trial-level surrogacy of PFS using data from 7 new first-line phase II/III ES-SCLC trials and across all 10 trials as well (7 new, 3 previous). Methods Individual patient data were utilized across the 7 new trials (2259 patients) and all 10 trials (2855 patients). Patient-level surrogacy (Kendall’s τ) was assessed using the Clayton copula bivariate survival model. Trial-level surrogacy was assessed via association of the log hazard ratios on OS and PFS across trials, including weighted (by trial size) least squares regression of Cox model effects (WLS R2) and correlation of the copula effects (Copula R2). The minimum effect on the surrogate (MES) needed to detect a non-zero treatment effect on OS was also calculated. Results The median OS and PFS across all 10 trials were 9.8 and 5.9 months, respectively. PFS showed strong surrogacy within the 7 new trials (Copula R2 = 0.90 (SE=0.27); WLS R2 = 0.83 (95% CI: 0.43, 0.95); MES=0.67; Kendall’s τ = 0.58) and across all 10 trials (Copula R2 =0.81 (SE=0.25); WLS R2=0.77 (95% CI: 0.47–0.91); MES=0.70; Kendall’s τ =0.57). Conclusions PFS demonstrated strong surrogacy for OS in first-line ES-SCLC based on this external validation study of individual patient data. PFS is a good alternative endpoint to OS and should be considered when resource constraints (time or patient) might make it useful or desirable in place of OS. Additional analyses are needed to assess its appropriateness for targeted agents in this disease setting. PMID:26134227

  5. Posttreatment prostatic-specific antigen doubling time as a surrogate endpoint for prostate cancer-specific survival: An analysis of Radiation Therapy Oncology Group Protocol 92-02

    International Nuclear Information System (INIS)

    Valicenti, Richard K.; DeSilvio, Michelle; Hanks, Gerald E.; Porter, Arthur; Brereton, Harmar; Rosenthal, Seth A.; Shipley, William U.; Sandler, Howard M.

    2006-01-01

    Purpose: We evaluated whether posttreatment prostatic-specific antigen doubling time (PSADT) was predictive of prostate cancer mortality by testing the Prentice requirements for a surrogate endpoint. Methods and Materials: We analyzed posttreatment PSA measurements in a cohort of 1,514 men with localized prostate cancer (T2c-4 and PSA level Cox = 0.002), PSADT Cox Cox Cox Cox = 0.4). The significant posttreatment PSADTs were also significant predictors of CSS (p Cox < 0.001). After adjusting for T stage, Gleason score and PSA, all of Prentice's requirements were not met, indicating that the effect of PSADT on CSS was not independent of the randomized treatment. Conclusions: Prostatic specific antigen doubling time is significantly associated with CSS, but did not meet all of Prentice's requirements for a surrogate endpoint of CSS. Thus, the risk of dying of prostate cancer is not fully explained by PSADT

  6. A Re-entrant Phase Transition in the Survival of Secondary Infections on Networks

    Science.gov (United States)

    Moore, Sam; Mörters, Peter; Rogers, Tim

    2018-06-01

    We study the dynamics of secondary infections on networks, in which only the individuals currently carrying a certain primary infection are susceptible to the secondary infection. In the limit of large sparse networks, the model is mapped to a branching process spreading in a random time-sensitive environment, determined by the dynamics of the underlying primary infection. When both epidemics follow the Susceptible-Infective-Recovered model, we show that in order to survive, it is necessary for the secondary infection to evolve on a timescale that is closely matched to that of the primary infection on which it depends.

  7. Refractory Graft-Versus-Host Disease-Free, Relapse-Free Survival as an Accurate and Easy-to-Calculate Endpoint to Assess the Long-Term Transplant Success.

    Science.gov (United States)

    Kawamura, Koji; Nakasone, Hideki; Kurosawa, Saiko; Yoshimura, Kazuki; Misaki, Yukiko; Gomyo, Ayumi; Hayakawa, Jin; Tamaki, Masaharu; Akahoshi, Yu; Kusuda, Machiko; Kameda, Kazuaki; Wada, Hidenori; Ishihara, Yuko; Sato, Miki; Terasako-Saito, Kiriko; Kikuchi, Misato; Kimura, Shun-Ichi; Tanihara, Aki; Kako, Shinichi; Kanamori, Heiwa; Mori, Takehiko; Takahashi, Satoshi; Taniguchi, Shuichi; Atsuta, Yoshiko; Kanda, Yoshinobu

    2018-02-21

    The aim of this study was to develop a new composite endpoint that accurately reflects the long-term success of allogeneic hematopoietic stem cell transplantation (allo-HSCT), as the conventional graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) overestimates the impact of GVHD. First, we validated current GRFS (cGRFS), which recently was proposed as a more accurate endpoint of long-term transplant success. cGRFS was defined as survival without disease relapse/progression or active chronic GVHD at a given time after allo-HSCT, calculated using 2 distinct methods: a linear combination of a Kaplan-Meier estimates approach and a multistate modelling approach. Next, we developed a new composite endpoint, refractory GRFS (rGRFS). rGRFS was calculated similarly to conventional GRFS treating grade III to IV acute GVHD, chronic GVHD requiring systemic treatment, and disease relapse/progression as events, except that GVHD that resolved and did not require systemic treatment at the last evaluation was excluded as an event in rGRFS. The 2 cGRFS curves obtained using 2 different approaches were superimposed and both were superior to that of conventional GRFS, reflecting the proportion of patients with resolved chronic GVHD. Finally, the curves of cGRFS and rGRFS overlapped after the first 2 years of post-transplant follow-up. These results suggest that cGRFS and rGRFS more accurately reflect transplant success than conventional GRFS. Especially, rGRFS can be more easily calculated than cGRFS and analyzed with widely used statistical approaches, whereas cGRFS more accurately represents the burden of GVHD-related morbidity in the first 2 years after transplantation. Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  8. Helicopter EMS: Research Endpoints and Potential Benefits

    Directory of Open Access Journals (Sweden)

    Stephen H. Thomas

    2012-01-01

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

  9. Impact of obesity on secondary cytoreductive surgery and overall survival in women with recurrent ovarian cancer.

    Science.gov (United States)

    Tran, Arthur-Quan; Cohen, Joshua G; Li, Andrew J

    2015-08-01

    Obesity may negatively influence tumor biology in women with epithelial ovarian cancers. To date, only body mass indices (BMI) determined at the time of diagnosis have correlated with clinical outcome. We hypothesized that obesity negatively affects survival throughout the disease course, and sought to determine the prognostic role of BMI at the time of secondary cytoreductive surgery (SCS) for recurrent ovarian cancer. We performed a review of patients undergoing SCS for recurrent epithelial ovarian or peritoneal cancer between 1997 and 2012. We retrospectively reviewed data which were analyzed using Fisher's exact test, Kaplan-Meier survival, and Cox regression analysis. BMI was defined according to the National Institutes of Health's categorizations. We identified 104 patients; 2 were underweight, 46 were of ideal body weight, 32 were overweight, and 24 were obese. Overall, 90 patients underwent optimal resection and BMI did not correlate with ability to perform optimal SCS (p=0.25). When examining BMI strata (underweight, ideal, overweight, and obese), we observed a statistical trend between increasing BMI and poor outcome; median survival was undetermined (greater than 50 months), 46 months, 38 months, and 34 months, respectively (p=0.04). In a multivariate analysis, BMI was an independent predictor of survival (p=0.02). In this cohort of women undergoing SCS for recurrent ovarian cancer, BMI significantly and independently correlated with overall survival. This observation suggests an effect of excess weight on tumor biology and/or response to treatment that is prevalent throughout the disease course. Copyright © 2015 Elsevier Inc. All rights reserved.

  10. Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy (the ASCENDE-RT Trial): An Analysis of Survival Endpoints for a Randomized Trial Comparing a Low-Dose-Rate Brachytherapy Boost to a Dose-Escalated External Beam Boost for High- and Intermediate-risk Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Morris, W. James, E-mail: jmorris@bccancer.bc.ca [Department of Surgery, University of British Columbia, Vancouver, British Columbia (Canada); BC Cancer Agency–Vancouver Centre, Vancouver, British Columbia (Canada); Tyldesley, Scott [Department of Surgery, University of British Columbia, Vancouver, British Columbia (Canada); BC Cancer Agency–Vancouver Centre, Vancouver, British Columbia (Canada); Rodda, Sree [Department of Surgery, University of British Columbia, Vancouver, British Columbia (Canada); Halperin, Ross [Department of Surgery, University of British Columbia, Vancouver, British Columbia (Canada); BC Cancer Agency–Centre for the Southern Interior, Vancouver, British Columbia (Canada); Pai, Howard [Department of Surgery, University of British Columbia, Vancouver, British Columbia (Canada); BC Cancer Agency–Vancouver Island Centre, Vancouver, British Columbia (Canada); McKenzie, Michael; Duncan, Graeme [Department of Surgery, University of British Columbia, Vancouver, British Columbia (Canada); BC Cancer Agency–Vancouver Centre, Vancouver, British Columbia (Canada); Morton, Gerard [Department of Radiation Oncology, University of Toronto, Sunnybrook Health Sciences Centre, Toronto, Ontario (Canada); Hamm, Jeremy [Department of Population Oncology, BC Cancer Agency, Vancouver, British Columbia (Canada); Murray, Nevin [BC Cancer Agency–Vancouver Centre, Vancouver, British Columbia (Canada); Department of Medicine, University of British Columbia, Vancouver, British Columbia (Canada)

    2017-06-01

    Purpose: To report the primary endpoint of biochemical progression-free survival (b-PFS) and secondary survival endpoints from ASCENDE-RT, a randomized trial comparing 2 methods of dose escalation for intermediate- and high-risk prostate cancer. Methods and Materials: ASCENDE-RT enrolled 398 men, with a median age of 68 years; 69% (n=276) had high-risk disease. After stratification by risk group, the subjects were randomized to a standard arm with 12 months of androgen deprivation therapy, pelvic irradiation to 46 Gy, followed by a dose-escalated external beam radiation therapy (DE-EBRT) boost to 78 Gy, or an experimental arm that substituted a low-dose-rate prostate brachytherapy (LDR-PB) boost. Of the 398 trial subjects, 200 were assigned to DE-EBRT boost and 198 to LDR-PB boost. The median follow-up was 6.5 years. Results: In an intent-to-treat analysis, men randomized to DE-EBRT were twice as likely to experience biochemical failure (multivariable analysis [MVA] hazard ratio [HR] 2.04; P=.004). The 5-, 7-, and 9-year Kaplan-Meier b-PFS estimates were 89%, 86%, and 83% for the LDR-PB boost versus 84%, 75%, and 62% for the DE-EBRT boost (log-rank P<.001). The LDR-PB boost benefited both intermediate- and high-risk patients. Because the b-PFS curves for the treatment arms diverge sharply after 4 years, the relative advantage of the LDR-PB should increase with longer follow-up. On MVA, the only variables correlated with reduced overall survival were age (MVA HR 1.06/y; P=.004) and biochemical failure (MVA HR 6.30; P<.001). Although biochemical failure was associated with increased mortality and randomization to DE-EBRT doubled the rate of biochemical failure, no significant overall survival difference was observed between the treatment arms (MVA HR 1.13; P=.62). Conclusions: Compared with 78 Gy EBRT, men randomized to the LDR-PB boost were twice as likely to be free of biochemical failure at a median follow-up of 6.5 years.

  11. Survival analysis

    International Nuclear Information System (INIS)

    Badwe, R.A.

    1999-01-01

    The primary endpoint in the majority of the studies has been either disease recurrence or death. This kind of analysis requires a special method since all patients in the study experience the endpoint. The standard method for estimating such survival distribution is Kaplan Meier method. The survival function is defined as the proportion of individuals who survive beyond certain time. Multi-variate comparison for survival has been carried out with Cox's proportional hazard model

  12. Chemical disease-free survival in localized carcinoma of prostate treated with external beam irradiation: comparison of American Society of Therapeutic Radiology and Oncology Consensus or 1 ng/mL as endpoint

    International Nuclear Information System (INIS)

    Perez, Carlos A.; Michalski, Jeff M.; Lockett, Mary Ann

    2001-01-01

    Purpose: To compare postirradiation biochemical disease-free survival using the American Society of Therapeutic Radiology and Oncology (ASTRO) Consensus or elevation of postirradiation prostate-specific antigen (PSA) level beyond 1 ng/mL as an endpoint and correlate chemical failure with subsequent appearance of clinically detected local recurrence or distant metastasis. Methods and Materials: Records of 466 patients with histologically confirmed adenocarcinoma of the prostate treated with irradiation alone between January 1987 and December 1995 were analyzed; 339 patients were treated with bilateral 120 deg. arc rotation and, starting in 1992, 117 with three-dimensional conformal irradiation. Doses were 68-77 Gy in 1.8 to 2 Gy daily fractions. Minimum follow-up is 4 years (mean, 5.5 years; maximum, 9.6 years). A chemical failure was recorded using the ASTRO Consensus or when postirradiation PSA level exceeded 1 ng/mL at any time. Clinical failures were determined by rectal examination, radiographic studies, and, when clinically indicated, biopsy. Results: Six-year chemical disease-free survival rates using the ASTRO Consensus according to pretreatment PSA level for T1 tumors were: ≤4 ng/mL, 100%; 4.1-20 ng/mL, 80%; and >20 ng/mL, 50%. For T2 tumors the rates were: ≤4 ng/mL, 91%; 4.1-10 ng/mL, 81%; 10.1-20 ng/mL, 55%; 20.1-40 ng/mL, 63%; and >40 ng/mL, 46%. When postirradiation PSA levels higher than 1 ng/mL were used, the corresponding 6-year chemical disease-free survival rates for T1 tumors were 92% for pretreatment PSA levels of ≤4 ng/mL, 58-60% for levels of 4.1-20 ng/mL, and 30% for levels >20 ng/mL. For T2 tumors, the 6-year chemical disease-free survival rates were 78% in patients with pretreatment PSA levels of 4-10 ng/mL, 45% for 10.1-40 ng/mL, and 25% for >40 ng/mL. Of 167 patients with T1 tumors, 30 (18%) developed a chemical failure, 97% within 5 years from completion of radiation therapy; no patient has developed a local recurrence or distant

  13. TBI Endpoints Development

    Science.gov (United States)

    2015-10-01

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

  14. Survival after parathyroidectomy in chronic hemodialysis patients with severe secondary hyperparathyroidism.

    Science.gov (United States)

    Moldovan, Diana; Racasan, Simona; Kacso, Ina Maria; Rusu, Crina; Potra, Alina; Bondor, Cosmina; Patiu, Ioan Mihai; Gherman-Căprioară, Mirela

    2015-11-01

    The life for end-stage renal disease patients has remarkably improved in the last years. Although mineral and bone disorders remain as unsolved complication, in severe secondary hyperparathyroidism (sHPT), the ultimate treatment is parathyroidectomy (PTX). It is an old treatment, but there are still insufficient data regarding survival after PTX. The study goals were to compare 2-year mortality and morbidity after PTX in surgically versus medically treated sHPT and to compare the efficacy and safety in subtotal versus total PTX in a cohort of patients receiving hemodialysis (HD). This prospective, longitudinal study was carried out on a cohort of chronic HD patients with severe sHPT (iPTH over 700 pg/ml). Among the overall HD population, 26 patients underwent PTX. This group was compared to a control group treated with specific drugs. Laboratory parameters, specific symptoms and mortality were registered after 24 months of follow-up for each group. The subgroups of subtotal and total PTX patients were also compared. All average values of mineral markers were significantly reduced after PTX, as a proof that surgical treatment was effective. The reduction in mineral markers and the improvement in symptoms and mortality rates were similar after total and subtotal PTX. Bone pain was significantly lower in patients after PTX than in those drug treated (p = 0.0005), but not muscle weakness and itching. Survival at 2 years was better in patients surgically treated (PTX) despite significantly higher mean baseline values of iPTH, Ca and ALP compared to patients medically treated (p = 0.03). We compared clinical and laboratory outcomes in HD patients with severe sHPT. Mortality, bone pain and mineral markers were improved by PTX. Total and subtotal PTX had similar clinical outcomes.

  15. 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).

    Science.gov (United States)

    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

  16. CA-125–indicated asymptomatic relapse confers survival benefit to ovarian cancer patients who underwent secondary cytoreduction surgery

    Directory of Open Access Journals (Sweden)

    Wang Fang

    2013-02-01

    Full Text Available Abstract Background There is no consensus regarding the management of ovarian cancer patients, who have shown complete clinical response (CCR to primary therapy and have rising cancer antigen CA-125 levels but have no symptoms of recurrent disease. The present study aims to determine whether follow-up CA-125 levels can be used to identify the need for imaging studies and secondary cytoreductive surgery (CRS. Methods We identified 410 ovarian cancer patients treated at The University of Texas MD Anderson Cancer Center between 1984 and 2011. These patients had shown CCR to primary therapy. Follow-up was conducted based on the surveillance protocol of the MD Anderson Cancer Center. We used the Cox proportional hazards model and log-rank test to assess the associations between the follow-up CA-125 levels and secondary CRS and survival duration. Results The CA-125 level of 1.68 × nadir was defined as the indicator of recurrent disease (p  1.68 × nadir at relapse (55.7 and 10.4 months; p = 0.04 and 0.01, respectively. The overall and progression free survival duration of patients with asymptomatic relapse and underwent a secondary CRS was longer than that of patients with symptomatic relapse (p = 0.02 and 0.04 respectively. Conclusions The increase of serum CA-125 levels is an early warning of clinical relapse in ovarian cancer. Using CA-125 levels in guiding the treatment of patients with asymptomatic recurrent ovarian cancer, who have shown CCR to primary therapy, can facilitate optimal secondary CRS and extend the survival duration of the patients.

  17. Biomarkers and correlative endpoints for immunotherapy trials.

    Science.gov (United States)

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

    2013-01-01

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

  18. Shared Contract-Obedient Endpoints

    Directory of Open Access Journals (Sweden)

    Étienne Lozes

    2012-12-01

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

  19. Long-term survival from gastrocolic fistula secondary to adenocarcinoma of the transverse colon

    Directory of Open Access Journals (Sweden)

    Murali Kothandaraman

    2005-02-01

    Full Text Available Abstract Background Gastrocolic fistula is a rare presentation of both benign and malignant diseases of the gastrointestinal tract. Malignant gastrocolic fistula is most commonly associated with adenocarcinoma of the transverse colon in the Western World. Despite radical approaches to treatment, long-term survival is rarely documented. Case presentation We report a case of a 24-year-old woman who presented with the classic triad of symptoms associated with gastrocolic fistula. Radical en-bloc surgery and adjuvant chemotherapy were performed. She is still alive ten years after treatment. Conclusions Gastrocolic fistula is an uncommon presentation of adenocarcinoma of the transverse colon. Radical en-bloc surgery with adjuvant chemotherapy may occasionally produce long-term survival.

  20. Calorimetry end-point predictions

    International Nuclear Information System (INIS)

    Fox, M.A.

    1981-01-01

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

  1. Improved Endpoints for Cancer Immunotherapy Trials

    Science.gov (United States)

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

    2010-01-01

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

  2. Endpoints in pediatric pain studies

    NARCIS (Netherlands)

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

    2011-01-01

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

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

    Science.gov (United States)

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

    2014-12-01

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

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

    Science.gov (United States)

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

    2016-02-02

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

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

    NARCIS (Netherlands)

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

    2014-01-01

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

  6. Impact of parathyroidectomy on cardiovascular outcomes and survival in chronic hemodialysis patients with secondary hyperparathyroidism. A retrospective study of 50 cases prior to the calcimimetics era.

    Science.gov (United States)

    Conzo, Giovanni; Perna, Alessandra F; Savica, Vincenzo; Palazzo, Antonietta; Della Pietra, Cristina; Ingrosso, Diego; Satta, Ersilia; Capasso, Giovambattista; Santini, Luigi; Docimo, Giovanni

    2013-01-01

    In chronic hemodialysis patients with secondary hyperparathyroidism, pathological modifications of bone and mineral metabolism increase the risk of cardiovascular morbidity and mortality. Parathyroidectomy, reducing the incidence of cardiovascular events, may improve outcomes; however, its effects on long-term survival are still subject of active research. From January 2004 to December 2006, 30 hemodialysis patients, affected by severe and unresponsive secondary hyperparathyroidism, underwent parathyroidectomy - 15 total parathyroidectomy and 15 total parathyroidectomy + subcutaneous autoimplantation. During a 5-year follow-up, patients did not receive a renal transplantation and were evaluated for biochemical modifications and major cardiovascular events - death, cardiovascular accidents, myocardial infarction and peripheral vascular disease. Results were compared with those obtained in a control group of 20 hemodialysis patients, affected by secondary hyperparathyroidism, and refusing surgical treatment, and following medical treatment only. The groups were comparable in terms of age, gender, dialysis vintage, and comorbidities. Postoperative cardiovascular events were observed in 18/30 - 54% - surgical patients and in 4/20 - 20%- medical patients, with a mortality rate respectively of 23.3% in the surgical group vs. 15% in the control group. Parathyroidectomy was not associated with a reduced risk of cardiovascular morbidity and survival rate was unaffected by surgical treatment. In secondary hyperparathyroidism hemodialysis patients affected by severe cardiovascular disease, surgery did not modify cardiovascular morbidity and mortality rates. Therefore, in secondary hyperparathyroidism hemodialysis patients, resistant to medical treatment, only an early indication to calcimimetics, or surgery, in the initial stage of chronic kidney disease - mineral bone disorders, may offer a higher long-term survival. Further studies will be useful to clarify the role of

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

    Science.gov (United States)

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

    2016-01-01

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

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

    Science.gov (United States)

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

    2016-04-01

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

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

    Science.gov (United States)

    Baker, Stuart G

    2018-02-20

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

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

    Science.gov (United States)

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

    2015-06-01

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

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

    Science.gov (United States)

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

    2015-01-01

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

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

    Science.gov (United States)

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

    2014-01-01

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

  13. Similar long-term survival of consecutive in-hospital and out-of-hospital cardiac arrest patients treated with targeted temperature management

    DEFF Research Database (Denmark)

    Engsig, Magaly; Søholm, Helle; Folke, Fredrik

    2016-01-01

    OBJECTIVE: The long-term survival of in-hospital cardiac arrest (IHCA) patients treated with targeted temperature management (TTM) is poorly described. The aim of this study was to compare the outcomes of consecutive IHCA with out-of-hospital cardiac arrest (OHCA) patients treated with TTM. DESIGN...... SETTING AND PATIENTS: Retrospectively collected data on all consecutive adult patients treated with TTM at a university tertiary heart center between 2005 and 2011 were analyzed. MEASUREMENTS: Primary endpoints were survival to hospital discharge and long-term survival. Secondary endpoint was neurological...... time to return of spontaneous circulation (ROSC). Survival to hospital discharge was 54% for OHCA and 53% for IHCA (adjusted odds ratio 0.98 [95% confidence interval {CI}; 0.43-2.24]). Age ≤60 years, bystander CPR, time to ROSC ≤10 min, and shockable rhythm at presentation were associated with survival...

  14. Establishing a group of endpoints in a parallel computer

    Science.gov (United States)

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

    2016-02-02

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

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

    International Nuclear Information System (INIS)

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

    2015-01-01

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

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

    Science.gov (United States)

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

    2007-10-01

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

  17. Fruit flies may face a nutrient-dependent life-history trade-off between secondary sexual trait quality, survival and developmental rate.

    Science.gov (United States)

    Gray, Lindsey J; Simpson, Stephen J; Polak, Michal

    2018-01-01

    Optimal life-history strategies are those that best allocate finite environmental resources to competing traits. We used the geometric framework for nutrition to evaluate life-history strategies followed by Drosophila melanogaster by measuring the condition-dependent performance of life-history traits, including the morphology of male secondary sexual characters, sex combs. We found that depending on their rearing environment flies faced different forms of trait trade-offs and accordingly followed different life-history strategies. High-energy, high-carbohydrate, low-protein diets supported development of the largest and most symmetrical sex combs, however, consistent with handicap models of sexual selection these foods were associated with reduced fly survival and developmental rate. Expressing the highest quality sex combs may have required secondary sexual trait quality to be traded-off with developmental rate, and our results indicated that flies unable to slow development died. As larval nutritional environments are predominantly determined by female oviposition substrate choice, we tested where mated female flies laid the most eggs. Mothers chose high-energy, high-protein foods associated with rapid larval development. Mothers avoided high-carbohydrate foods associated with maximal sex comb expression, showing they may avoid producing fewer 'sexy' sons in favour of producing offspring that develop rapidly. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. A summation free β+-endpoint spectrometer

    International Nuclear Information System (INIS)

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

    1990-08-01

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

  19. End-point sharpness in thermometric titrimetry.

    Science.gov (United States)

    Tyrrell, H J

    1967-07-01

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

  20. Forecasting interest rates with shifting endpoints

    DEFF Research Database (Denmark)

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

    2014-01-01

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

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

    International Nuclear Information System (INIS)

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

    1986-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Sukwan Handali

    2012-01-01

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

  3. Endpoint singularities in unintegrated parton distributions

    CERN Document Server

    Hautmann, F

    2007-01-01

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

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

    Science.gov (United States)

    Carrera, Gemma; Garcia-Albeniz, Xabier; Ayuso, Juan Ramón; Aparicio, Jorge; Castells, Antoni; Codony-Servat, Jordi; Feliu, Jaime; Fuster, David; Gallego, Rosa; Pagés, Mario; Torres, Ferran; Maurel, Joan

    2011-05-01

    Meta-analytic reviews of Randomized Clinical Trials (RCT) have reached contradictory conclusions regarding the benefit of medical interventions in Advanced Colorectal Cancer (ACRC). Surrogate markers of survival benefit, such as response rate (RR) and progression free-survival (PFS) often show contradictory and highly variable correlations. These contradictions can be due to differences in 1) the studies analysed (sources), 2) the quality of clinical trials (intrinsic bias in the design, biased data analysis, heterogeneous PFS definitions) and 3) the second-line strategies between arms. PFS is a more vulnerable target than overall survival (OS), but the latter can also be affected by different biases and additional medical interventions such as secondary resection of metastases or second-line therapies. Therefore the correlation between PFS and survival must be clearly stated if PFS is to be considered as a primary endpoint. Of the differences between studies, only the quality of clinical trials can be improved by a deeper knowledge of both the area of study (i.e. colorectal cancer) and the methodology needed (i.e., clinical and translational trials). The aim of this manuscript is to offer the basic resources to develop experimental trials in ACRC. To this end, techniques for diagnosis and for response assessment are discussed, prognostic factors and treatment standards are critically exposed, and notes about how to design useful translational studies are provided.

  5. A prospective study of proton reirradiation for recurrent and secondary soft tissue sarcoma.

    Science.gov (United States)

    Guttmann, David M; Frick, Melissa A; Carmona, Ruben; Deville, Curtiland; Levin, William P; Berman, Abigail T; Chinniah, Chidambaram; Hahn, Stephen M; Plastaras, John P; Simone, Charles B

    2017-08-01

    Proton reirradiation for sarcoma has not been previously described. We hypothesized that this strategy would provide favorable toxicity and survival outcomes. Patients with soft tissue sarcoma in a previously-irradiated field were enrolled on a prospective trial of proton reirradiation. The primary endpoint was provider-reported acute toxicity. Secondary endpoints included late toxicities, local control, and overall survival. 23 patients underwent proton reirradiation. Median time between radiation courses was 40.7months (range 10-272). No grade 4-5 toxicities were observed. One patient (4%) experienced acute grade 3 dysphagia. Common grade 2 acute toxicities were fatigue (26%), anorexia (17%), and urinary incontinence (13%). There were two grade 3 late wound infections (10%) and one grade 3 late wound complication (5%). Grade 2 late complications included lymphedema (10%), fracture (5%), and fibrosis (5%). At a median follow-up of 36months, the 3-year cumulative incidence of local failure was 41% (95% CI [20-63%]). Median overall survival and progression-free survival were 44 and 29months, respectively. In extremity patients, amputation was spared in 7/10 (70%). Proton reirradiation of recurrent/secondary soft tissue sarcomas is well tolerated. While longer follow-up is needed, early survival outcomes in this high-risk population are encouraging. Copyright © 2017 Elsevier B.V. All rights reserved.

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

    International Nuclear Information System (INIS)

    Visser, S.

    1999-01-01

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

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

    Science.gov (United States)

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

    2015-09-01

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

  8. Extracting gluino endpoints with event topology patterns

    Energy Technology Data Exchange (ETDEWEB)

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

    2012-06-15

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

  9. Radiological endpoints relevant to ecological risk assessment

    International Nuclear Information System (INIS)

    Harrison, F.

    1997-01-01

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

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

    International Nuclear Information System (INIS)

    Guelden, Michael; Moerchel, Sabine; Seibert, Hasso

    2005-01-01

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

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

    Science.gov (United States)

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

    2018-06-01

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

  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).

    Science.gov (United States)

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

    2014-11-01

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

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

    Science.gov (United States)

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

    2013-03-01

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

  14. The intermediate endpoint effect in logistic and probit regression

    Science.gov (United States)

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

    2010-01-01

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

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

    Science.gov (United States)

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

    2018-01-04

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

  16. Endpoint distinctiveness facilitates analogical mapping in pigeons.

    Science.gov (United States)

    Hagmann, Carl Erick; Cook, Robert G

    2015-03-01

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

  17. Endpoint Distinctiveness Facilitates Analogical Mapping in Pigeons

    Science.gov (United States)

    Hagmann, Carl Erick; Cook, Robert G.

    2015-01-01

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

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

    Science.gov (United States)

    Sun, Anna; Dong, Xiaoyu; Tsong, Yi

    2014-01-01

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

  19. Ordered kinematic endpoints for 5-body cascade decays

    Energy Technology Data Exchange (ETDEWEB)

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

    2016-12-23

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

  20. Creation of a Prognostic Index for Spine Metastasis to Stratify Survival in Patients Treated With Spinal Stereotactic Radiosurgery: Secondary Analysis of Mature Prospective Trials

    International Nuclear Information System (INIS)

    Tang, Chad; Hess, Kenneth; Bishop, Andrew J.; Pan, Hubert Y.; Christensen, Eva N.; Yang, James N.; Tannir, Nizar; Amini, Behrang; Tatsui, Claudio; Rhines, Laurence; Brown, Paul; Ghia, Amol

    2015-01-01

    Purpose: There exists uncertainty in the prognosis of patients following spinal metastasis treatment. We sought to create a scoring system that stratifies patients based on overall survival. Methods and Materials: Patients enrolled in 2 prospective trials investigating stereotactic spine radiation surgery (SSRS) for spinal metastasis with ≥3-year follow-up were analyzed. A multivariate Cox regression model was used to create a survival model. Pretreatment variables included were race, sex, age, performance status, tumor histology, extent of vertebrae involvement, previous therapy at the SSRS site, disease burden, and timing of diagnosis and metastasis. Four survival groups were generated based on the model-derived survival score. Results: Median follow-up in the 206 patients included in this analysis was 70 months (range: 37-133 months). Seven variables were selected: female sex (hazard ratio [HR] = 0.7, P=.02), Karnofsky performance score (HR = 0.8 per 10-point increase above 60, P=.007), previous surgery at the SSRS site (HR = 0.7, P=.02), previous radiation at the SSRS site (HR = 1.8, P=.001), the SSRS site as the only site of metastatic disease (HR = 0.5, P=.01), number of organ systems involved outside of bone (HR = 1.4 per involved system, P<.001), and >5 year interval from initial diagnosis to detection of spine metastasis (HR = 0.5, P<.001). The median survival among all patients was 25.5 months and was significantly different among survival groups (in group 1 [excellent prognosis], median survival was not reached; group 2 reached 32.4 months; group 3 reached 22.2 months; and group 4 [poor prognosis] reached 9.1 months; P<.001). Pretreatment symptom burden was significantly higher in the patient group with poor survival than in the group with excellent survival (all metrics, P<.05). Conclusions: We developed the prognostic index for spinal metastases (PRISM) model, a new model that identified patient subgroups with poor and excellent prognoses

  1. Creation of a Prognostic Index for Spine Metastasis to Stratify Survival in Patients Treated With Spinal Stereotactic Radiosurgery: Secondary Analysis of Mature Prospective Trials

    Energy Technology Data Exchange (ETDEWEB)

    Tang, Chad [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Hess, Kenneth [Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Bishop, Andrew J.; Pan, Hubert Y.; Christensen, Eva N. [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Yang, James N. [Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Tannir, Nizar [Department of Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Amini, Behrang [Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Tatsui, Claudio; Rhines, Laurence [Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Brown, Paul [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Ghia, Amol, E-mail: ajghia@mdanderson.org [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States)

    2015-09-01

    Purpose: There exists uncertainty in the prognosis of patients following spinal metastasis treatment. We sought to create a scoring system that stratifies patients based on overall survival. Methods and Materials: Patients enrolled in 2 prospective trials investigating stereotactic spine radiation surgery (SSRS) for spinal metastasis with ≥3-year follow-up were analyzed. A multivariate Cox regression model was used to create a survival model. Pretreatment variables included were race, sex, age, performance status, tumor histology, extent of vertebrae involvement, previous therapy at the SSRS site, disease burden, and timing of diagnosis and metastasis. Four survival groups were generated based on the model-derived survival score. Results: Median follow-up in the 206 patients included in this analysis was 70 months (range: 37-133 months). Seven variables were selected: female sex (hazard ratio [HR] = 0.7, P=.02), Karnofsky performance score (HR = 0.8 per 10-point increase above 60, P=.007), previous surgery at the SSRS site (HR = 0.7, P=.02), previous radiation at the SSRS site (HR = 1.8, P=.001), the SSRS site as the only site of metastatic disease (HR = 0.5, P=.01), number of organ systems involved outside of bone (HR = 1.4 per involved system, P<.001), and >5 year interval from initial diagnosis to detection of spine metastasis (HR = 0.5, P<.001). The median survival among all patients was 25.5 months and was significantly different among survival groups (in group 1 [excellent prognosis], median survival was not reached; group 2 reached 32.4 months; group 3 reached 22.2 months; and group 4 [poor prognosis] reached 9.1 months; P<.001). Pretreatment symptom burden was significantly higher in the patient group with poor survival than in the group with excellent survival (all metrics, P<.05). Conclusions: We developed the prognostic index for spinal metastases (PRISM) model, a new model that identified patient subgroups with poor and excellent prognoses.

  2. A comparison of the recording of comorbidity in primary and secondary care by using the Charlson Index to predict short-term and long-term survival in a routine linked data cohort.

    Science.gov (United States)

    Crooks, C J; West, J; Card, T R

    2015-06-05

    Hospital admission records provide snapshots of clinical histories for a subset of the population admitted to hospital. In contrast, primary care records provide continuous clinical histories for complete populations, but might lack detail about inpatient stays. Therefore, combining primary and secondary care records should improve the ability of comorbidity scores to predict survival in population-based studies, and provide better adjustment for case-mix differences when assessing mortality outcomes. Cohort study. English primary and secondary care 1 January 2005 to 1 January 2010. All patients 20 years and older registered to a primary care practice contributing to the linked Clinical Practice Research Datalink from England. The performance of the Charlson index with mortality was compared when derived from either primary or secondary care data or both. This was assessed in relation to short-term and long-term survival, age, consultation rate, and specific acute and chronic diseases. 657,264 people were followed up from 1 January 2005. Although primary care recorded more comorbidity than secondary care, the resulting C statistics for the Charlson index remained similar: 0.86 and 0.87, respectively. Higher consultation rates and restricted age bands reduced the performance of the Charlson index, but the index's excellent performance persisted over longer follow-up; the C statistic was 0.87 over 1 year, and 0.85 over all 5 years of follow-up. The Charlson index derived from secondary care comorbidity had a greater effect than primary care comorbidity in reducing the association of upper gastrointestinal bleeding with mortality. However, they had a similar effect in reducing the association of diabetes with mortality. These findings support the use of the Charlson index from linked data and show that secondary care comorbidity coding performed at least as well as that derived from primary care in predicting survival. Published by the BMJ Publishing Group Limited

  3. Anemia: friend or foe? Low hemoglobin is associated with decreased survival, loco-regional control and late complications: a secondary analysis of RTOG 85-27

    International Nuclear Information System (INIS)

    Lee, W. Robert; Berkey, B.; Marcial, V.; Fu, K.K.; Cooper, J. S.; Vikram, B.; Coia, L.R.; Rotman, M.; Ortiz, H.

    1997-01-01

    Purpose: Classical teaching holds that hypoxia reduces the lethal effects of ionizing radiation. Many reports have correlated low hemoglobin (Hgb) levels with reduced loco-regional control (LRC) following radiotherapy (RT) suggesting that anemia may be associated with tumor hypoxia. If hypoxia protects tumors from the lethal effects of ionizing radiation then it might protect normal tissues in a similar fashion. The purpose of the present study was to examine the effect of Hgb level on the LRC, survival and late complications in patients with advanced head and neck cancer treated with conventional radiotherapy with or without a hypoxic cell sensitizer. Methods: From March 1988 to September 1991, 521 patients with Stage III or IV squamous cell carcinoma of the head and neck were entered onto a randomized trial examining the addition of etanidazole (SR 2508) to conventional RT (66 Gy in 33 fractions to 74 Gy in 37 fractions, 5 days a week). Hgb levels were stratified as high (≥ 14.5 grams-percent for men, ≥ 13.0 grams-percent for women) or low (<14.5 for men, <13.0 for women). Loco-regional failure rates were calculated using the cumulative incidence approach. Overall survival was estimated according to the Kaplan-Meier method. Late RT toxicity was scored according to the RTOG morbidity scale. Differences in rates of LRC, survival and late complications were tested by the Cox proportional hazard model. The median follow-up of surviving patients was 57 months with a range of 1-7.5 years. Results: Of 504 eligible patients, 451 had Hgb measured prior to the second week of RT. One hundred and sixty-two patients (35.9%) were classified as having a high Hgb (HH) and 289 (64.1%) patients were classified as having a low Hgb (LH). Patients in the LH group had significantly lower survival and a trend towards lower LRC and late RT complications (see Table). Conclusion: Low Hgb levels are associated with a statistically significant reduction in survival and a trend towards

  4. Hippeastrum hybridum anthocyanins as indicators of endpoint in acid

    African Journals Online (AJOL)

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

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

    African Journals Online (AJOL)

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

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

    NARCIS (Netherlands)

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

    1992-01-01

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

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

    Science.gov (United States)

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

    2014-01-01

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

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

    Science.gov (United States)

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

    2016-02-01

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

  9. Preoperative radiation with concurrent chemotherapy for resectable rectal cancer: Effect of dose escalation on pathologic complete response, local recurrence-free survival, disease-free survival, and overall survival

    International Nuclear Information System (INIS)

    Wiltshire, Kirsty L.; Ward, Iain G.; Swallow, Carol; Oza, Amit M.; Cummings, Bernard; Pond, Gregory R.; Catton, Pamela; Kim, John; Ringash, Jolie; Wong, Chong S.; Wong, Rebecca; Siu, Lillian L.; Moore, Malcolm; Brierley, James

    2006-01-01

    Purpose: Three Phase II studies of preoperative radiotherapy and concurrent 5FU chemotherapy were undertaken. The primary endpoints were acute toxicity and pathologic complete response rate (pCR). Secondary endpoints were local recurrence-free survival (LRFS), disease-free survival (DFS), and overall survival (OS). Methods and Materials: A total of 134 patients with adenocarcinoma of the rectum (clinical T3/T4 or N1/N2) were treated. The initial cohort received 40 Gy in 20 fractions, the second 46 Gy in 23 fractions, and the third 50 Gy in 25 fractions. 5FU (225 mg/m 2 /day) was given continuously throughout radiotherapy. A total of 121 patients underwent surgical resection. Results: Treatment was well tolerated. Grade 3/4 acute toxicity was observed in 13%, 4%, and 14% of patients in the 40 Gy, 46 Gy, and 50 Gy cohorts, respectively (p = 0.20). pCR was documented in 15%, 23%, and 33% of patients, respectively (p = 0.07). The 2-year actuarial LRFS was 72%, 90%, and 89% (p = 0.02); DFS was 62%, 84%, and 78% (p = 0.02); and OS was 72%, 94%, and 92%, respectively (p = 0.03). Conclusions: All treatment schedules were well tolerated. There was a trend toward increased pCR with higher doses. A statistically significant increase in LRFS, DFS, and OS was seen with radiation doses of 46 Gy and greater, but there was no difference between 46 Gy and 50 Gy

  10. The Influence of Total Nodes Examined, Number of Positive Nodes, and Lymph Node Ratio on Survival After Surgical Resection and Adjuvant Chemoradiation for Pancreatic Cancer: A Secondary Analysis of RTOG 9704

    Energy Technology Data Exchange (ETDEWEB)

    Showalter, Timothy N. [Department of Radiation Oncology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA (United States); Winter, Kathryn A. [Radiation Therapy Oncology Group, RTOG Statistical Center, Philadelphia, PA (United States); Berger, Adam C., E-mail: adam.berger@jefferson.edu [Department of Surgery, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA (United States); Regine, William F. [Department of Radiation Oncology, University of Maryland Medical Center, Baltimore, MD (United States); Abrams, Ross A. [Department of Radiation Oncology, Rush University Medical Center, Chicago, IL (United States); Safran, Howard [Department of Medicine, Miriam Hospital, Brown University Oncology Group, Providence, RI (United States); Hoffman, John P. [Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA (United States); Benson, Al B. [Division of Hematology-Oncology, Northwestern University, Chicago, IL (United States); MacDonald, John S. [St. Vincent' s Cancer Care Center, New York, NY (United States); Willett, Christopher G. [Department of Radiation Oncology, Duke University Medical Center, Durham, NC (United States)

    2011-12-01

    Purpose: Lymph node status is an important predictor of survival in pancreatic cancer. We performed a secondary analysis of Radiation Therapy Oncology Group (RTOG) 9704, an adjuvant chemotherapy and chemoradiation trial, to determine the influence of lymph node factors-number of positive nodes (NPN), total nodes examined (TNE), and lymph node ratio (LNR ratio of NPN to TNE)-on OS and disease-free survival (DFS). Patient and Methods: Eligible patients from RTOG 9704 form the basis of this secondary analysis of lymph node parameters. Actuarial estimates for OS and DFS were calculated using Kaplan-Meier methods. Cox proportional hazards models were performed to evaluate associations of NPN, TNE, and LNR with OS and DFS. Multivariate Cox proportional hazards models were also performed. Results: There were 538 patients enrolled in the RTOG 9704 trial. Of these, 445 patients were eligible with lymph nodes removed. Overall median NPN was 1 (min-max, 0-18). Increased NPN was associated with worse OS (HR = 1.06, p = 0.001) and DFS (HR = 1.05, p = 0.01). In multivariate analyses, both NPN and TNE were associated with OS and DFS. TNE > 12, and >15 were associated with increased OS for all patients, but not for node-negative patients (n = 142). Increased LNR was associated with worse OS (HR = 1.01, p < 0.0001) and DFS (HR = 1.006, p = 0.002). Conclusion: In patients who undergo surgical resection followed by adjuvant chemoradiation, TNE, NPN, and LNR are associated with OS and DFS. This secondary analysis of a prospective, cooperative group trial supports the influence of these lymph node parameters on outcomes after surgery and adjuvant therapy using contemporary techniques.

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

    Science.gov (United States)

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

    2016-07-01

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

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

    International Nuclear Information System (INIS)

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

    2016-01-01

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

  13. Planning and analyzing clinical trials with composite endpoints

    CERN Document Server

    Rauch, Geraldine; Kieser, Meinhard

    2017-01-01

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

  14. Gastroenterological endpoints in drug trials for cystic fibrosis

    NARCIS (Netherlands)

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

    2016-01-01

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

  15. Endpoint behavior of high-energy scattering cross sections

    International Nuclear Information System (INIS)

    Chay, Junegone; Kim, Chul

    2010-01-01

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

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

    International Nuclear Information System (INIS)

    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

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

    Science.gov (United States)

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

    2005-11-01

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

  18. Volume-based quantitative FDG PET/CT metrics and their association with optimal debulking and progression-free survival in patients with recurrent ovarian cancer undergoing secondary cytoreductive surgery

    Energy Technology Data Exchange (ETDEWEB)

    Vargas, H.A.; Burger, I.A.; Micco, M.; Sosa, R.E.; Weber, W.; Hricak, H.; Sala, E. [Memorial Sloan Kettering Cancer Center, Department of Radiology, New York, NY (United States); Goldman, D.A. [Memorial Sloan Kettering Cancer Center, Department of Epidemiology and Biostatistics, New York, NY (United States); Chi, D.S. [Memorial Sloan Kettering Cancer Center, Department of Surgery, New York, NY (United States)

    2015-11-15

    Our aim was to evaluate the associations between quantitative {sup 18}F-fluorodeoxyglucose positron-emission tomography (FDG-PET) uptake metrics, optimal debulking (OD) and progression-free survival (PFS) in patients with recurrent ovarian cancer undergoing secondary cytoreductive surgery. Fifty-five patients with recurrent ovarian cancer underwent FDG-PET/CT within 90 days prior to surgery. Standardized uptake values (SUV{sub max}), metabolically active tumour volumes (MTV), and total lesion glycolysis (TLG) were measured on PET. Exact logistic regression, Kaplan-Meier curves and the log-rank test were used to assess associations between imaging metrics, OD and PFS. MTV (p = 0.0025) and TLG (p = 0.0043) were associated with OD; however, there was no significant association between SUV{sub max} and debulking status (p = 0.83). Patients with an MTV above 7.52 mL and/or a TLG above 35.94 g had significantly shorter PFS (p = 0.0191 for MTV and p = 0.0069 for TLG). SUV{sub max} was not significantly related to PFS (p = 0.10). PFS estimates at 3.5 years after surgery were 0.42 for patients with an MTV ≤ 7.52 mL and 0.19 for patients with an MTV > 7.52 mL; 0.46 for patients with a TLG ≤ 35.94 g and 0.15 for patients with a TLG > 35.94 g. FDG-PET metrics that reflect metabolic tumour burden are associated with optimal secondary cytoreductive surgery and progression-free survival in patients with recurrent ovarian cancer. (orig.)

  19. Volume-based quantitative FDG PET/CT metrics and their association with optimal debulking and progression-free survival in patients with recurrent ovarian cancer undergoing secondary cytoreductive surgery

    International Nuclear Information System (INIS)

    Vargas, H.A.; Burger, I.A.; Micco, M.; Sosa, R.E.; Weber, W.; Hricak, H.; Sala, E.; Goldman, D.A.; Chi, D.S.

    2015-01-01

    Our aim was to evaluate the associations between quantitative 18 F-fluorodeoxyglucose positron-emission tomography (FDG-PET) uptake metrics, optimal debulking (OD) and progression-free survival (PFS) in patients with recurrent ovarian cancer undergoing secondary cytoreductive surgery. Fifty-five patients with recurrent ovarian cancer underwent FDG-PET/CT within 90 days prior to surgery. Standardized uptake values (SUV max ), metabolically active tumour volumes (MTV), and total lesion glycolysis (TLG) were measured on PET. Exact logistic regression, Kaplan-Meier curves and the log-rank test were used to assess associations between imaging metrics, OD and PFS. MTV (p = 0.0025) and TLG (p = 0.0043) were associated with OD; however, there was no significant association between SUV max and debulking status (p = 0.83). Patients with an MTV above 7.52 mL and/or a TLG above 35.94 g had significantly shorter PFS (p = 0.0191 for MTV and p = 0.0069 for TLG). SUV max was not significantly related to PFS (p = 0.10). PFS estimates at 3.5 years after surgery were 0.42 for patients with an MTV ≤ 7.52 mL and 0.19 for patients with an MTV > 7.52 mL; 0.46 for patients with a TLG ≤ 35.94 g and 0.15 for patients with a TLG > 35.94 g. FDG-PET metrics that reflect metabolic tumour burden are associated with optimal secondary cytoreductive surgery and progression-free survival in patients with recurrent ovarian cancer. (orig.)

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

    International Nuclear Information System (INIS)

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

    2013-01-01

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

  1. Sample size determination in clinical trials with multiple endpoints

    CERN Document Server

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

    2015-01-01

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

  2. Surviving Sengstaken.

    Science.gov (United States)

    Jayakumar, S; Odulaja, A; Patel, S; Davenport, M; Ade-Ajayi, N

    2015-07-01

    To report the outcomes of children who underwent Sengstaken-Blakemore tube (SBT) insertion for life-threatening haemetemesis. Single institution retrospective review (1997-2012) of children managed with SBT insertion. Patient demographics, diagnosis and outcomes were noted. Data are expressed as median (range). 19 children [10 male, age 1 (0.4-16) yr] were identified; 18 had gastro-oesophageal varices and 1 aorto-oesophageal fistula. Varices were secondary to: biliary atresia (n=8), portal vein thrombosis (n=5), alpha-1-anti-trypsin deficiency (n=1), cystic fibrosis (n=1), intrahepatic cholestasis (n=1), sclerosing cholangitis (n=1) and nodular hyperplasia with arterio-portal shunt (n=1). Three children deteriorated rapidly and did not survive to have post-SBT endoscopy. The child with an aortooesophageal fistula underwent aortic stent insertion and subsequently oesophageal replacement. Complications included gastric mucosal ulceration (n=3, 16%), pressure necrosis at lips and cheeks (n=6, 31%) and SBT dislodgment (n=1, 6%). Six (31%) children died. The remaining 13 have been followed up for 62 (2-165) months; five required liver transplantation, two underwent a mesocaval shunt procedure and 6 have completed endoscopic variceal obliteration and are under surveillance. SBT can be an effective, albeit temporary, life-saving manoeuvre in children with catastrophic haematemesis. Copyright © 2015 Elsevier Inc. All rights reserved.

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

    Science.gov (United States)

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

    2015-09-01

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

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

    Science.gov (United States)

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

    2015-01-01

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

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

    International Nuclear Information System (INIS)

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

    2008-01-01

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

  6. Association Between Change in Body Mass Index, Unified Parkinson's Disease Rating Scale Scores, and Survival Among Persons With Parkinson Disease: Secondary Analysis of Longitudinal Data From NINDS Exploratory Trials in Parkinson Disease Long-term Study 1.

    Science.gov (United States)

    Wills, Anne-Marie A; Pérez, Adriana; Wang, Jue; Su, Xiao; Morgan, John; Rajan, Suja S; Leehey, Maureen A; Pontone, Gregory M; Chou, Kelvin L; Umeh, Chizoba; Mari, Zoltan; Boyd, James

    2016-03-01

    Greater body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) is associated with improved survival among persons with Huntington disease or amyotrophic lateral sclerosis. Weight loss is common among persons with Parkinson disease (PD) and is associated with worse quality of life. To explore the association between change in BMI, Unified Parkinson's Disease Rating Scale (UPDRS) motor and total scores, and survival among persons with PD and to test whether there is a positive association between BMI at randomization and survival. Secondary analysis (from May 27, 2014, to October 13, 2015) of longitudinal data (3-6 years) from 1673 participants who started the National Institute of Neurological Disorders and Stroke Exploratory Trials in PD Long-term Study-1 (NET-PD LS-1). This was a double-blind randomized placebo-controlled clinical trial of creatine monohydrate (10 g/d) that was performed at 45 sites throughout the United States and Canada. Participants with early (within 5 years of diagnosis) and treated (receiving dopaminergic therapy) PD were enrolled from March 2007 to May 2010 and followed up until September 2013. Change across time in motor UPDRS score, change across time in total UPDRS score, and time to death. Generalized linear mixed models were used to estimate the effect of BMI on the change in motor and total UPDRS scores after controlling for covariates. Survival was analyzed using Cox proportional hazards models of time to death. A participant's BMI was measured at randomization, and BMI trajectory groups were classified according to whether participants experienced weight loss ("decreasing BMI"), weight stability ("stable BMI"), or weight gain ("increasing BMI") during the study. Of the 1673 participants (mean [SD] age, 61.7 [9.6] years; 1074 [64.2%] were male), 158 (9.4%) experienced weight loss (decreasing BMI), whereas 233 (13.9%) experienced weight gain (increasing BMI). After adjusting for covariates, we

  7. The Asthma Control Questionnaire as a clinical trial endpoint

    DEFF Research Database (Denmark)

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

    2014-01-01

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

  8. Secondary Hypertension

    Science.gov (United States)

    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, ...

  9. Modelling survival

    DEFF Research Database (Denmark)

    Ashauer, Roman; Albert, Carlo; Augustine, Starrlight

    2016-01-01

    The General Unified Threshold model for Survival (GUTS) integrates previously published toxicokinetic-toxicodynamic models and estimates survival with explicitly defined assumptions. Importantly, GUTS accounts for time-variable exposure to the stressor. We performed three studies to test...

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

    Science.gov (United States)

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

    2012-10-01

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

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

    Science.gov (United States)

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

    2013-11-01

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

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

    Science.gov (United States)

    Artico, Marco; D'Angelo, Daniela; Piredda, Michela; Petitti, Tommasangelo; Lamarca, Luciano; De Marinis, Maria Grazia; Dante, Angelo; Lusignani, Maura; Matarese, Maria

    2018-07-01

    Patients with advanced illnesses show the highest prevalence for pressure injuries. In the palliative care setting, the ultimate goal is injury healing, but equally important is wound maintenance, wound palliation (wound-related pain and symptom management), and primary and secondary wound prevention. To describe the course of healing for pressure injuries in a home palliative care setting according to different end-points, and to explore patient and caregiver characteristics and specific care activities associated with their achievement. Four-year retrospective chart review of 669 patients cared for in a home palliative care service, of those 124 patients (18.5%) had at least one pressure injury with a survival rate less than or equal to six months. The proportion of healed pressure injuries was 24.4%. Of the injuries not healed, 34.0% were in a maintenance phase, whereas 63.6% were in a process of deterioration. Body mass index (P = 0.0014), artificial nutrition (P = 0.002), and age pay attention to artificial nutrition, continuous deep sedation, and the caregiver's role and gender. Copyright © 2018 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.

  13. A retrospective analysis of survival and prognostic factors after stereotactic radiosurgery for aggressive meningiomas

    International Nuclear Information System (INIS)

    Ferraro, Daniel J; Zoberi, Imran; Simpson, Joseph R; Jaboin, Jerry J; Funk, Ryan K; Blackett, John William; Ju, Michelle R; DeWees, Todd A; Chicoine, Michael R; Dowling, Joshua L; Rich, Keith M; Drzymala, Robert E

    2014-01-01

    While most meningiomas are benign, aggressive meningiomas are associated with high levels of recurrence and mortality. A single institution’s Gamma Knife radiosurgical experience with atypical and malignant meningiomas is presented, stratified by the most recent WHO classification. Thirty-one patients with atypical and 4 patients with malignant meningiomas treated with Gamma Knife radiosurgery between July 2000 and July 2011 were retrospectively reviewed. All patients underwent prior surgical resection. Overall survival was the primary endpoint and rate of disease recurrence in the brain was a secondary endpoint. Patients who had previous radiotherapy or prior surgical resection were included. Kaplan-Meier and Cox proportional hazards models were used to estimate survival and identify factors predictive of recurrence and survival. Post-Gamma Knife recurrence was identified in 11 patients (31.4%) with a median overall survival of 36 months and progression-free survival of 25.8 months. Nine patients (25.7%) had died. Three-year overall survival (OS) and progression-free survival (PFS) rates were 78.0% and 65.0%, respectively. WHO grade II 3-year OS and PFS were 83.4% and 70.1%, while WHO grade III 3-year OS and PFS were 33.3% and 0%. Recurrence rate was significantly higher in patients with a prior history of benign meningioma, nuclear atypia, high mitotic rate, spontaneous necrosis, and WHO grade III diagnosis on univariate analysis; only WHO grade III diagnosis was significant on multivariate analysis. Overall survival was adversely affected in patients with WHO grade III diagnosis, prior history of benign meningioma, prior fractionated radiotherapy, larger tumor volume, and higher isocenter number on univariate analysis; WHO grade III diagnosis and larger treated tumor volume were significant on multivariate analysis. Atypical and anaplastic meningiomas remain difficult tumors to treat. WHO grade III diagnosis and treated tumor volume were significantly

  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

    International Nuclear Information System (INIS)

    Brown-Peterson, Nancy J.; Krasnec, Michelle; Takeshita, Ryan; Ryan, Caitlin N.; Griffitt, Kimberly J.; Lay, Claire; Mayer, Gregory D.; Bayha, Keith M.; Hawkins, William E.; Lipton, Ian; Morris, Jeffrey

    2015-01-01

    Highlights: • Juvenile southern flounder were exposed to sediment mixed with different amount of oil from the Deepwater Horizon spill. • The exposure was performed for 32 days, with growth and survival assessed throughout. • After the termination of the experiment, the survivors were examined at multiple endpoints, including histopathology and microbiome analysis. • The results indicated that the flounder were adversely affected at each endpoint examined. • Growth and survival were significantly reduced. • Histopathology found effects on gills and livers of exposed fish. • The microbiomes of the exposed fish were significantly altered by the exposure to sediment-associated oil in both gills and intestines. - Abstract: Exposure to oiled sediments can negatively impact the health of fish species. Here, we examine the effects of chronic exposure of juvenile southern flounder, Paralichthys lethostigma, to a sediment-oil mixture. Oil:sediment mixtures are persistent over time and can become bioavailable following sediment perturbation or resuspension. Juvenile flounder were exposed for 32 days under controlled laboratory conditions to five concentrations of naturally weathered Macondo MC252 oil mixed into uncontaminated, field-collected sediments. The percent composition of individual polycyclic aromatic hydrocarbons (PAHs) of the weathered oil did not change after mixing with the sediment. Spiked exposure sediments contained 0.04–395 mg/kg tPAH50 (sum of 50 individual PAH concentration measurements). Mortality increased with both exposure duration and concentration of sediment-associated PAHs, and flounder exposed to concentrations above 8 mg/kg tPAH50 showed significantly reduced growth over the course of the experiment. Evident histopathologic changes were observed in liver and gill tissues of fish exposed to more than 8 mg/kg tPAH50. All fish at these concentrations showed hepatic intravascular congestion, macrovesicular hepatic vacoulation

  15. A multiple endpoint analysis of the effects of chronic exposure to sediment contaminated with Deepwater Horizon oil on juvenile Southern flounder and their associated microbiomes

    Energy Technology Data Exchange (ETDEWEB)

    Brown-Peterson, Nancy J., E-mail: nancy.brown-peterson@usm.edu [Department of Coastal Sciences, The University of Southern Mississippi, 703 East Beach Dr., Ocean Springs, MS 39564 (United States); Krasnec, Michelle, E-mail: MKrasnec@stratusconsulting.com [Abt Associates, 1881 Ninth Street, Suite 201, Boulder, Colorado 80302 (United States); Takeshita, Ryan, E-mail: RTakeshita@stratusconsulting.com [Abt Associates, 1881 Ninth Street, Suite 201, Boulder, Colorado 80302 (United States); Ryan, Caitlin N., E-mail: Caitlin.ryan@ttu.edu [The Institute of Environmental and Human Health, Department of Environmental Toxicology, Texas Tech University, Box 41163, Lubbock, TX 79409 (United States); Griffitt, Kimberly J., E-mail: kim.griffitt@gmail.com [Department of Coastal Sciences, The University of Southern Mississippi, 703 East Beach Dr., Ocean Springs, MS 39564 (United States); Lay, Claire, E-mail: claymsc@stratusconsulting.com [Abt Associates, 1881 Ninth Street, Suite 201, Boulder, Colorado 80302 (United States); Mayer, Gregory D., E-mail: greg.mayer@ttu.edu [The Institute of Environmental and Human Health, Department of Environmental Toxicology, Texas Tech University, Box 41163, Lubbock, TX 79409 (United States); Bayha, Keith M., E-mail: kmbayha@gmail.com [Department of Coastal Sciences, The University of Southern Mississippi, 703 East Beach Dr., Ocean Springs, MS 39564 (United States); Hawkins, William E., E-mail: william.hawkins@usm.edu [Department of Coastal Sciences, The University of Southern Mississippi, 703 East Beach Dr., Ocean Springs, MS 39564 (United States); Lipton, Ian, E-mail: ianlipton@stratusconsulting.com [Abt Associates, 1881 Ninth Street, Suite 201, Boulder, Colorado 80302 (United States); Morris, Jeffrey, E-mail: JMorrisMSCanyon252@stratusconsulting.com [Abt Associates, 1881 Ninth Street, Suite 201, Boulder, Colorado 80302 (United States); and others

    2015-08-15

    Highlights: • Juvenile southern flounder were exposed to sediment mixed with different amount of oil from the Deepwater Horizon spill. • The exposure was performed for 32 days, with growth and survival assessed throughout. • After the termination of the experiment, the survivors were examined at multiple endpoints, including histopathology and microbiome analysis. • The results indicated that the flounder were adversely affected at each endpoint examined. • Growth and survival were significantly reduced. • Histopathology found effects on gills and livers of exposed fish. • The microbiomes of the exposed fish were significantly altered by the exposure to sediment-associated oil in both gills and intestines. - Abstract: Exposure to oiled sediments can negatively impact the health of fish species. Here, we examine the effects of chronic exposure of juvenile southern flounder, Paralichthys lethostigma, to a sediment-oil mixture. Oil:sediment mixtures are persistent over time and can become bioavailable following sediment perturbation or resuspension. Juvenile flounder were exposed for 32 days under controlled laboratory conditions to five concentrations of naturally weathered Macondo MC252 oil mixed into uncontaminated, field-collected sediments. The percent composition of individual polycyclic aromatic hydrocarbons (PAHs) of the weathered oil did not change after mixing with the sediment. Spiked exposure sediments contained 0.04–395 mg/kg tPAH50 (sum of 50 individual PAH concentration measurements). Mortality increased with both exposure duration and concentration of sediment-associated PAHs, and flounder exposed to concentrations above 8 mg/kg tPAH50 showed significantly reduced growth over the course of the experiment. Evident histopathologic changes were observed in liver and gill tissues of fish exposed to more than 8 mg/kg tPAH50. All fish at these concentrations showed hepatic intravascular congestion, macrovesicular hepatic vacoulation

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

    Science.gov (United States)

    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

    Directory of Open Access Journals (Sweden)

    Robert D. Chow

    2014-02-01

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

  18. Effects of perineural invasion on biochemical recurrence and prostate cancer-specific survival in patients treated with definitive external beam radiotherapy.

    Science.gov (United States)

    Peng, Luke C; Narang, Amol K; Gergis, Carol; Radwan, Noura A; Han, Peijin; Marciscano, Ariel E; Robertson, Scott P; He, Pei; Trieu, Janson; Ram, Ashwin N; McNutt, Todd R; Griffith, Emily; DeWeese, Theodore A; Honig, Stephanie; Singh, Harleen; Greco, Stephen C; Tran, Phuoc T; Deville, Curtiland; DeWeese, Theodore L; Song, Daniel Y

    2018-03-15

    Perineural invasion (PNI) has not yet gained universal acceptance as an independent predictor of adverse outcomes for prostate cancer treated with external beam radiotherapy (EBRT). We analyzed the prognostic influence of PNI for a large institutional cohort of prostate cancer patients who underwent EBRT with and without androgen deprivation therapy (ADT). We, retrospectively, reviewed prostate cancer patients treated with EBRT from 1993 to 2007 at our institution. The primary endpoint was biochemical failure-free survival (BFFS), with secondary endpoints of metastasis-free survival (MFS), prostate cancer-specific survival (PCSS), and overall survival (OS). Univariate and multivariable Cox proportional hazards models were constructed for all survival endpoints. Hazard ratios for PNI were analyzed for the entire cohort and for subsets defined by NCCN risk level. Additionally, Kaplan-Meier survival curves were generated for all survival endpoints after stratification by PNI status, with significant differences computed using the log-rank test. Of 888 men included for analysis, PNI was present on biopsy specimens in 187 (21.1%). PNI was associated with clinical stage, pretreatment PSA level, biopsy Gleason score, and use of ADT (all P<0.01). Men with PNI experienced significantly inferior 10-year BFFS (40.0% vs. 57.8%, P = 0.002), 10-year MFS (79.7% vs. 89.0%, P = 0.001), and 10-year PCSS (90.9% vs. 95.9%, P = 0.009), but not 10-year OS (67.5% vs. 77.5%, P = 0.07). On multivariate analysis, PNI was independently associated with inferior BFFS (P<0.001), but not MFS, PCSS, or OS. In subset analysis, PNI was associated with inferior BFFS (P = 0.04) for high-risk patients and with both inferior BFFS (P = 0.01) and PCSS (P = 0.05) for low-risk patients. Biochemical failure occurred in 33% of low-risk men with PNI who did not receive ADT compared to 8% for low-risk men with PNI treated with ADT (P = 0.01). PNI was an independently significant predictor of adverse survival

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

    Science.gov (United States)

    Beitz, J

    2001-04-01

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

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

    Science.gov (United States)

    Benda, Norbert; Gerlinger, Christoph

    2007-11-30

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2004-05-18

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

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

    Science.gov (United States)

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

    2017-08-15

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

  3. Exposing the cancer genome atlas as a SPARQL endpoint

    Science.gov (United States)

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

    2011-01-01

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

  4. Overview of Biomarkers and Surrogate Endpoints in Drug Development

    Directory of Open Access Journals (Sweden)

    John A. Wagner

    2002-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Sandberg DavidE

    2010-08-01

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

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

    Directory of Open Access Journals (Sweden)

    Amory Koch

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

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

    International Nuclear Information System (INIS)

    Diatloff-Zito, C.; Loria, E.; Maciera-Coelho, A.; Deschavanne, P.J.; Malaise, E.P.

    1981-01-01

    A comparative study has been made of the radiosensitivity of fibroblastic cell lines from three different animal species: human, mouse and chicken. Endpoints reflecting short term responses were utilized: colony forming ability (CFA), DNA single strand break (SSB) repair and repair of potentially lethal damage (PLD). Regardless of the criterion employed, the response to radiation varies from one species to another. According to survival curves, chicken cells appear to be more radioresistant than those of human and mouse. SSB repair is apparently absent in murine cells, partial in chicken cells and complete in human cells. This lack of correlation between survival curves and SSB repair demonstrates that survival of irradiated cells does not depend only (or at all) on the repair of SSB. The repair of PLD is much more efficient in human and chicken cells than in murine cells. (author)

  8. Final analysis of survival outcomes in the phase 3 FIRST trial of up-front treatment for multiple myeloma.

    Science.gov (United States)

    Facon, Thierry; Dimopoulos, Meletios A; Dispenzieri, Angela; Catalano, John V; Belch, Andrew; Cavo, Michele; Pinto, Antonello; Weisel, Katja; Ludwig, Heinz; Bahlis, Nizar J; Banos, Anne; Tiab, Mourad; Delforge, Michel; Cavenagh, Jamie D; Geraldes, Catarina; Lee, Je-Jung; Chen, Christine; Oriol, Albert; De La Rubia, Javier; White, Darrell; Binder, Daniel; Lu, Jin; Anderson, Kenneth C; Moreau, Philippe; Attal, Michel; Perrot, Aurore; Arnulf, Bertrand; Qiu, Lugui; Roussel, Murielle; Boyle, Eileen; Manier, Salomon; Mohty, Mohamad; Avet-Loiseau, Herve; Leleu, Xavier; Ervin-Haynes, Annette; Chen, Guang; Houck, Vanessa; Benboubker, Lotfi; Hulin, Cyrille

    2018-01-18

    This FIRST trial final analysis examined survival outcomes in patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM) treated with lenalidomide and low-dose dexamethasone until disease progression (Rd continuous), Rd for 72 weeks (18 cycles; Rd18), or melphalan, prednisone, and thalidomide (MPT; 72 weeks). The primary endpoint was progression-free survival (PFS; primary comparison: Rd continuous vs MPT). Overall survival (OS) was a key secondary endpoint (final analysis prespecified ≥60 months' follow-up). Patients were randomized to Rd continuous (n = 535), Rd18 (n = 541), or MPT (n = 547). At a median follow-up of 67 months, PFS was significantly longer with Rd continuous vs MPT (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.59-0.79; P < .00001) and was similarly extended vs Rd18. Median OS was 10 months longer with Rd continuous vs MPT (59.1 vs 49.1 months; HR, 0.78; 95% CI, 0.67-0.92; P = .0023), and similar with Rd18 (62.3 months). In patients achieving complete or very good partial responses, Rd continuous had an ≈30-month longer median time to next treatment vs Rd18 (69.5 vs 39.9 months). Over half of all patients who received second-line treatment were given a bortezomib-based therapy. Second-line outcomes were improved in patients receiving bortezomib after Rd continuous and Rd18 vs after MPT. No new safety concerns, including risk for secondary malignancies, were observed. Treatment with Rd continuous significantly improved survival outcomes vs MPT, supporting Rd continuous as a standard of care for patients with transplant-ineligible NDMM. This trial was registered at www.clinicaltrials.gov as #NCT00689936 and EudraCT as 2007-004823-39. © 2018 by The American Society of Hematology.

  9. Guidelines for time-to-event end point definitions in breast cancer trials: results of the DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials)†.

    Science.gov (United States)

    Gourgou-Bourgade, S; Cameron, D; Poortmans, P; Asselain, B; Azria, D; Cardoso, F; A'Hern, R; Bliss, J; Bogaerts, J; Bonnefoi, H; Brain, E; Cardoso, M J; Chibaudel, B; Coleman, R; Cufer, T; Dal Lago, L; Dalenc, F; De Azambuja, E; Debled, M; Delaloge, S; Filleron, T; Gligorov, J; Gutowski, M; Jacot, W; Kirkove, C; MacGrogan, G; Michiels, S; Negreiros, I; Offersen, B V; Penault Llorca, F; Pruneri, G; Roche, H; Russell, N S; Schmitt, F; Servent, V; Thürlimann, B; Untch, M; van der Hage, J A; van Tienhoven, G; Wildiers, H; Yarnold, J; Bonnetain, F; Mathoulin-Pélissier, S; Bellera, C; Dabakuyo-Yonli, T S

    2015-05-01

    Using surrogate end points for overall survival, such as disease-free survival, is increasingly common in randomized controlled trials. However, the definitions of several of these time-to-event (TTE) end points are imprecisely which limits interpretation and cross-trial comparisons. The estimation of treatment effects may be directly affected by the definitions of end points. The DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials) aims to provide recommendations for definitions of TTE end points. We report guidelines for randomized cancer clinical trials (RCTs) in breast cancer. A literature review was carried out to identify TTE end points (primary or secondary) reported in publications of randomized trials or guidelines. An international multidisciplinary panel of experts proposed recommendations for the definitions of these end points based on a validated consensus method that formalize the degree of agreement among experts. Recommended guidelines for the definitions of TTE end points commonly used in RCTs for breast cancer are provided for non-metastatic and metastatic settings. The use of standardized definitions should facilitate comparisons of trial results and improve the quality of trial design and reporting. These guidelines could be of particular interest to those involved in the design, conducting, reporting, or assessment of RCT. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

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

    Science.gov (United States)

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

    2010-12-01

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

  11. Two-temperature LATE-PCR endpoint genotyping

    Directory of Open Access Journals (Sweden)

    Reis Arthur H

    2006-12-01

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

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

    Science.gov (United States)

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

    2014-08-12

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

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

    Science.gov (United States)

    Lin, Ray F; Drury, Colin G

    2013-01-01

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

  14. Imaging biomarkers as surrogate endpoints for drug development

    International Nuclear Information System (INIS)

    Richter, Wolf S.

    2006-01-01

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

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

    Science.gov (United States)

    Kolamunnage-Dona, Ruwanthi; Williamson, Paula R

    2018-06-01

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

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

    Directory of Open Access Journals (Sweden)

    Zhuo Min

    2011-07-01

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

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

    Science.gov (United States)

    2007-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Eliedonna Cacao

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

  19. Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis.

    Science.gov (United States)

    Yardley, Denise A; Noguchi, Shinzaburo; Pritchard, Kathleen I; Burris, Howard A; Baselga, José; Gnant, Michael; Hortobagyi, Gabriel N; Campone, Mario; Pistilli, Barbara; Piccart, Martine; Melichar, Bohuslav; Petrakova, Katarina; Arena, Francis P; Erdkamp, Frans; Harb, Wael A; Feng, Wentao; Cahana, Ayelet; Taran, Tetiana; Lebwohl, David; Rugo, Hope S

    2013-10-01

    Effective treatments for hormone-receptor-positive (HR(+)) breast cancer (BC) following relapse/progression on nonsteroidal aromatase inhibitor (NSAI) therapy are needed. Initial Breast Cancer Trials of OraL EveROlimus-2 (BOLERO-2) trial data demonstrated that everolimus and exemestane significantly prolonged progression-free survival (PFS) versus placebo plus exemestane alone in this patient population. BOLERO-2 is a phase 3, double-blind, randomized, international trial comparing everolimus (10 mg/day) plus exemestane (25 mg/day) versus placebo plus exemestane in postmenopausal women with HR(+) advanced BC with recurrence/progression during or after NSAIs. The primary endpoint was PFS by local investigator review, and was confirmed by independent central radiology review. Overall survival, response rate, and clinical benefit rate were secondary endpoints. Final study results with median 18-month follow-up show that median PFS remained significantly longer with everolimus plus exemestane versus placebo plus exemestane [investigator review: 7.8 versus 3.2 months, respectively; hazard ratio = 0.45 (95% confidence interval 0.38-0.54); log-rank P NSAIs. These results further support the use of everolimus plus exemestane in this patient population. ClinicalTrials.gov #NCT00863655.

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

    International Nuclear Information System (INIS)

    Bojtor, I.; Koeteles, G.J.

    1998-01-01

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

  1. Hausdorff dimension of exponential parameter rays and their endpoints

    International Nuclear Information System (INIS)

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

    2008-01-01

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

  2. Biomarkers of intermediate endpoints in environmental and occupational health

    DEFF Research Database (Denmark)

    Knudsen, Lisbeth E; Hansen, Ase M

    2007-01-01

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

  3. Efficacy Endpoints of Radiation Therapy Group Protocol 0247: A Randomized, Phase 2 Study of Neoadjuvant Radiation Therapy Plus Concurrent Capecitabine and Irinotecan or Capecitabine and Oxaliplatin for Patients With Locally Advanced Rectal Cancer

    International Nuclear Information System (INIS)

    Wong, Stuart J.; Moughan, Jennifer; Meropol, Neal J.; Anne, Pramila Rani; Kachnic, Lisa A.; Rashid, Asif; Watson, James C.; Mitchell, Edith P.; Pollock, Jondavid; Lee, R. Jeffrey; Haddock, Michael; Erickson, Beth A.; Willett, Christopher G.

    2015-01-01

    Purpose: To report secondary efficacy endpoints of Radiation Therapy Oncology Group protocol 0247, primary endpoint analysis of which demonstrated that preoperative radiation therapy (RT) with capecitabine plus oxaliplatin achieved a pathologic complete remission prespecified threshold (21%) to merit further study, whereas RT with capecitabine plus irinotecan did not (10%). Methods and Materials: A randomized, phase 2 trial evaluated preoperative RT (50.4 Gy in 1.8-Gy fractions) with 2 concurrent chemotherapy regimens: (1) capecitabine (1200 mg/m 2 /d Monday-Friday) plus irinotecan (50 mg/m 2 /wk × 4); and (2) capecitabine (1650 mg/m 2 /d Monday-Friday) plus oxaliplatin (50 mg/m 2 /wk × 5) for clinical T3 or T4 rectal cancer. Surgery was performed 4 to 8 weeks after chemoradiation, then 4 to 6 weeks later, adjuvant chemotherapy (oxaliplatin 85 mg/m 2 ; leucovorin 400 mg/m 2 ; 5-fluorouracil 400 mg/m 2 ; 5-fluorouracil 2400 mg/m 2 ) every 2 weeks × 9. Disease-free survival (DFS) and overall survival (OS) were estimated univariately by the Kaplan-Meier method. Local–regional failure (LRF), distant failure (DF), and second primary failure (SP) were estimated by the cumulative incidence method. No statistical comparisons were made between arms because each was evaluated individually. Results: A total of 104 patients (median age, 57 years) were treated; characteristics were similar for both arms. Median follow-up for RT with capecitabine/irinotecan arm was 3.77 years and for RT with capecitabine/oxaliplatin arm was 3.97 years. Four-year DFS, OS, LRF, DF, and SP estimates for capecitabine/irinotecan arm were 68%, 85%, 16%, 24%, and 2%, respectively. The 4-year DFS, OS, LRF, DF, and SP failure estimates for capecitabine/oxaliplatin arm were 62%, 75%, 18%, 30%, and 6%, respectively. Conclusions: Efficacy results for both arms are similar to other reported studies but suggest that pathologic complete remission is an unsuitable surrogate for

  4. Efficacy Endpoints of Radiation Therapy Group Protocol 0247: A Randomized, Phase 2 Study of Neoadjuvant Radiation Therapy Plus Concurrent Capecitabine and Irinotecan or Capecitabine and Oxaliplatin for Patients With Locally Advanced Rectal Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Wong, Stuart J. [Medical College of Wisconsin, Madison, Wisconsin (United States); Moughan, Jennifer [Radiation Therapy Oncology Group Statistical Center, Philadelphia, Pennsylvania (United States); Meropol, Neal J., E-mail: Neal.Meropol@case.edu [University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio (United States); Anne, Pramila Rani [Department of Radiation Oncology and Medical Oncology, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania (United States); Kachnic, Lisa A. [Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts (United States); Rashid, Asif [Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Watson, James C. [Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania (United States); Mitchell, Edith P. [Department of Radiation Oncology and Medical Oncology, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania (United States); Pollock, Jondavid [The Schiffler Cancer Center, Wheeling, West Virginia (United States); Lee, R. Jeffrey [Intermountain Medical Center, Murray, Utah (United States); Haddock, Michael [Division of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States); Erickson, Beth A. [Medical College of Wisconsin, Madison, Wisconsin (United States); Willett, Christopher G. [Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina (United States)

    2015-01-01

    Purpose: To report secondary efficacy endpoints of Radiation Therapy Oncology Group protocol 0247, primary endpoint analysis of which demonstrated that preoperative radiation therapy (RT) with capecitabine plus oxaliplatin achieved a pathologic complete remission prespecified threshold (21%) to merit further study, whereas RT with capecitabine plus irinotecan did not (10%). Methods and Materials: A randomized, phase 2 trial evaluated preoperative RT (50.4 Gy in 1.8-Gy fractions) with 2 concurrent chemotherapy regimens: (1) capecitabine (1200 mg/m{sup 2}/d Monday-Friday) plus irinotecan (50 mg/m{sup 2}/wk × 4); and (2) capecitabine (1650 mg/m{sup 2}/d Monday-Friday) plus oxaliplatin (50 mg/m{sup 2}/wk × 5) for clinical T3 or T4 rectal cancer. Surgery was performed 4 to 8 weeks after chemoradiation, then 4 to 6 weeks later, adjuvant chemotherapy (oxaliplatin 85 mg/m{sup 2}; leucovorin 400 mg/m{sup 2}; 5-fluorouracil 400 mg/m{sup 2}; 5-fluorouracil 2400 mg/m{sup 2}) every 2 weeks × 9. Disease-free survival (DFS) and overall survival (OS) were estimated univariately by the Kaplan-Meier method. Local–regional failure (LRF), distant failure (DF), and second primary failure (SP) were estimated by the cumulative incidence method. No statistical comparisons were made between arms because each was evaluated individually. Results: A total of 104 patients (median age, 57 years) were treated; characteristics were similar for both arms. Median follow-up for RT with capecitabine/irinotecan arm was 3.77 years and for RT with capecitabine/oxaliplatin arm was 3.97 years. Four-year DFS, OS, LRF, DF, and SP estimates for capecitabine/irinotecan arm were 68%, 85%, 16%, 24%, and 2%, respectively. The 4-year DFS, OS, LRF, DF, and SP failure estimates for capecitabine/oxaliplatin arm were 62%, 75%, 18%, 30%, and 6%, respectively. Conclusions: Efficacy results for both arms are similar to other reported studies but suggest that pathologic complete remission is an

  5. Survival Analysis

    CERN Document Server

    Miller, Rupert G

    2011-01-01

    A concise summary of the statistical methods used in the analysis of survival data with censoring. Emphasizes recently developed nonparametric techniques. Outlines methods in detail and illustrates them with actual data. Discusses the theory behind each method. Includes numerous worked problems and numerical exercises.

  6. [Secondary hypertension].

    Science.gov (United States)

    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.

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

    Science.gov (United States)

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

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

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

    DEFF Research Database (Denmark)

    Christiansen, Sofie

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

  9. Secondary Evaluations.

    Science.gov (United States)

    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,…

  10. Carbonaceous Survivability on Impact

    Science.gov (United States)

    Bunch, T. E.; Becker, Luann; Morrison, David (Technical Monitor)

    1994-01-01

    In order to gain knowledge about the potential contributions of comets and cosmic dust to the origin of life on Earth, we need to explore the survivability of their potential organic compounds on impact and the formation of secondary products that may have arisen from the chaotic events sustained by the carriers as they fell to Earth. We have performed a series of hypervelocity impact experiments using carbon-bearing impactors (diamond, graphite, kerogens, PAH crystals, and Murchison and Nogoya meteorites) into Al plate targets at velocities - 6 km/s. Estimated peak shock pressures probably did not exceed 120 GPa and peak shock temperatures were probably less than 4000 K for times of nano- to microsecs. Nominal crater dia. are less than one mm. The most significant results of these experiments are the preservation of the higher mass PAHs (e. g., pyrene relative to napthalene) and the formation of additional alkylated PAHs. We have also examined the residues of polystyrene projectiles impacted by a microparticle accelerator into targets at velocities up to 15 km/s. This talk will discuss the results of these experiments and their implications with respect to the survival of carbonaceous deliverables to early Earth. The prospects of survivability of organic molecules on "intact" capture of cosmic dust in space via soft: and hard cosmic dust collectors will also be discussed.

  11. Adding Erlotinib to Chemoradiation Improves Overall Survival but Not Progression-Free Survival in Stage III Non-Small Cell Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Komaki, Ritsuko, E-mail: rkomaki@mdanderson.org [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Allen, Pamela K.; Wei, Xiong [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Blumenschein, George R. [Department of Thoracic Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Tang, Ximing [Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Lee, J. Jack [Department of Biostatatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Welsh, James W. [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Wistuba, Ignacio I. [Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Liu, Diane D. [Department of Biostatatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Hong, Waun Ki [Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States)

    2015-06-01

    Purpose: To test, in a single-arm, prospective, phase 2 trial, whether adding the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib to concurrent chemoradiotherapy for previously untreated, locally advanced, inoperable non-small cell lung cancer would improve survival and disease control without increasing toxicity. Methods and Materials: Forty-eight patients with previously untreated non-small cell lung cancer received intensity modulated radiation therapy (63 Gy/35 fractions) on Monday through Friday, with chemotherapy (paclitaxel 45 mg/m², carboplatin area under the curve [AUC] = 2) on Mondays, for 7 weeks. All patients also received the EGFR tyrosine kinase inhibitor erlotinib (150 mg orally 1/d) on Tuesday-Sunday for 7 weeks, followed by consolidation paclitaxel–carboplatin. The primary endpoint was time to progression; secondary endpoints were overall survival (OS), toxicity, response, and disease control and whether any endpoint differed by EGFR mutation status. Results: Of 46 patients evaluable for response, 40 were former or never-smokers, and 41 were evaluable for EGFR mutations (37 wild-type [WT] and 4 mutated [all adenocarcinoma]). Median time to progression was 14.0 months and did not differ by EGFR status. Toxicity was acceptable (no grade 5, 1 grade 4, 11 grade 3). Twelve patients (26%) had complete responses (10 WT, 2 mutated), 27 (59%) partial (21 WT, 2 mutated, 4 unknown), and 7 (15%) none (6 WT, 2 mutated, 1 unknown) (P=.610). At 37.0 months' follow-up (range, 3.6-76.5 months) for all patients, median OS time was 36.5 months, and 1-, 2-, and 5-year OS rates were 82.6%, 67.4%, and 35.9%, respectively; none differed by mutation status. Twelve patients had no progression, and 34 had local and/or distant failure. Eleven of 27 distant failures were in the brain (7 WT, 3 mutated, 1 unknown). Conclusions: Toxicity and OS were promising, but time to progression did not meet expectations. The prevalence of

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

    NARCIS (Netherlands)

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

    2011-01-01

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

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

    Indian Academy of Sciences (India)

    2017-10-09

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

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

    Science.gov (United States)

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

    2014-01-01

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

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

    Science.gov (United States)

    Daniel C. Dey; Callie Jo. Schweitzer

    2014-01-01

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

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

    Science.gov (United States)

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

    2018-03-08

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

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

    Science.gov (United States)

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

    2017-10-01

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

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

    Science.gov (United States)

    Wilson, Heather L; Tran, Thomas; Druce, Julian; Dupont-Rouzeyrol, Myrielle; Catton, Michael

    2017-10-01

    The global spread and infective complications of Zika virus (ZKV) and dengue virus (DENV) have made them flaviviruses of public health concern. Serological diagnosis can be challenging due to antibody cross-reactivity, particularly in secondary flavivirus infections or when there is a history of flavivirus vaccination. The virus neutralization assay is considered to be the most specific assay for measurement of anti-flavivirus antibodies. This study describes an assay where the neutralization endpoint is measured by real-time PCR, providing results within 72 h. It demonstrated 100% sensitivity (24/24 ZKV and 15/15 DENV) and 100% specificity (11/11 specimens) when testing well-characterized sera. In addition, the assay was able to determine the correct DENV serotype in 91.7% of cases. The high sensitivity and specificity of the real-time PCR neutralization assay makes it suitable to use as a confirmatory test for sera that are reactive in commercial IgM/IgG enzyme immunoassays. Results are objective and the PCR-based measurement of the neutralization endpoint lends itself to automation so that throughput may be increased in times of high demand. Copyright © 2017 American Society for Microbiology.

  19. Secondary Headaches

    Science.gov (United States)

    ... 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 ...

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

    Science.gov (United States)

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

    2000-09-08

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2017-01-01

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

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

    Science.gov (United States)

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

    2013-03-11

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

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

    Science.gov (United States)

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

    2018-05-01

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

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

    Science.gov (United States)

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

    2017-10-05

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

  5. Effects of dietary uranium on reproductive endpoints--fecundity, survival, reproductive success--of the fish Danio rerio.

    Science.gov (United States)

    Simon, Olivier; Mottin, Elmina; Geffroy, Benjamin; Hinton, Thomas

    2011-01-01

    Exposure to metal-contaminated water has been shown to result in a number of reproductive abnormalities in adult and larvae fish, such as failure of oocyte maturation and teratogenic effects. Recently, dietary uptake of metals by fish has been recognized as a critical route of exposure, however, the mechanisms of metal uptake and toxicity are poorly understood and in need of further investigation. The objectives of the present study are to quantify uranium (U dietary transfers from spiked artificial diets) in Danio rerio tissues and embryos, as well as establish its effect on reproduction and embryonic development. Uranium's environmental prominence is currently increasing because of new mining and milling activities. Uranium concentrations range from 0.02 µg/L in natural waters to 2 mg/L. The focus of this study was to examine the trophic transfer and effects of U following exposure modalities (dose, exposure duration 1 to 20 d). Two different isotopes were used to distinguish between chemical and radioactivity toxicity of U. Results showed that U trophic transfer was low (0.52%). Uranium tissue distributions showed that accumulation occurred in digestive organs (liver, digestive tract) following dietary exposure. High levels of U were measured in the gonads (female in particular, >20% of relative burden). High U accumulation levels in eggs indicated maternal transfer of the contaminant. Moreover, U trophic exposure led to a reduction in reproduction success as a function of U accumulated levels. High U exposure conditions strongly reduced the total number of eggs (50%) and their viability at 10 d (reduction of the clutch number, low quality of eggs). © 2010 SETAC.

  6. Instrumental variables estimation of exposure effects on a time-to-event endpoint using structural cumulative survival models

    DEFF Research Database (Denmark)

    Martinussen, Torben; Vansteelandt, Stijn; Tchetgen Tchetgen, Eric J.

    2017-01-01

    The use of instrumental variables for estimating the effect of an exposure on an outcome is popular in econometrics, and increasingly so in epidemiology. This increasing popularity may be attributed to the natural occurrence of instrumental variables in observational studies that incorporate elem...

  7. IMRT for Sinonasal Tumors Minimizes Severe Late Ocular Toxicity and Preserves Disease Control and Survival

    International Nuclear Information System (INIS)

    Duprez, Fréderic; Madani, Indira; Morbée, Lieve; Bonte, Katrien; Deron, Philippe; Domján, Vilmos; Boterberg, Tom; De Gersem, Werner; De Neve, Wilfried

    2012-01-01

    Purpose: To report late ocular (primary endpoint) and other toxicity, disease control, and survival (secondary endpoints) after intensity-modulated radiotherapy (IMRT) for sinonasal tumors. Methods and Materials: Between 1998 and 2009, 130 patients with nonmetastatic sinonasal tumors were treated with IMRT at Ghent University Hospital. Prescription doses were 70 Gy (n = 117) and 60–66 Gy (n = 13) at 2 Gy per fraction over 6–7 weeks. Most patients had adenocarcinoma (n = 82) and squamous cell carcinoma (n = 23). One hundred and one (101) patients were treated postoperatively. Of 17 patients with recurrent tumors, 9 were reirradiated. T-stages were T1–2 (n = 39), T3 (n = 21), T4a (n = 38), and T4b (n = 22). Esthesioneuroblastoma was staged as Kadish A, B, and C in 1, 3, and 6 cases, respectively. Results: Median follow-up was 52, range 15–121 months. There was no radiation-induced blindness in 86 patients available for late toxicity assessment (≥6 month follow-up). We observed late Grade 3 tearing in 10 patients, which reduced to Grade 1–2 in 5 patients and Grade 3 visual impairment because of radiation-induced ipsilateral retinopathy and neovascular glaucoma in 1 patient. There was no severe dry eye syndrome. The worst grade of late ocular toxicity was Grade 3 (n = 11), Grade 2 (n = 31), Grade 1 (n = 33), and Grade 0 (n = 11). Brain necrosis and osteoradionecrosis occurred in 6 and 1 patients, respectively. Actuarial 5-year local control and overall survival were 59% and 52%, respectively. On multivariate analysis local control was negatively affected by cribriform plate and brain invasion (p = 0.044 and 0.029, respectively) and absence of surgery (p = 0.009); overall survival was negatively affected by cribriform plate and orbit invasion (p = 0.04 and <0.001, respectively) and absence of surgery (p = 0.001). Conclusions: IMRT for sinonasal tumors allowed delivering high doses to targets at minimized ocular toxicity, while maintaining disease control and

  8. IMRT for Sinonasal Tumors Minimizes Severe Late Ocular Toxicity and Preserves Disease Control and Survival

    Energy Technology Data Exchange (ETDEWEB)

    Duprez, Frederic, E-mail: frederic.duprez@ugent.be [Department of Radiotherapy, Ghent University Hospital, Ghent (Belgium); Madani, Indira; Morbee, Lieve [Department of Radiotherapy, Ghent University Hospital, Ghent (Belgium); Bonte, Katrien; Deron, Philippe; Domjan, Vilmos [Department of Head and Neck Surgery, Ghent University Hospital, Ghent (Belgium); Boterberg, Tom; De Gersem, Werner; De Neve, Wilfried [Department of Radiotherapy, Ghent University Hospital, Ghent (Belgium)

    2012-05-01

    Purpose: To report late ocular (primary endpoint) and other toxicity, disease control, and survival (secondary endpoints) after intensity-modulated radiotherapy (IMRT) for sinonasal tumors. Methods and Materials: Between 1998 and 2009, 130 patients with nonmetastatic sinonasal tumors were treated with IMRT at Ghent University Hospital. Prescription doses were 70 Gy (n = 117) and 60-66 Gy (n = 13) at 2 Gy per fraction over 6-7 weeks. Most patients had adenocarcinoma (n = 82) and squamous cell carcinoma (n = 23). One hundred and one (101) patients were treated postoperatively. Of 17 patients with recurrent tumors, 9 were reirradiated. T-stages were T1-2 (n = 39), T3 (n = 21), T4a (n = 38), and T4b (n = 22). Esthesioneuroblastoma was staged as Kadish A, B, and C in 1, 3, and 6 cases, respectively. Results: Median follow-up was 52, range 15-121 months. There was no radiation-induced blindness in 86 patients available for late toxicity assessment ({>=}6 month follow-up). We observed late Grade 3 tearing in 10 patients, which reduced to Grade 1-2 in 5 patients and Grade 3 visual impairment because of radiation-induced ipsilateral retinopathy and neovascular glaucoma in 1 patient. There was no severe dry eye syndrome. The worst grade of late ocular toxicity was Grade 3 (n = 11), Grade 2 (n = 31), Grade 1 (n = 33), and Grade 0 (n = 11). Brain necrosis and osteoradionecrosis occurred in 6 and 1 patients, respectively. Actuarial 5-year local control and overall survival were 59% and 52%, respectively. On multivariate analysis local control was negatively affected by cribriform plate and brain invasion (p = 0.044 and 0.029, respectively) and absence of surgery (p = 0.009); overall survival was negatively affected by cribriform plate and orbit invasion (p = 0.04 and <0.001, respectively) and absence of surgery (p = 0.001). Conclusions: IMRT for sinonasal tumors allowed delivering high doses to targets at minimized ocular toxicity, while maintaining disease control and survival

  9. Similar long-term survival of consecutive in-hospital and out-of-hospital cardiac arrest patients treated with targeted temperature management

    Directory of Open Access Journals (Sweden)

    Engsig M

    2016-11-01

    Full Text Available Magaly Engsig,1 Helle Søholm,2 Fredrik Folke,3,4 Peter J Gadegaard,1 Julie Therese Wiis,5 Rune Molin,6 Thomas Mohr,1 Frederik N Engsig7 1Department of Anaesthesiology and Intensive Care, Copenhagen University Hospital, Hellerup, 2Department of Cardiology, Copenhagen University Hospital, Herlev, 3Department of Cardiology, Copenhagen University Hospital, Hellerup, 4Pre-Hospital Emergency Medical Services, Capital Region of Denmark, Ballerup, 5Department of Intensive Care, Copenhagen University Hospital, Copenhagen, 6Department of Anaesthesiology, Copenhagen University Hospital, Hillerød, 7Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Denmark Objective: The long-term survival of in-hospital cardiac arrest (IHCA patients treated with targeted temperature management (TTM is poorly described. The aim of this study was to compare the outcomes of consecutive IHCA with out-of-hospital cardiac arrest (OHCA patients treated with TTM. Design, setting, and patients: Retrospectively collected data on all consecutive adult patients treated with TTM at a university tertiary heart center between 2005 and 2011 were analyzed. Measurements: Primary endpoints were survival to hospital discharge and long-term survival. Secondary endpoint was neurological outcome assessed using the Pittsburgh cerebral performance category (CPC. Results: A total of 282 patients were included in this study; 233 (83% OHCA and 49 (17% IHCA. The IHCA group presented more often with asystole, received bystander cardiopulmonary resuscitation (CPR in all cases, and had shorter time to return of spontaneous circulation (ROSC. Survival to hospital discharge was 54% for OHCA and 53% for IHCA (adjusted odds ratio 0.98 [95% confidence interval {CI}; 0.43–2.24]. Age ≤60 years, bystander CPR, time to ROSC ≤10 min, and shockable rhythm at presentation were associated with survival to hospital discharge. Good neurologic outcome among survivors was achieved by 86

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

    International Nuclear Information System (INIS)

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

    2010-01-01

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

  11. 78 FR 49530 - Gastroenterology Regulatory Endpoints and the Advancement of Therapeutics; Public Workshop

    Science.gov (United States)

    2013-08-14

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

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

    Directory of Open Access Journals (Sweden)

    Stepanov Vladimir

    1997-01-01

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

  13. 76 FR 51993 - Draft Guidance for Industry on Standards for Clinical Trial Imaging Endpoints; Availability

    Science.gov (United States)

    2011-08-19

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

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

    DEFF Research Database (Denmark)

    Lifson, A; Rhame, F; Bellosa, W

    2006-01-01

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

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

    OpenAIRE

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

    2016-01-01

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

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

    Science.gov (United States)

    Krischer, Jeffrey P

    2013-09-01

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

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

    Science.gov (United States)

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

    2018-06-19

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

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

    Science.gov (United States)

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

    2009-02-01

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

  19. Is progression-free survival a more relevant endpoint than overall survival in first-line HR+/HER2− metastatic breast cancer?

    OpenAIRE

    Forsythe A; Chandiwana D; Barth J; Thabane M; Baeck J; Shor A; Tremblay G

    2018-01-01

    Anna Forsythe,1 David Chandiwana,2 Janina Barth,3 Marroon Thabane,4 Johan Baeck,5 Anastasiya Shor,1 Gabriel Tremblay6 1Health Technology Assessment Evidence, Purple Squirrel Economics, New York, NY, USA; 2Global Value and Access, Novartis Pharmaceutical Corporation, East Hanover, NJ, USA; 3German Market Access, Novartis Pharma GmbH, Nuremberg, Germany; 4Health Policy and Patient Access, Novartis Pharmaceuticals Incorporated, Dorval, QC, Canada; 5Global Medical Affairs (Oncology Business Unit)...

  20. Is progression-free survival a more relevant endpoint than overall survival in first-line HR+/HER2− metastatic breast cancer?

    OpenAIRE

    Forsythe,Anna; Chandiwana,David; Barth,Janina; Thabane,Marroon; Baeck,Johan; Shor,Anastasiya; Tremblay,Gabriel

    2018-01-01

    Anna Forsythe,1 David Chandiwana,2 Janina Barth,3 Marroon Thabane,4 Johan Baeck,5 Anastasiya Shor,1 Gabriel Tremblay6 1Health Technology Assessment Evidence, Purple Squirrel Economics, New York, NY, USA; 2Global Value and Access, Novartis Pharmaceutical Corporation, East Hanover, NJ, USA; 3German Market Access, Novartis Pharma GmbH, Nuremberg, Germany; 4Health Policy and Patient Access, Novartis Pharmaceuticals Incorporated, Dorval, QC, Canada; 5Global Medical Affairs (Oncology Business Unit)...

  1. Restenosis after carotid artery stenting and endarterectomy: a secondary analysis of CREST, a randomised controlled trial.

    Science.gov (United States)

    Lal, Brajesh K; Beach, Kirk W; Roubin, Gary S; Lutsep, Helmi L; Moore, Wesley S; Malas, Mahmoud B; Chiu, David; Gonzales, Nicole R; Burke, J Lee; Rinaldi, Michael; Elmore, James R; Weaver, Fred A; Narins, Craig R; Foster, Malcolm; Hodgson, Kim J; Shepard, Alexander D; Meschia, James F; Bergelin, Robert O; Voeks, Jenifer H; Howard, George; Brott, Thomas G

    2012-09-01

    In the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST), the composite primary endpoint of stroke, myocardial infarction, or death during the periprocedural period or ipsilateral stroke thereafter did not differ between carotid artery stenting and carotid endarterectomy for symptomatic or asymptomatic carotid stenosis. A secondary aim of this randomised trial was to compare the composite endpoint of restenosis or occlusion. Patients with stenosis of the carotid artery who were asymptomatic or had had a transient ischaemic attack, amaurosis fugax, or a minor stroke were eligible for CREST and were enrolled at 117 clinical centres in the USA and Canada between Dec 21, 2000, and July 18, 2008. In this secondary analysis, the main endpoint was a composite of restenosis or occlusion at 2 years. Restenosis and occlusion were assessed by duplex ultrasonography at 1, 6, 12, 24, and 48 months and were defined as a reduction in diameter of the target artery of at least 70%, diagnosed by a peak systolic velocity of at least 3·0 m/s. Studies were done in CREST-certified laboratories and interpreted at the Ultrasound Core Laboratory (University of Washington). The frequency of restenosis was calculated by Kaplan-Meier survival estimates and was compared during a 2-year follow-up period. We used proportional hazards models to assess the association between baseline characteristics and risk of restenosis. Analyses were per protocol. CREST is registered with ClinicalTrials.gov, number NCT00004732. 2191 patients received their assigned treatment within 30 days of randomisation and had eligible ultrasonography (1086 who had carotid artery stenting, 1105 who had carotid endarterectomy). In 2 years, 58 patients who underwent carotid artery stenting (Kaplan-Meier rate 6·0%) and 62 who had carotid endarterectomy (6·3%) had restenosis or occlusion (hazard ratio [HR] 0·90, 95% CI 0·63-1·29; p=0·58). Female sex (1·79, 1·25-2·56), diabetes (2·31, 1·61-3·31

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

    International Nuclear Information System (INIS)

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

    2010-01-01

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

  3. Secondary osteoporosis.

    Science.gov (United States)

    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

  4. Secondary osteoporosis.

    Science.gov (United States)

    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

  5. Evolution of a pseudogene: exclusive survival of a functional mitochondrial nad7 gene supports Haplomitrium as the earliest liverwort lineage and proposes a secondary loss of RNA editing in Marchantiidae.

    Science.gov (United States)

    Groth-Malonek, Milena; Wahrmund, Ute; Polsakiewicz, Monika; Knoop, Volker

    2007-04-01

    Gene transfer from the mitochondrion into the nucleus is a corollary of the endosymbiont hypothesis. The frequent and independent transfer of genes for mitochondrial ribosomal proteins is well documented with many examples in angiosperms, whereas transfer of genes for components of the respiratory chain is a rarity. A notable exception is the nad7 gene, encoding subunit 7 of complex I, in the liverwort Marchantia polymorpha, which resides as a full-length, intron-carrying and transcribed, but nonspliced pseudogene in the chondriome, whereas its functional counterpart is nuclear encoded. To elucidate the patterns of pseudogene degeneration, we have investigated the mitochondrial nad7 locus in 12 other liverworts of broad phylogenetic distribution. We find that the mitochondrial nad7 gene is nonfunctional in 11 of them. However, the modes of pseudogene degeneration vary: whereas point mutations, accompanied by single-nucleotide indels, predominantly introduce stop codons into the reading frame in marchantiid liverworts, larger indels introduce frameshifts in the simple thalloid and leafy jungermanniid taxa. Most notably, however, the mitochondrial nad7 reading frame appears to be intact in the isolated liverwort genus Haplomitrium. Its functional expression is shown by cDNA analysis identifying typical RNA-editing events to reconstitute conserved codon identities and also confirming functional splicing of the 2 liverwort-specific group II introns. We interpret our results 1) to indicate the presence of a functional mitochondrial nad7 gene in the earliest land plants and strongly supporting a basal placement of Haplomitrium among the liverworts, 2) to indicate different modes of pseudogene degeneration and chondriome evolution in the later branching liverwort clades, 3) to suggest a surprisingly long maintenance of a nonfunctional gene in the presumed oldest group of land plants, and 4) to support the model of a secondary loss of RNA-editing activity in marchantiid

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

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

    Science.gov (United States)

    Zakour, Sihem Ben; Taleb, Hassen

    2017-09-01

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

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

    Directory of Open Access Journals (Sweden)

    Zhendong Yang

    2015-12-01

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

  9. The subset of patients with acute heart failure able to secrete relaxin-2 at pregnancy concentrations could have a longer survival: a pilot study.

    Science.gov (United States)

    Miró, Òscar; Herrero-Puente, Pablo; Prieto, Belén; García-García, María; García-Hernández, Pablo; Martín-Sánchez, Francisco J; Jacob, Javier; Ríos, José; Romero, Rodolfo; Gil, Víctor; Gayat, Étienne; Llorens, Pere; Mebazaa, Alexandre

    2018-05-01

    To investigate how many patients with acute heart failure (AHF) hypersecrete relaxin-2 concentrations similar to those of pregnant women and determine their long-term outcome. In consecutive AHF patients relaxin-2 was quantified by ELISA sandwich method. Patients were divided into pregnancy-like group (PLG, relaxin-2 ≥ 500 pg/mL) and control group (CG, relaxin-2 10 days), combined endpoint (death, rehospitalisation, ED revisit) 30 days after discharge, and 30-day, one-year and three-year death rates. We included 814 patients [81 (SD = 9) years; 53.0% women] followed during 1.9 (SD 2.8) years; 517 (63.5%) died. Twenty patients (2.5%) formed the PLG (median relaxin-2 = 1459 pg/mL; IQR = 1722) and 794 the CG (median = 26; IQR = 44). There was no interaction with variables included on adjustment (age, sex, ischaemic cardiomyopathy, NT-proBNP, glycaemia, and sodium). PLG patients did not have better short-term secondary endpoints, but did show a significantly lower three-year mortality [OR adjusted  = 0.17 (0.05-0.5), p = 0.003]. The small proportion of AHF patients achieving relaxin-2 concentrations similar to those observed in pregnancy may survive longer.

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

    DEFF Research Database (Denmark)

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

    2008-01-01

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

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

    International Nuclear Information System (INIS)

    Chay, Junegone; Kim, Chul

    2007-01-01

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

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

    DEFF Research Database (Denmark)

    Dellavalle, B; Kirchhoff, J; Maretty, L

    2014-01-01

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

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

    Science.gov (United States)

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

    2015-06-25

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

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

    Science.gov (United States)

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

    2017-01-01

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

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

    International Nuclear Information System (INIS)

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

    1980-01-01

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

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

    Science.gov (United States)

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

    2017-01-01

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

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

    International Nuclear Information System (INIS)

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

    2015-01-01

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

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

    Science.gov (United States)

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

    2015-01-01

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

  19. Sequential versus simultaneous use of chemotherapy and gonadotropin-releasing hormone agonist (GnRHa) among estrogen receptor (ER)-positive premenopausal breast cancer patients: effects on ovarian function, disease-free survival, and overall survival.

    Science.gov (United States)

    Zhang, Ying; Ji, Yajie; Li, Jianwei; Lei, Li; Wu, Siyu; Zuo, Wenjia; Jia, Xiaoqing; Wang, Yujie; Mo, Miao; Zhang, Na; Shen, Zhenzhou; Wu, Jiong; Shao, Zhimin; Liu, Guangyu

    2018-04-01

    To investigate ovarian function and therapeutic efficacy among estrogen receptor (ER)-positive, premenopausal breast cancer patients treated with gonadotropin-releasing hormone agonist (GnRHa) and chemotherapy simultaneously or sequentially. This study was a phase 3, open-label, parallel, randomized controlled trial (NCT01712893). Two hundred sixteen premenopausal patients (under 45 years) diagnosed with invasive ER-positive breast cancer were enrolled from July 2009 to May 2013 and randomized at a 1:1 ratio to receive (neo)adjuvant chemotherapy combined with sequential or simultaneous GnRHa treatment. All patients were advised to receive GnRHa for at least 2 years. The primary outcome was the incidence of early menopause, defined as amenorrhea lasting longer than 12 months after the last chemotherapy or GnRHa dose, with postmenopausal or unknown follicle-stimulating hormone and estradiol levels. The menstrual resumption period and survivals were the secondary endpoints. The median follow-up time was 56.9 months (IQR 49.5-72.4 months). One hundred and eight patients were enrolled in each group. Among them, 92 and 78 patients had complete primary endpoint data in the sequential and simultaneous groups, respectively. The rates of early menopause were 22.8% (21/92) in the sequential group and 23.1% (18/78) in the simultaneous group [simultaneous vs. sequential: OR 1.01 (95% CI 0.50-2.08); p = 0.969; age-adjusted OR 1.13; (95% CI 0.54-2.37); p = 0.737]. The median menstruation resumption period was 12.0 (95% CI 9.3-14.7) months and 10.3 (95% CI 8.2-12.4) months for the sequential and simultaneous groups, respectively [HR 0.83 (95% CI 0.59-1.16); p = 0.274; age-adjusted HR 0.90 (95%CI 0.64-1.27); p = 0.567]. No significant differences were evident for disease-free survival (p = 0.290) or overall survival (p = 0.514) between the two groups. For ER-positive premenopausal patients, the sequential use of GnRHa and chemotherapy showed ovarian preservation

  20. Impact of marital status on survival of gastric adenocarcinoma patients: Results from the Surveillance Epidemiology and End Results (SEER) Database

    OpenAIRE

    Qiu, Miaozhen; Yang, Dajun; Xu, Ruihua

    2016-01-01

    Marital status was found to be an independent prognostic factor for survival in various cancer types. In this study, we used the Surveillance, Epidemiology and End Results database to analyze the survival difference among different marital status in the United States. Gastric adenocarcinoma patients from 2004?2012 were enrolled for study. The 5-year cause specific survival (CSS) was our primary endpoint. Totally 29,074 eligible patients were identified. We found that more male patients were m...

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

    DEFF Research Database (Denmark)

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

    2018-01-01

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

  2. 78 FR 73199 - Draft Guidance for Industry on Bioequivalence Studies With Pharmacokinetic Endpoints for Drugs...

    Science.gov (United States)

    2013-12-05

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

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

    DEFF Research Database (Denmark)

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

    2012-01-01

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

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

    Science.gov (United States)

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

    2016-05-12

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

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

    Science.gov (United States)

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

    2011-01-01

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

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

    International Nuclear Information System (INIS)

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

    1988-01-01

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

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

    International Nuclear Information System (INIS)

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

    2014-01-01

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

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

    Science.gov (United States)

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

    2018-04-01

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

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

    International Nuclear Information System (INIS)

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

    2013-01-01

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

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

    International Nuclear Information System (INIS)

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

    2013-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2013-07-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2013-07-01

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

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

    DEFF Research Database (Denmark)

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

    2018-01-01

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

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

    NARCIS (Netherlands)

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

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

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

    DEFF Research Database (Denmark)

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

    2013-01-01

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

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

    Science.gov (United States)

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

    2014-01-01

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

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

    Science.gov (United States)

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

    2008-06-01

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

  18. Survival pathways under stress

    Indian Academy of Sciences (India)

    First page Back Continue Last page Graphics. Survival pathways under stress. Bacteria survive by changing gene expression. pattern. Three important pathways will be discussed: Stringent response. Quorum sensing. Proteins performing function to control oxidative damage.

  19. Secondary acute leukemia - review of 15 cases

    Energy Technology Data Exchange (ETDEWEB)

    Venugopal, P; Rajni, A; Gopal, R; Saikia, T; Kurkure, P A; Nair, C N; Advani, S H

    1988-12-01

    Acute leukemia is a rare complication of long-term chemotherapy, immunosuppressive therapy and radiotherapy. With improved survival in cancer patients resulting from modern methods of investigations and treatment, more case of secondary leukemia have come to light. In this review, fifteen cases of secondary leukemia, its prognostic implications and methods to reduce the risk of its development are emphasised. Relevant literature is also reviewed. (author). 3 tabs., 24 refs.

  20. Tracking plasma cell differentiation and survival.

    Science.gov (United States)

    Roth, Katrin; Oehme, Laura; Zehentmeier, Sandra; Zhang, Yang; Niesner, Raluca; Hauser, Anja E

    2014-01-01

    Plasma cells play a crucial role for the humoral immune response as they represent the body's factories for antibody production. The differentiation from a B cell into a plasma cell is controlled by a complex transcriptional network and happens within secondary lymphoid organs. Based on their lifetime, two types of antibody secreting cells can be distinguished: Short-lived plasma cells are located in extrafollicular sites of secondary lymphoid organs such as lymph node medullary cords and the splenic red pulp. A fraction of plasmablasts migrate from secondary lymphoid organs to the bone marrow where they can become long-lived plasma cells. Bone marrow plasma cells reside in special microanatomical environments termed survival niches, which provide factors promoting their longevity. Reticular stromal cells producing the chemokine CXCL12, which is known to attract plasmablasts to the bone marrow but also to promote plasma cell survival, play a crucial role in the maintenance of these niches. In addition, hematopoietic cells are contributing to the niches by providing other soluble survival factors. Here, we review the current knowledge on the factors involved in plasma cell differentiation, their localization and migration. We also give an overview on what is known regarding the maintenance of long lived plasma cells in survival niches of the bone marrow. © 2013 International Society for Advancement of Cytometry.

  1. Illness perceptions predict survival in haemodialysis patients.

    Science.gov (United States)

    Chilcot, Joseph; Wellsted, David; Farrington, Ken

    2011-01-01

    Illness perceptions have been shown to be important determinants of functional and psychosocial outcomes, including quality of life and treatment adherence in end-stage renal disease patients. The aim of this prospective study was to determine whether haemodialysis patients' illness perceptions impact upon survival. Haemodialysis patients from a UK renal service completed the Revised Illness Perception Questionnaire. Over the study period (May 2007 to December 2010), all-cause mortality was recorded as the endpoint. 223 patients were followed up for a median of 15.9 months (min. 10 days, max. 42.7 months). The median dialysis vintage was 17.6 months (min. 4 days, max. 391.3 months). Treatment control perceptions demonstrated a significant association with mortality (HR = 0.91, 95% CI: 0.83-0.99, p = 0.03). After controlling for covariates, including age, albumin, extra renal comorbidity and depression scores, perception of treatment control remained a significant predictor of mortality (HR = 0.89, 95% CI: 0.80-0.99, p = 0.03). Patients' perceptions of treatment control (dialysis therapy) predict survival independently of survival risk factors, including comorbidity. Studies are required to test whether psychological interventions designed to modify maladaptive illness perceptions influence clinical outcomes in this patient setting. Copyright © 2011 S. Karger AG, Basel.

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

    Science.gov (United States)

    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.

  3. Network survivability performance

    Science.gov (United States)

    1993-11-01

    This technical report has been developed to address the survivability of telecommunications networks including services. It responds to the need for a common understanding of, and assessment techniques for network survivability, availability, integrity, and reliability. It provides a basis for designing and operating telecommunications networks to user expectations for network survivability and a foundation for continuing industry activities in the subject area. This report focuses on the survivability of both public and private networks and covers a wide range of users. Two frameworks are established for quantifying and categorizing service outages, and for classifying network survivability techniques and measures. The performance of the network survivability techniques is considered; however, recommended objectives are not established for network survivability performance.

  4. Survival and Complications Following Surgery and Radiation for Localized Prostate Cancer: An International Collaborative Review.

    Science.gov (United States)

    Wallis, Christopher J D; Glaser, Adam; Hu, Jim C; Huland, Hartwig; Lawrentschuk, Nathan; Moon, Daniel; Murphy, Declan G; Nguyen, Paul L; Resnick, Matthew J; Nam, Robert K

    2018-01-01

    Evaluation of treatment options for localized prostate cancer (PCa) remains among the highest priorities for comparative effectiveness research. Surgery and radiotherapy (RT) are the two interventions most commonly used. To provide a critical narrative review of evidence of the comparative effectiveness and harms of surgery and RT in the treatment of localized PCa. A collaborative critical narrative review of the literature was conducted. Evidence to clearly guide treatment choice in PCa remains insufficient. Randomized trials are underpowered for clinically meaningful endpoints and have demonstrated no difference in overall or PCa-specific survival. Observational studies have consistently demonstrated an absolute survival benefit for men treated with radical prostatectomy, but are limited by selection bias and residual confounding errors. Surgery and RT are associated with comparable health-related quality of life following treatment in three randomized trials. Randomized data regarding urinary, erectile, and bowel function show few long-term (>5 yr) differences, although short-term continence and erectile function were worse following surgery and short-term urinary bother and bowel function were worse following RT. There has been recent recognition of other complications that may significantly affect the life trajectory of those undergoing PCa treatment. Of these, hospitalization, the need for urologic, rectoanal, and other major surgical procedures, and secondary cancers are more common among men treated with RT. Androgen deprivation therapy, frequently co-administered with RT, may additionally contribute to treatment-related morbidity. Technological innovations in surgery and RT have shown inconsistent oncologic and functional benefits. Owing to underpowered randomized control studies and the selection biases inherent in observational studies, the question of which treatment provides better PCa control cannot be definitively answered now or in the near future

  5. MRE11-Deficiency Associated with Improved Long-Term Disease Free Survival and Overall Survival in a Subset of Stage III Colon Cancer Patients in Randomized CALGB 89803 Trial

    Science.gov (United States)

    Pavelitz, Thomas; Renfro, Lindsay; Foster, Nathan R.; Caracol, Amber; Welsch, Piri; Lao, Victoria Valinluck; Grady, William B.; Niedzwiecki, Donna; Saltz, Leonard B.; Bertagnolli, Monica M.; Goldberg, Richard M.; Rabinovitch, Peter S.; Emond, Mary; Monnat, Raymond J.; Maizels, Nancy

    2014-01-01

    Purpose Colon cancers deficient in mismatch repair (MMR) may exhibit diminished expression of the DNA repair gene, MRE11, as a consequence of contraction of a T11 mononucleotide tract. This study investigated MRE11 status and its association with prognosis, survival and drug response in patients with stage III colon cancer. Patients and Methods Cancer and Leukemia Group B 89803 (Alliance) randomly assigned 1,264 patients with stage III colon cancer to postoperative weekly adjuvant bolus 5-fluorouracil/leucovorin (FU/LV) or irinotecan+FU/LV (IFL), with 8 year follow-up. Tumors from these patients were analyzed to determine stability of a T11 tract in the MRE11 gene. The primary endpoint was overall survival (OS), and a secondary endpoint was disease-free survival (DFS). Non-proportional hazards were addressed using time-dependent covariates in Cox analyses. Results Of 625 tumor cases examined, 70 (11.2%) exhibited contraction at the T11 tract in one or both MRE11 alleles and were thus predicted to be deficient in MRE11 (dMRE11). In pooled treatment analyses, dMRE11 patients showed initially reduced DFS and OS but improved long-term DFS and OS compared with patients with an intact MRE11 T11 tract. In the subgroup of dMRE11 patients treated with IFL, an unexplained early increase in mortality but better long-term DFS than IFL-treated pMRE11 patients was observed. Conclusions Analysis of this relatively small number of patients and events showed that the dMRE11 marker predicts better prognosis independent of treatment in the long-term. In subgroup analyses, dMRE11 patients treated with irinotecan exhibited unexplained short-term mortality. MRE11 status is readily assayed and may therefore prove to be a useful prognostic marker, provided that the results reported here for a relatively small number of patients can be generalized in independent analyses of larger numbers of samples. Trial Registration ClinicalTrials.gov NCT00003835 PMID:25310185

  6. MRE11-deficiency associated with improved long-term disease free survival and overall survival in a subset of stage III colon cancer patients in randomized CALGB 89803 trial.

    Directory of Open Access Journals (Sweden)

    Thomas Pavelitz

    Full Text Available Colon cancers deficient in mismatch repair (MMR may exhibit diminished expression of the DNA repair gene, MRE11, as a consequence of contraction of a T11 mononucleotide tract. This study investigated MRE11 status and its association with prognosis, survival and drug response in patients with stage III colon cancer.Cancer and Leukemia Group B 89803 (Alliance randomly assigned 1,264 patients with stage III colon cancer to postoperative weekly adjuvant bolus 5-fluorouracil/leucovorin (FU/LV or irinotecan+FU/LV (IFL, with 8 year follow-up. Tumors from these patients were analyzed to determine stability of a T11 tract in the MRE11 gene. The primary endpoint was overall survival (OS, and a secondary endpoint was disease-free survival (DFS. Non-proportional hazards were addressed using time-dependent covariates in Cox analyses.Of 625 tumor cases examined, 70 (11.2% exhibited contraction at the T11 tract in one or both MRE11 alleles and were thus predicted to be deficient in MRE11 (dMRE11. In pooled treatment analyses, dMRE11 patients showed initially reduced DFS and OS but improved long-term DFS and OS compared with patients with an intact MRE11 T11 tract. In the subgroup of dMRE11 patients treated with IFL, an unexplained early increase in mortality but better long-term DFS than IFL-treated pMRE11 patients was observed.Analysis of this relatively small number of patients and events showed that the dMRE11 marker predicts better prognosis independent of treatment in the long-term. In subgroup analyses, dMRE11 patients treated with irinotecan exhibited unexplained short-term mortality. MRE11 status is readily assayed and may therefore prove to be a useful prognostic marker, provided that the results reported here for a relatively small number of patients can be generalized in independent analyses of larger numbers of samples.ClinicalTrials.gov NCT00003835.

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

    Science.gov (United States)

    Fogolari, Federico; Corazza, Alessandra; Esposito, Gennaro

    2018-01-01

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

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

    International Nuclear Information System (INIS)

    Fan Wanchun; Shi Ren

    2000-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Federico Fogolari

    2018-02-01

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

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

    Science.gov (United States)

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

    2005-12-01

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

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

    Science.gov (United States)

    Inouye, Joshua M; Valero-Cuevas, Francisco J

    2016-02-01

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

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

    International Nuclear Information System (INIS)

    Xu Jinsheng; Purcell, Wendy M.

    2006-01-01

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

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

    Science.gov (United States)

    Sajó, I

    1968-06-01

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

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

    Science.gov (United States)

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

    2011-01-01

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

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

    Science.gov (United States)

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

    2015-11-01

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

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

    Science.gov (United States)

    Erden, Mustafa Suphi; Billard, Aude

    2015-06-01

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

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

    Science.gov (United States)

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

    2008-01-01

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

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

    Science.gov (United States)

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

    2017-03-01

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

  19. Multinationals and plant survival

    DEFF Research Database (Denmark)

    Bandick, Roger

    2010-01-01

    The aim of this paper is twofold: first, to investigate how different ownership structures affect plant survival, and second, to analyze how the presence of foreign multinational enterprises (MNEs) affects domestic plants’ survival. Using a unique and detailed data set on the Swedish manufacturing...... sector, I am able to separate plants into those owned by foreign MNEs, domestic MNEs, exporting non-MNEs, and purely domestic firms. In line with previous findings, the result, when conditioned on other factors affecting survival, shows that foreign MNE plants have lower survival rates than non......-MNE plants. However, separating the non-MNEs into exporters and non-exporters, the result shows that foreign MNE plants have higher survival rates than non-exporting non-MNEs, while the survival rates of foreign MNE plants and exporting non-MNE plants do not seem to differ. Moreover, the simple non...

  20. Resection for secondary malignancy of the pancreas.

    Science.gov (United States)

    Hung, Jui-Hsia; Wang, Shin-E; Shyr, Yi-Ming; Su, Cheng-Hsi; Chen, Tien-Hua; Wu, Chew-Wun

    2012-01-01

    This study tried to clarify the role of pancreatic resection in the treatment of secondary malignancy with metastasis or local invasion to the pancreas in terms of surgical risk and survival benefit. Data of secondary malignancy of the pancreas from our 19 patients and cases reported in the English literature were pooled together for analysis. There were 329 cases of resected secondary malignancy of the pancreas, including 241 cases of metastasis and 88 cases of local invasion. The most common primary tumor metastatic to the pancreas and amenable to resection was renal cell carcinoma (RCC) (73.9%). More than half (52.3%) of the primary cancers with local invasion to the pancreas were colon cancer, and nearly half (40.9%) were stomach cancer. The median metastatic interval was 84 months (7 years) for overall primary tumors and 108 months (9 years) for RCC. The 5-year survival for secondary malignancy of the pancreas after resection was 61.1% for metastasis and 58.9% for local invasion, with 72.8% for RCC metastasis, 69.0% for colon cancer, and 43.8% for stomach cancer with local invasion to the pancreas. Pancreatic resection should not be precluded for secondary malignancy of the pancreas because long-term survival could be achieved with acceptable surgical risk in selected patients.

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

    International Nuclear Information System (INIS)

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

    2016-01-01

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

  2. ASURV: Astronomical SURVival Statistics

    Science.gov (United States)

    Feigelson, E. D.; Nelson, P. I.; Isobe, T.; LaValley, M.

    2014-06-01

    ASURV (Astronomical SURVival Statistics) provides astronomy survival analysis for right- and left-censored data including the maximum-likelihood Kaplan-Meier estimator and several univariate two-sample tests, bivariate correlation measures, and linear regressions. ASURV is written in FORTRAN 77, and is stand-alone and does not call any specialized libraries.

  3. Survival with AGS-003, an autologous dendritic cell-based immunotherapy, in combination with sunitinib in unfavorable risk patients with advanced renal cell carcinoma (RCC): Phase 2 study results.

    Science.gov (United States)

    Amin, Asim; Dudek, Arkadiusz Z; Logan, Theodore F; Lance, Raymond S; Holzbeierlein, Jeffrey M; Knox, Jennifer J; Master, Viraj A; Pal, Sumanta K; Miller, Wilson H; Karsh, Lawrence I; Tcherepanova, Irina Y; DeBenedette, Mark A; Williams, W Lee; Plessinger, Douglas C; Nicolette, Charles A; Figlin, Robert A

    2015-01-01

    AGS-003 is an autologous immunotherapy prepared from fully matured and optimized monocyte-derived dendritic cells, which are co-electroporated with amplified tumor RNA plus synthetic CD40L RNA. AGS-003 was evaluated in combination with sunitinib in an open label phase 2 study in intermediate and poor risk, treatment naïve patients with metastatic clear cell renal cell carcinoma (mRCC). Twenty-one intermediate and poor risk patients were treated continuously with sunitinib (4 weeks on, 2 weeks off per 6 week cycle). After completion of the first cycle of sunitinib, patients were treated with AGS-003 every 3 weeks for 5 doses, then every 12 weeks until progression or end of study. The primary endpoint was to determine the complete response rate. Secondary endpoints included clinical benefit, safety, progression free survival (PFS) and overall survival (OS). Immunologic response was also monitored. Thirteen patients (62%) experienced clinical benefit (9 partial responses, 4 with stable disease); however there were no complete responses in this group of intermediate and poor risk mRCC patients and enrollment was terminated early. Median PFS from registration was 11.2 months (95% CI 6.0, 19.4) and the median OS from registration was 30.2 months (95% CI 9.4, 57.1) for all patients. Seven (33%) patients survived for at least 4.5 years, while five (24%) survived for more than 5 years, including 2 patients who remain progression-free with durable responses for more than 5 years at the time of this report. AGS-003 was well tolerated with only mild injection-site reactions. The most common adverse events were related to expected toxicity from sunitinib therapy. In patients who had sequential samples available for immune monitoring, the magnitude of the increase in the absolute number of CD8(+) CD28(+) CD45RA(-) effector/memory T cells (CTLs) after 5 doses of AGS-003 relative to baseline, correlated with overall survival. AGS-003 in combination with sunitinib was

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2013-07-01

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

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

    International Nuclear Information System (INIS)

    Deeb, Rula A.; Hawley, Elisabeth L.

    2013-01-01

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

  6. Surrogacy of progression-free survival (PFS) for overall survival (OS) in esophageal cancer trials with preoperative therapy: Literature-based meta-analysis.

    Science.gov (United States)

    Kataoka, K; Nakamura, K; Mizusawa, J; Kato, K; Eba, J; Katayama, H; Shibata, T; Fukuda, H

    2017-10-01

    There have been no reports evaluating progression-free survival (PFS) as a surrogate endpoint in resectable esophageal cancer. This study was conducted to evaluate the trial level correlations between PFS and overall survival (OS) in resectable esophageal cancer with preoperative therapy and to explore the potential benefit of PFS as a surrogate endpoint for OS. A systematic literature search of randomized trials with preoperative chemotherapy or preoperative chemoradiotherapy for esophageal cancer reported from January 1990 to September 2014 was conducted using PubMed and the Cochrane Library. Weighted linear regression using sample size of each trial as a weight was used to estimate coefficient of determination (R 2 ) within PFS and OS. The primary analysis included trials in which the HR for both PFS and OS was reported. The sensitivity analysis included trials in which either HR or median survival time of PFS and OS was reported. In the sensitivity analysis, HR was estimated from the median survival time of PFS and OS, assuming exponential distribution. Of 614 articles, 10 trials were selected for the primary analysis and 15 for the sensitivity analysis. The primary analysis did not show a correlation between treatment effects on PFS and OS (R 2 0.283, 95% CI [0.00-0.90]). The sensitivity analysis did not show an association between PFS and OS (R 2 0.084, 95% CI [0.00-0.70]). Although the number of randomized controlled trials evaluating preoperative therapy for esophageal cancer is limited at the moment, PFS is not suitable for primary endpoint as a surrogate endpoint for OS. Copyright © 2017 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

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

    Science.gov (United States)

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

    2009-07-01

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

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

    International Nuclear Information System (INIS)

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

    2005-01-01

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

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

    Science.gov (United States)

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

    2014-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Svenja Schüler

    2017-08-01

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

  11. Obesity and subcutaneous fat patterning in relation to survival of postmenopausal breast cancer patients participating in the DOM-project

    NARCIS (Netherlands)

    den Tonkelaar, I.; de Waard van de Spek, FB; Seidell, J C; Fracheboud, J

    1995-01-01

    The effect of obesity and fat distribution on survival of breast cancer patients was studied prospectively in 241 women with a natural menopause who participated in a breast cancer screening project, the DOM-project in Utrecht, The Netherlands. Mean follow-up time was 9.1 years and endpoint of

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

    Science.gov (United States)

    Jung, Sin-Ho

    2017-07-01

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

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

    Directory of Open Access Journals (Sweden)

    Vladimir Stepanov

    1997-01-01

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

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

    International Nuclear Information System (INIS)

    Fan Wanchun; Shi Ren

    2001-01-01

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

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

    Science.gov (United States)

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

    2013-04-01

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

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

    Science.gov (United States)

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

    2013-01-01

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

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

    DEFF Research Database (Denmark)

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

    2007-01-01

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

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

    Science.gov (United States)

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

    2007-03-01

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

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

    DEFF Research Database (Denmark)

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

    2007-01-01

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

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

    Science.gov (United States)

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

    2007-03-01

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

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

    Science.gov (United States)

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

    2015-02-10

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

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

    Science.gov (United States)

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

    2017-09-20

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

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

    International Nuclear Information System (INIS)

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

    2015-01-01

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

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

    Science.gov (United States)

    Groot, Robert D.

    2013-06-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2017-02-24

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

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

    Science.gov (United States)

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

    2017-05-01

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

  7. Network ties and survival

    DEFF Research Database (Denmark)

    Acheampong, George; Narteh, Bedman; Rand, John

    2017-01-01

    Poultry farming has been touted as one of the major ways by which poverty can be reduced in low-income economies like Ghana. Yet, anecdotally there is a high failure rate among these poultry farms. This current study seeks to understand the relationship between network ties and survival chances...... of small commercial poultry farms (SCPFs). We utilize data from a 2-year network survey of SCPFs in rural Ghana. The survival of these poultry farms are modelled using a lagged probit model of farms that persisted from 2014 into 2015. We find that network ties are important to the survival chances...... but this probability reduces as the number of industry ties increases but moderation with dynamic capability of the firm reverses this trend. Our findings show that not all network ties aid survival and therefore small commercial poultry farmers need to be circumspect in the network ties they cultivate and develop....

  8. Survival of falling robots

    Science.gov (United States)

    Cameron, Jonathan M.; Arkin, Ronald C.

    1992-01-01

    As mobile robots are used in more uncertain and dangerous environments, it will become important to design them so that they can survive falls. In this paper, we examine a number of mechanisms and strategies that animals use to withstand these potentially catastrophic events and extend them to the design of robots. A brief survey of several aspects of how common cats survive falls provides an understanding of the issues involved in preventing traumatic injury during a falling event. After outlining situations in which robots might fall, a number of factors affecting their survival are described. From this background, several robot design guidelines are derived. These include recommendations for the physical structure of the robot as well as requirements for the robot control architecture. A control architecture is proposed based on reactive control techniques and action-oriented perception that is geared to support this form of survival behavior.

  9. Survivability and Hope

    Science.gov (United States)

    ... Current Issue Past Issues Special Section Survivability and Hope Past Issues / Spring 2007 Table of Contents For ... cure or long-term survivorship." This message of hope is a hallmark of the latest advances in ...

  10. Survival of falling robots

    Science.gov (United States)

    Cameron, Jonathan M.; Arkin, Ronald C.

    1992-02-01

    As mobile robots are used in more uncertain and dangerous environments, it will become important to design them so that they can survive falls. In this paper, we examine a number of mechanisms and strategies that animals use to withstand these potentially catastrophic events and extend them to the design of robots. A brief survey of several aspects of how common cats survive falls provides an understanding of the issues involved in preventing traumatic injury during a falling event. After outlining situations in which robots might fall, a number of factors affecting their survival are described. From this background, several robot design guidelines are derived. These include recommendations for the physical structure of the robot as well as requirements for the robot control architecture. A control architecture is proposed based on reactive control techniques and action-oriented perception that is geared to support this form of survival behavior.

  11. Assessment of Correlation Between Early and Late Efficacy Endpoints to Identify Potential Surrogacy Relationships in Non-Hodgkin Lymphoma: a Literature-Based Meta-analysis of 108 Phase II and Phase III Studies.

    Science.gov (United States)

    Zhu, Rui; Lu, Dan; Chu, Yu-Waye; Chai, Akiko; Green, Michelle; Zhang, Nancy; Jin, Jin Yan

    2017-05-01

    Correlations between early and late efficacy endpoints were assessed to identify potential surrogate endpoints for overall survival (OS) or progression-free survival (PFS) with clinical trial-level data in three non-Hodgkin lymphoma (NHL) subtypes: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL). One hundred and eight phase II-III trials (129 trial arms) in DLBCL, FL, and MCL were identified and included in the database. Correlations between efficacy endpoints were analyzed using weighted linear regression and Pearson's coefficient of determination (R 2 ). In newly diagnosed DLBCL, 6-month PFS was strongly correlated with 2-year OS (R 2  = 0.81, 95% confidence interval [CI] 0.51-0.96). Six-month PFS was strongly correlated with 3-year PFS (R 2  = 0.89, 95% CI 0.62-0.96) in FL and was moderately correlated with 2-year OS (R 2  = 0.69, 95% CI 0.40-0.91) in MCL trials. Linear regression determined that a 10% increase in 6-month PFS would yield a 13% ± 1.2% increase in 2-year OS in DLBCL, a 23% ± 1.1% increase in 3-year PFS in FL, or a 6.7% ± 1.0% increase in 2-year OS in MCL. Both 6-month PFS and complete response (CR) rate were moderately correlated with median PFS in FL trials with R 2  = 0.66 (95% CI 0.52-0.98) and R 2  = 0.69 (95% CI 0.22-0.89), respectively. Six-month PFS is a potential surrogate endpoint for 2-year OS in newly diagnosed DLBCL and MCL and for 3-year PFS in FL. Both 6-month PFS and CR rate are potential surrogate endpoints for median PFS in FL patients. Confirmation and validation of these correlations may facilitate early interpretation of NHL trials.

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

    Directory of Open Access Journals (Sweden)

    Bridges JFP

    2018-02-01

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

  13. Scenario-targeted toxicity assessment through multiple endpoint bioassays in a soil posing unacceptable environmental risk according to regulatory screening values.

    Science.gov (United States)

    Rodriguez-Ruiz, A; Etxebarria, J; Boatti, L; Marigómez, I

    2015-09-01

    Lanestosa is a chronically polluted site (derelict mine) where the soil (Lanestosa (LA) soil) exceeds screening values (SVs) of regulatory policies in force (Basque Country; Europe) for Zn, Pb and Cd. A scenario-targeted toxicity assessment was carried out on the basis of a multi-endpoint bioassay approach. Acute and chronic toxicity bioassays were conducted with selected test species (Vibrio fischeri, Dictyostelium discoideum, Lactuca sativa, Raphanus sativus and Eisenia fetida) in combination with chemical analysis of soils and elutriates and with bioaccumulation studies in earthworms. Besides, the toxicity profile was compared with that of the mine runoff (RO) soil and of a fresh artificially polluted soil (LAAPS) resembling LA soil pollutant profile. Extractability studies in LA soil revealed that Pb, Zn and Cd were highly available for exchange and/or release into the environment. Indeed, Pb and Zn were accumulated in earthworms and LA soil resulted to be toxic. Soil respiration, V. fischeri, vegetative and developmental cycles of D. discoideum and survival and juvenile production of E. fetida were severely affected. These results confirmed that LA soil had unacceptable environmental risk and demanded intervention. In contrast, although Pb and Zn concentrations in RO soil revealed also unacceptable risk, both metal extractability and toxicity were much lower than in LA soil. Thus, within the polluted site, the need for intervention varied between areas that posed dissimilar risk. Besides, since LAAPS, with a high exchangeable metal fraction, was the most toxic, ageing under in situ natural conditions seemingly contributed to attenuate LA soil risk. As a whole, combining multi-endpoint bioassays with scenario-targeted analysis (including leaching and ageing) provides reliable risk assessment in soils posing unacceptable environmental risk according to SVs, which is useful to optimise the required intervention measures.

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

    Directory of Open Access Journals (Sweden)

    Isam Alyaseri

    2017-03-01

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

  15. Adjuvant IMRT/XELOX radiochemotherapy improves long-term overall- and disease-free survival in advanced gastric cancer

    International Nuclear Information System (INIS)

    Boda-Heggemann, J.; Schneider, V.; Weiss, C.

    2013-01-01

    Purpose: In a retrospective analysis, adjuvant intensity-modulated radiation therapy (IMRT) combined with modern chemotherapy improved advanced gastric cancer survival rates compared to a combination of three-dimensional conformal radiation therapy (3D-CRT) and conventional chemotherapy. We report on the long-term outcomes of two consecutive patient cohorts that were treated with either IMRT and intensive chemotherapy, or 3D-CRT and conventional chemotherapy. Patients and methods: Between 2001 and 2008, 65 consecutive gastric cancer patients received either 3D-CRT (n = 27) or IMRT (n = 38) following tumor resection. Chemotherapy comprised predominantly 5-fluorouracil/folinic acid (5-FU/FA) in the earlier cohort and capecitabine plus oxaliplatin (XELOX) in the latter. The primary endpoints were overall survival (OS) and disease-free survival (DFS). Results: Median OS times were 18 and 43 months in the 3D-CRT and IMRT groups, respectively (p = 0.0602). Actuarial 5-year OS rates were 26 and 47 %, respectively. Within the IMRT group, XELOX gave better results than 5-FU/FA in terms of OS, but this difference was not statistically significant. The primary cause of death in both groups was distant metastasis. Median DFS times were 14 and 35 months in the 3D-CRT and IMRT groups, respectively (p = 0.0693). Actuarial 5-year DFS rates were 22 and 44 %, respectively. Among patients receiving 5-FU/FA, DFS tended to be better in the IMRT group, but this was not statistically significant. A similar analysis for the XELOX group was not possible as 3D-CRT was almost never used to treat these patients. No late toxicity exceeding grade 3 or secondary tumors were observed. Conclusion: After a median follow-up period of over 5 years, OS and DFS were improved in the IMRT/XELOX treated patients compared to the 3D-CRT/5-FU/FA group. Long-term observation revealed no clinical indications of therapy-induced secondary tumors or renal toxicity. (orig.)

  16. Adjuvant IMRT/XELOX radiochemotherapy improves long-term overall- and disease-free survival in advanced gastric cancer

    Energy Technology Data Exchange (ETDEWEB)

    Boda-Heggemann, J.; Schneider, V. [Heidelberg Univ., Universitaetsmedizin Mannheim (Germany). Dept. of Radiation Oncology; Weiss, C. [Heidelberg Univ., Universitaetsmedizin Mannheim (Germany). Dept. of Biomathematics and Medical Statistics] [and others

    2013-05-15

    Purpose: In a retrospective analysis, adjuvant intensity-modulated radiation therapy (IMRT) combined with modern chemotherapy improved advanced gastric cancer survival rates compared to a combination of three-dimensional conformal radiation therapy (3D-CRT) and conventional chemotherapy. We report on the long-term outcomes of two consecutive patient cohorts that were treated with either IMRT and intensive chemotherapy, or 3D-CRT and conventional chemotherapy. Patients and methods: Between 2001 and 2008, 65 consecutive gastric cancer patients received either 3D-CRT (n = 27) or IMRT (n = 38) following tumor resection. Chemotherapy comprised predominantly 5-fluorouracil/folinic acid (5-FU/FA) in the earlier cohort and capecitabine plus oxaliplatin (XELOX) in the latter. The primary endpoints were overall survival (OS) and disease-free survival (DFS). Results: Median OS times were 18 and 43 months in the 3D-CRT and IMRT groups, respectively (p = 0.0602). Actuarial 5-year OS rates were 26 and 47 %, respectively. Within the IMRT group, XELOX gave better results than 5-FU/FA in terms of OS, but this difference was not statistically significant. The primary cause of death in both groups was distant metastasis. Median DFS times were 14 and 35 months in the 3D-CRT and IMRT groups, respectively (p = 0.0693). Actuarial 5-year DFS rates were 22 and 44 %, respectively. Among patients receiving 5-FU/FA, DFS tended to be better in the IMRT group, but this was not statistically significant. A similar analysis for the XELOX group was not possible as 3D-CRT was almost never used to treat these patients. No late toxicity exceeding grade 3 or secondary tumors were observed. Conclusion: After a median follow-up period of over 5 years, OS and DFS were improved in the IMRT/XELOX treated patients compared to the 3D-CRT/5-FU/FA group. Long-term observation revealed no clinical indications of therapy-induced secondary tumors or renal toxicity. (orig.)

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

    International Nuclear Information System (INIS)

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

    2012-01-01

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

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

    Science.gov (United States)

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

    2014-10-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2012-04-15

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

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

    Directory of Open Access Journals (Sweden)

    A. Tawfik

    2013-01-01

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

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

    DEFF Research Database (Denmark)

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

    2018-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Carneiro Mário J. D.

    2002-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Shuhuan Wen

    2012-12-01

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

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

    Science.gov (United States)

    DeLuca, R.

    2006-03-01

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

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

    Science.gov (United States)

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

    2013-01-01

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

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

    International Nuclear Information System (INIS)

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

    2015-01-01

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

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

    Science.gov (United States)

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

    2016-01-01

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

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

    Science.gov (United States)

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

    2013-01-01

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

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

    International Nuclear Information System (INIS)

    Thiery, Thimothée; Le Doussal, Pierre

    2014-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2006-03-15

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

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

    International Nuclear Information System (INIS)

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

    2006-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Shao Yuanlin

    2005-06-01

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

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

    Science.gov (United States)

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

    2017-09-01

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

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

    Directory of Open Access Journals (Sweden)

    Aline Andrade Godoy

    2017-01-01

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

  15. Surviving After Suicide

    Science.gov (United States)

    ... fewer tools for communicating their feelings. Surviving After Suicide Fact Sheet 3 Children are especially vulnerable to feelings of guilt and ... to take care of them. Secrecy about the suicide in the hopes of protecting children may cause further complications. Explain the situation and ...

  16. Survivability via Control Objectives

    Energy Technology Data Exchange (ETDEWEB)

    CAMPBELL,PHILIP L.

    2000-08-11

    Control objectives open an additional front in the survivability battle. A given set of control objectives is valuable if it represents good practices, it is complete (it covers all the necessary areas), and it is auditable. CobiT and BS 7799 are two examples of control objective sets.

  17. Education for Survival.

    Science.gov (United States)

    Allen, James E., Jr.

    In this address, James E. Allen, Jr., Assistant Secretary for Education and U.S. Commissioner of Education, discusses the relationship of education to the problem of ecological destruction. He states that the solutions to the problems of air, water, and soil pollution may be found in redirected education. This "education for survival" can serve to…

  18. Artists’ Survival Rate

    DEFF Research Database (Denmark)

    Bille, Trine; Jensen, Søren

    2017-01-01

    The literature of cultural economics generally finds that an artistic education has no significant impact on artists’ income and careers in the arts. In our research, we have readdressed this question by looking at the artists’ survival in the arts occupations. The results show that an artistic...... education has a significant impact on artists’ careers in the arts and we find important industry differences....

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

    Science.gov (United States)

    Sung, Cynthia; Wei, Yuan; Watanabe, Satoru; Lee, How Sung; Khoo, Yok Moi; Fan, Lu; Rathore, Abhay P S; Chan, Kitti Wing-Ki; Choy, Milly M; Kamaraj, Uma S; Sessions, October M; Aw, Pauline; de Sessions, Paola F; Lee, Bernett; Connolly, John E; Hibberd, Martin L; Vijaykrishna, Dhanasekaran; Wijaya, Limin; Ooi, Eng Eong; Low, Jenny Guek-Hong; Vasudevan, Subhash G

    2016-08-01

    CELADEN was a randomized placebo-controlled trial of 50 patients with confirmed dengue fever to evaluate the efficacy and safety of celgosivir (A study registered at ClinicalTrials.gov, number NCT01619969). Celgosivir was given as a 400 mg loading dose and 200 mg bid (twice a day) over 5 days. Replication competent virus was measured by plaque assay and compared to reverse transcription quantitative PCR (qPCR) of viral RNA. Pharmacokinetics (PK) correlations with viremia, immunological profiling, next generation sequence (NGS) analysis and hematological data were evaluated as exploratory endpoints here to identify possible signals of pharmacological activity. Viremia by plaque assay strongly correlated with qPCR during the first four days. Immunological profiling demonstrated a qualitative shift in T helper cell profile during the course of infection. NGS analysis did not reveal any prominent signature that could be associated with drug treatment; however the phylogenetic spread of patients' isolates underlines the importance of strain variability that may potentially confound interpretation of dengue drug trials conducted during different outbreaks and in different countries. Celgosivir rapidly converted to castanospermine (Cast) with mean peak and trough concentrations of 5727 ng/mL (30.2 μM) and 430 ng/mL (2.3 μM), respectively and cleared with a half-life of 2.5 (± 0.6) hr. Mean viral log reduction between day 2 and 4 (VLR2-4) was significantly greater in secondary dengue than primary dengue (p = 0.002). VLR2-4 did not correlate with drug AUC but showed a trend of greater response with increasing Cmin. PK modeling identified dosing regimens predicted to achieve 2.4 to 4.5 times higher Cmin. than in the CELADEN trial for only 13% to 33% increase in overall dose. A small, non-statistical trend towards better outcome on platelet nadir and difference between maximum and minimum hematocrit was observed in celgosivir-treated patients with secondary dengue

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

    Science.gov (United States)

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

    2013-01-28

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

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

    Directory of Open Access Journals (Sweden)

    Patrick P J Phillips

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

  2. The enrichment secondary market

    International Nuclear Information System (INIS)

    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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1980-01-01

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

  4. Quantitative secondary electron detection

    Science.gov (United States)

    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.

  5. Radiation cell survival and growth delay studies in multicellular spheroids of small-cell lung carcinoma

    International Nuclear Information System (INIS)

    Duchesne, G.M.; Peacock, J.H.

    1987-01-01

    The radiation sensitivity of two small-cell lung carcinoma cell lines growing as multicellular spheroids in static culture was determined using clonogenic cell survival and growth delay as endpoints. Growth delay determination suggested that clonogenic cell kill was less than was obtained by direct assay of cell survival. Recovery from potentially lethal damage was assayed in one line (HC12) but was not demonstrable, and clonogenic cell survival decreased with time in treated spheroids with diameters greater than 300 μm which contained a hypoxic cell population. Microscopic examination of the treated spheroids showed the emergence of an abnormal giant-cell population, and the progressive clonogenic cell loss that occurred after treatment was thought to be due to oxygen and nutrient deprivation of the remaining viable cells by this doomed cell population. Correction of the growth delay measurements for changes in cell size and clonogenic cell population allowed correlation of the growth delay and cell survival data. (author)

  6. Role of TIPS in Improving Survival of Patients with Decompensated Liver Disease

    Directory of Open Access Journals (Sweden)

    Sundeep J. Punamiya

    2011-01-01

    Full Text Available Liver cirrhosis is associated with higher morbidity and reduced survival with appearance of portal hypertension and resultant decompensation. Portal decompression plays a key role in improving survival in these patients. Transjugular intrahepatic portosystemic shunts are known to be efficacious in reducing portal venous pressure and control of complications such as variceal bleeding and ascites. However, they have been associated with significant problems such as poor shunt durability, increased encephalopathy, and unchanged survival when compared with conservative treatment options. The last decade has seen a significant improvement in these complications, with introduction of covered stents, better selection of patients, and clearer understanding of procedural end-points. Use of TIPS early in the period of decompensation also appears promising in further improvement of survival of cirrhotic patients.

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

    Science.gov (United States)

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

    2017-08-01

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

  8. Radiobilogical cell survival models

    International Nuclear Information System (INIS)

    Zackrisson, B.

    1992-01-01

    A central issue in clinical radiobiological research is the prediction of responses to different radiation qualities. The choice of cell survival and dose-response model greatly influences the results. In this context the relationship between theory and model is emphasized. Generally, the interpretations of experimental data depend on the model. Cell survival models are systematized with respect to their relations to radiobiological theories of cell kill. The growing knowlegde of biological, physical, and chemical mechanisms is reflected in the formulation of new models. The present overview shows that recent modelling has been more oriented towards the stochastic fluctuations connected to radiation energy deposition. This implies that the traditional cell surivival models ought to be complemented by models of stochastic energy deposition processes and repair processes at the intracellular level. (orig.)

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

    Science.gov (United States)

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

    2014-11-11

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

  10. Secondary acute pneumonias

    International Nuclear Information System (INIS)

    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

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

    International Nuclear Information System (INIS)

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

    1995-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2000-09-01

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

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

    International Nuclear Information System (INIS)

    Yoo, S. D.; Aspnes, D. E.

    2001-01-01

    Reciprocal-space analysis offers several advantages for determining critical point parameters in optical and other spectra, for example the separation of baseline effects, information, and noise in low-, medium-, and high-index Fourier coefficients, respectively. However, endpoint-discontinuity artifacts can obscure much of the information when segments are isolated for analysis. We developed a procedure for eliminating these artifacts and recovering buried information by minimizing in the white-noise region the mean-square deviation between the Fourier coefficients of the data and those of low-order polynomials, then subtracting the resulting coefficients from the data over the entire range. We find that spectral analysis is optimized if no false data are used, i.e., when the number of points transformed equals the number of actual data points in the segment. Using fractional differentiation we develop a simple derivation of the variation of the reciprocal-space coefficients with index n for Lorentzian and Gaussian line shapes in direct space. More generally, we show that the definition of critical point energies in terms of phase coherence of the Fourier coefficients allows these energies to be determined for a broad class of line shapes even if the direct-space line shapes themselves are not known. Limitations for undersampled or highly broadened spectra are discussed, along with extensions to two- or higher-dimensional arrays of data. [copyright] 2001 American Institute of Physics

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

    Science.gov (United States)

    Renfro, Lindsay A.; Shi, Qian; Xue, Yuan; Li, Junlong; Shang, Hongwei; Sargent, Daniel J.

    2014-01-01

    Evaluation of candidate surrogate endpoints using individual patient data from multiple clinical trials is considered the gold standard approach to validate surrogates at both patient and trial levels. However, this approach assumes the availability of patient-level data from a relatively large collection of similar trials, which may not be possible to achieve for a given disease application. One common solution to the problem of too few similar trials involves performing trial-level surrogacy analyses on trial sub-units (e.g., centers within trials), thereby artificially increasing the trial-level sample size for feasibility of the multi-trial analysis. To date, the practical impact of treating trial sub-units (centers) identically to trials in multi-trial surrogacy analyses remains unexplored, and conditions under which this ad hoc solution may in fact be reasonable have not been identified. We perform a simulation study to identify such conditions, and demonstrate practical implications using a multi-trial dataset of patients with early stage colon cancer. PMID:25061255

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

    Science.gov (United States)

    Jiang, Rui; Weingart, Jacob; Zhang, Hailong; Ma, Yong; Sun, Xue-Long

    2012-01-01

    We report an enzymatic end-point modification and immobilization of recombinant human thrombomodulin (TM), a cofactor for activation of anticoagulant protein C pathway via thrombin. First, a truncated TM mutant consisting of epidermal growth factor-like domains 4–6 (TM456) with a conserved pentapeptide LPETG motif at its C-terminal was expressed and purified in E. coli. Next, the truncated TM456 derivative was site-specifically modified with N-terminal diglycine containing molecules such as biotin and the fluorescent probe dansyl via sortase A (SrtA) mediated ligation (SML). The successful ligations were confirmed by SDS-PAGE and fluorescence imaging. Finally, the truncated TM456 was immobilized onto N-terminal diglycine-functionalized glass slide surface via SML directly. Alternatively, the truncated TM456 was biotinylated via SML and then immobilized onto streptavidin-functionalized glass slide surface indirectly. The successful immobilizations were confirmed by fluorescence imaging. The bioactivity of the immobilized truncated TM456 was further confirmed by protein C activation assay, in which enhanced activation of protein C by immobilized recombinant TM was observed. The sortase A-catalyzed surface ligation took place under mild conditions and is rapid occurring in a single step without prior chemical modification of the target protein. This site-specific covalent modification leads to molecules being arranged in a definitively ordered fashion and facilitating the preservation of the protein’s biological activity. PMID:22372933

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

    Energy Technology Data Exchange (ETDEWEB)

    Chow, Edward, E-mail: Edward.Chow@sunnybrook.ca [Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON (Canada); Hoskin, Peter [Mount Vernon Centre for Cancer Treatment, Mount Vernon Hospital, Northwood, Middlesex (United Kingdom); Mitera, Gunita; Zeng Liang [Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON (Canada); Lutz, Stephen [Department of Radiation Oncology, Blanchard Valley Regional Cancer Center, Findlay, OH (United States); Roos, Daniel [Department of Radiation Oncology, Royal Adelaide Hospital, Adelaide, South Australia (Australia); Hahn, Carol [Department of Radiation Oncology, Duke University Medical Center, Durham, NC (United States); Linden, Yvette van der [Radiotherapeutic Institute Friesland, Leeuwarden (Netherlands); Hartsell, William [Department of Radiation Oncology, Advocate Good Samaritan Cancer Center, Downers Grove, IL (United States); Kumar, Eshwar [Department of Oncology, Atlantic Health Sciences Cancer Centre, Saint John Regional Hospital, Saint John, NB (Canada)

    2012-04-01

    Purpose: To update the international consensus on palliative radiotherapy endpoints for future clinical trials in bone metastases by surveying international experts regarding previous uncertainties within the 2002 consensus, changes that may be necessary based on practice pattern changes and research findings since that time. Methods and Materials: A two-phase survey was used to determine revisions and new additions to the 2002 consensus. A total of 49 experts from the American Society for Radiation Oncology, the European Society for Therapeutic Radiology and Oncology, the Faculty of Radiation Oncology of the Royal Australian and New Zealand College of Radiologists, and the Canadian Association of Radiation Oncology who are directly involved in the care of patients with bone metastases participated in this survey. Results: Consensus was established in areas involving response definitions, eligibility criteria for future trials, reirradiation, changes in systemic therapy, radiation techniques, parameters at follow-up, and timing of assessments. Conclusion: An outline for trials in bone metastases was updated based on survey and consensus. Investigators leading trials in bone metastases are encouraged to adopt the revised guideline to promote consistent reporting. Areas for future research were identified. It is intended for the consensus to be re-examined in the future on a regular basis.

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

    Energy Technology Data Exchange (ETDEWEB)

    Hinton, T.G.; Congdon, J.; Rowe, C.; Scott, D. [Univ. of Georgia, Aiken, SC (US). Savannah River Ecology Lab.; Bedford, J.; Whicker, F.W. [Colorado State Univ., Fort Collins, CO (US)

    1997-11-01

    'This report summarizes the first year''s progress of research funded under the Department of Energy''s Environmental Management Science Program. The research was initiated to better determine ecological risks from toxic and radioactive contaminants. More precisely, the research is designed to determine the relevancy of sublethal cellular damage to the performance of individuals and to identify characteristics of non-human populations exposed to chronic, low-level radiation, as is typically found on many DOE sites. The authors propose to establish a protocol to assess risks to non-human species at higher levels of biological organization by relating molecular damage to more relevant responses that reflect population health. They think that they can achieve this by coupling changes in metabolic rates and energy allocation patterns to meaningful population response variables, and by using novel biological dosimeters in controlled, manipulative dose/effects experiments. They believe that a scientifically defensible endpoint for measuring ecological risks can only be determined once its understood the extent to which molecular damage from contaminant exposure is detrimental at the individual and population levels of biological organization.'

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

    International Nuclear Information System (INIS)

    Suto, Yasuzo; Ueno, Shigeru.

    1997-01-01

    Image interpolation is frequently used to improve slice resolution to reach spatial resolution. Improved quality of reconstructed three-dimensional images can be attained with this technique as a result. Linear interpolation is a well-known and widely used method. The distance-image method, which is a non-linear interpolation technique, is also used to convert CT value images to distance images. This paper describes a newly developed method that makes use of end-point coordinates: CT-value images are initially converted to binary images by thresholding them and then sequences of pixels with 1-value are arranged in vertical or horizontal directions. A sequence of pixels with 1-value is defined as a line segment which has starting and end points. For each pair of adjacent line segments, another line segment was composed by spatial interpolation of the start and end points. Binary slice images are constructed from the composed line segments. Three-dimensional images were reconstructed from clinical X-ray CT images, using three different interpolation methods and their quality and processing speed were evaluated and compared. (author)

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

    Science.gov (United States)

    McClain, Matthew; Romanowski, Brian

    2009-05-01

    Non-language speech sounds (NLSS) are sounds produced by humans that do not carry linguistic information. Examples of these sounds are coughs, clicks, breaths, and filled pauses such as "uh" and "um" in English. NLSS are prominent in conversational speech, but can be a significant source of errors in speech processing applications. Traditionally, these sounds are ignored by speech endpoint detection algorithms, where speech regions are identified in the audio signal prior to processing. The ability to filter NLSS as a pre-processing step can significantly enhance the performance of many speech processing applications, such as speaker identification, language identification, and automatic speech recognition. In order to be used in all such applications, NLSS detection must be performed without the use of language models that provide knowledge of the phonology and lexical structure of speech. This is especially relevant to situations where the languages used in the audio are not known apriori. We present the results of preliminary experiments using data from American and British English speakers, in which segments of audio are classified as language speech sounds (LSS) or NLSS using a set of acoustic features designed for language-agnostic NLSS detection and a hidden-Markov model (HMM) to model speech generation. The results of these experiments indicate that the features and model used are capable of detection certain types of NLSS, such as breaths and clicks, while detection of other types of NLSS such as filled pauses will require future research.

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

    Science.gov (United States)

    Jakubowska, Małgorzata; Baś, Bogusław; Kubiak, Władysław W

    2009-10-15

    The aim of this work was construction of the new wavelet function and verification that a continuous wavelet transform with a specially defined dedicated mother wavelet is a useful tool for precise detection of end-point in a potentiometric titration. The proposed algorithm does not require any initial information about the nature or the type of analyte and/or the shape of the titration curve. The signal imperfection, as well as random noise or spikes has no influence on the operation of the procedure. The optimization of the new algorithm was done using simulated curves and next experimental data were considered. In the case of well-shaped and noise-free titration data, the proposed method gives the same accuracy and precision as commonly used algorithms. But, in the case of noisy or badly shaped curves, the presented approach works good (relative error mainly below 2% and coefficients of variability below 5%) while traditional procedures fail. Therefore, the proposed algorithm may be useful in interpretation of the experimental data and also in automation of the typical titration analysis, specially in the case when random noise interfere with analytical signal.

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

    DEFF Research Database (Denmark)

    Bottomley, Andrew; Pe, Madeline; Sloan, Jeff

    2016-01-01

    Measures of health-related quality of life (HRQOL) and other patient-reported outcomes generate important data in cancer randomised trials to assist in assessing the risks and benefits of cancer therapies and fostering patient-centred cancer care. However, the various ways these measures are anal......Measures of health-related quality of life (HRQOL) and other patient-reported outcomes generate important data in cancer randomised trials to assist in assessing the risks and benefits of cancer therapies and fostering patient-centred cancer care. However, the various ways these measures...... are analysed and interpreted make it difficult to compare results across trials, and hinders the application of research findings to inform publications, product labelling, clinical guidelines, and health policy. To address these problems, the Setting International Standards in Analyzing Patient......-Reported Outcomes and Quality of Life Endpoints Data (SISAQOL) initiative has been established. This consortium, directed by the European Organisation for Research and Treatment of Cancer (EORTC), was convened to provide recommendations on how to standardise the analysis of HRQOL and other patient-reported outcomes...

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

    International Nuclear Information System (INIS)

    Chow, Edward; Hoskin, Peter; Mitera, Gunita; Zeng Liang; Lutz, Stephen; Roos, Daniel; Hahn, Carol; Linden, Yvette van der; Hartsell, William; Kumar, Eshwar

    2012-01-01

    Purpose: To update the international consensus on palliative radiotherapy endpoints for future clinical trials in bone metastases by surveying international experts regarding previous uncertainties within the 2002 consensus, changes that may be necessary based on practice pattern changes and research findings since that time. Methods and Materials: A two-phase survey was used to determine revisions and new additions to the 2002 consensus. A total of 49 experts from the American Society for Radiation Oncology, the European Society for Therapeutic Radiology and Oncology, the Faculty of Radiation Oncology of the Royal Australian and New Zealand College of Radiologists, and the Canadian Association of Radiation Oncology who are directly involved in the care of patients with bone metastases participated in this survey. Results: Consensus was established in areas involving response definitions, eligibility criteria for future trials, reirradiation, changes in systemic therapy, radiation techniques, parameters at follow-up, and timing of assessments. Conclusion: An outline for trials in bone metastases was updated based on survey and consensus. Investigators leading trials in bone metastases are encouraged to adopt the revised guideline to promote consistent reporting. Areas for future research were identified. It is intended for the consensus to be re-examined in the future on a regular basis.

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

    Science.gov (United States)

    Liu, Hui; Hou, Tingjun

    2016-07-15

    Accurate prediction of binding free energy is of particular importance to computational biology and structure-based drug design. Among those methods for binding affinity predictions, the end-point approaches, such as MM/PBSA and LIE, have been widely used because they can achieve a good balance between prediction accuracy and computational cost. Here we present an easy-to-use pipeline tool named Calculation of Free Energy (CaFE) to conduct MM/PBSA and LIE calculations. Powered by the VMD and NAMD programs, CaFE is able to handle numerous static coordinate and molecular dynamics trajectory file formats generated by different molecular simulation packages and supports various force field parameters. CaFE source code and documentation are freely available under the GNU General Public License via GitHub at https://github.com/huiliucode/cafe_plugin It is a VMD plugin written in Tcl and the usage is platform-independent. tingjunhou@zju.edu.cn. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  4. Selection of appropriate end-points (pCR vs 2yDFS) for tailoring treatments with prediction models in locally advanced rectal cancer

    International Nuclear Information System (INIS)

    Valentini, Vincenzo; Stiphout, Ruud G.P.M. van; Lammering, Guido; Gambacorta, Maria A.; Barba, Maria C.; Bebenek, Marek; Bonnetain, Franck; Bosset, Jean F.; Bujko, Krzysztof; Cionini, Luca; Gerard, Jean P.; Rödel, Claus; Sainato, Aldo; Sauer, Rolf; Minsky, Bruce D.; Collette, Laurence; Lambin, Philippe

    2015-01-01

    Purpose: Personalized treatments based on predictions for patient outcome require early characterization of a rectal cancer patient’s sensitivity to treatment. This study has two aims: (1) identify the main patterns of recurrence and response to the treatments (2) evaluate pathologic complete response (pCR) and two-year disease-free survival (2yDFS) for overall survival (OS) and their potential to be relevant intermediate endpoints to predict. Methods: Pooled and treatment subgroup analyses were performed on five large European rectal cancer trials (2795 patients), who all received long-course radiotherapy with or without concomitant and/or adjuvant chemotherapy. The ratio of distant metastasis (DM) and local recurrence (LR) rates was used to identify patient characteristics that increase the risk of recurrences. Findings: The DM/LR ratio decreased to a plateau in the first 2 years, revealing it to be a critical follow-up period. According to the patterns of recurrences, three patient groups were identified: 5–15% had pCR and were disease free after 2 years (excellent prognosis), 65–75% had no pCR but were disease free (good prognosis) and 15–30% had neither pCR nor 2yDFS (poor prognosis). Interpretation: Compared with pCR, 2yDFS is a stronger predictor of OS. To adapt treatment most efficiently, accurate prediction models should be developed for pCR to select patients for organ preservation and for 2yDFS to select patients for more intensified treatment strategies

  5. Progression-free survival, post-progression survival, and tumor response as surrogate markers for overall survival in patients with extensive small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Hisao Imai

    2015-01-01

    Full Text Available Objectives: The effects of first-line chemotherapy on overall survival (OS might be confounded by subsequent therapies in patients with small cell lung cancer (SCLC. We examined whether progression-free survival (PFS, post-progression survival (PPS, and tumor response could be valid surrogate endpoints for OS after first-line chemotherapies for patients with extensive SCLC using individual-level data. Methods: Between September 2002 and November 2012, we analyzed 49 cases of patients with extensive SCLC who were treated with cisplatin and irinotecan as first-line chemotherapy. The relationships of PFS, PPS, and tumor response with OS were analyzed at the individual level. Results: Spearman rank correlation analysis and linear regression analysis showed that PPS was strongly correlated with OS (r = 0.97, p < 0.05, R 2 = 0.94, PFS was moderately correlated with OS (r = 0.58, p < 0.05, R 2 = 0.24, and tumor shrinkage was weakly correlated with OS (r = 0.37, p < 0.05, R 2 = 0.13. The best response to second-line treatment, and the number of regimens employed after progression beyond first-line chemotherapy were both significantly associated with PPS ( p ≤ 0.05. Conclusion: PPS is a potential surrogate for OS in patients with extensive SCLC. Our findings also suggest that subsequent treatment after disease progression following first-line chemotherapy may greatly influence OS.

  6. Secondary fuel delivery system

    Science.gov (United States)

    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.

  7. Secondary and tertiary hyperparathyroidism.

    Science.gov (United States)

    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.

  8. Survival analysis models and applications

    CERN Document Server

    Liu, Xian

    2012-01-01

    Survival analysis concerns sequential occurrences of events governed by probabilistic laws.  Recent decades have witnessed many applications of survival analysis in various disciplines. This book introduces both classic survival models and theories along with newly developed techniques. Readers will learn how to perform analysis of survival data by following numerous empirical illustrations in SAS. Survival Analysis: Models and Applications: Presents basic techniques before leading onto some of the most advanced topics in survival analysis.Assumes only a minimal knowledge of SAS whilst enablin

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

    Science.gov (United States)

    Hu, Li-Xin; Ying, Guang-Guo; Chen, Xiao-Wen; Huang, Guo-Yong; Liu, You-Sheng; Jiang, Yu-Xia; Pan, Chang-Gui; Tian, Fei; Martin, Francis L

    2017-02-01

    Traditional duckweed toxicity tests only measure plant growth inhibition as an endpoint, with limited effects-based data. The present study aimed to investigate whether Fourier-transform infrared (FTIR) spectroscopy could enhance the duckweed (Lemna minor L.) toxicity test. Four chemicals (Cu, Cd, atrazine, and acetochlor) and 4 metal-containing industrial wastewater samples were tested. After exposure of duckweed to the chemicals, standard toxicity endpoints (frond number and chlorophyll content) were determined; the fronds were also interrogated using FTIR spectroscopy under optimized test conditions. Biochemical alterations associated with each treatment were assessed and further analyzed by multivariate analysis. The results showed that comparable x% of effective concentration (ECx) values could be achieved based on FTIR spectroscopy in comparison with those based on traditional toxicity endpoints. Biochemical alterations associated with different doses of toxicant were mainly attributed to lipid, protein, nucleic acid, and carbohydrate structural changes, which helped to explain toxic mechanisms. With the help of multivariate analysis, separation of clusters related to different exposure doses could be achieved. The present study is the first to show successful application of FTIR spectroscopy in standard duckweed toxicity tests with biochemical alterations as new endpoints. Environ Toxicol Chem 2017;36:346-353. © 2016 SETAC. © 2016 SETAC.

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

    Science.gov (United States)

    Rawat, S; Bruce, E D

    2014-01-01

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

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

    NARCIS (Netherlands)

    A.P. Kappetein (Arie Pieter); S.J. Head (Stuart); P. Généreux (Philippe); N. Piazza (Nicolo); N.M. van Mieghem (Nicolas); E.H. Blackstone (Eugene); T.G. Brott (Thomas); D.J. Cohen (David J.); D.E. Cutlip (Donald); G.A. van Es (Gerrit Anne); R.T. Hahn (Rebecca); A.J. Kirtane (Ajay); M. Krucoff (Mitchell); S. Kodali (Susheel); M.J. Mack (Michael); R. Mehran (Roxana); J. Rodés-Cabau (Josep); P. Vranckx (Pascal); J.G. Webb (John); S.W. Windecker (Stephan); P.W.J.C. Serruys (Patrick); M.B. Leon (Martin)

    2012-01-01

    textabstractObjectives: The aim of the current Valvular Academic Research Consortium (VARC)-2 initiative was to revisit the selection and definitions of transcatheter aortic valve implantation (TAVI)- clinical endpoints to make them more suitable to the present and future needs of clinical trials.

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

    NARCIS (Netherlands)

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

    2007-01-01

    OBJECTIVE: There are clear advantages to using biomarkers and surrogate endpoints, but concerns about clinical and statistical validity and systematic methods to evaluate these aspects hinder their efficient application. Our objective was to review the literature on biomarkers and surrogates to

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

    NARCIS (Netherlands)

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

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

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

    Science.gov (United States)

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

    2016-04-01

    Organismal energetics provide important insights into the effects of environmental toxicants. We aimed to determine the effects of pyraclostrobin on Lymnaea stagnalis by examining energy allocation patterns and life history traits. Juvenile snails exposed to pyraclostrobin decreased feeding rate and increased apparent avoidance behaviors at environmentally relevant concentrations. In adults, we found that sublethal concentrations of pyraclostrobin did not affect reproductive output, however, there were significant effects on developmental endpoints with longer time to hatch and decreased hatching success in pyraclostrobin-exposed egg masses. Further, there were apparent differences in developmental effects depending on whether mothers were also exposed to pyraclostrobin suggesting this chemical can exert intergenerational effects. Pyraclostrobin also affected protein and carbohydrate content of eggs in mothers that were exposed to pyraclostrobin. Significant effects on macronutrient content of eggs occurred at lower concentrations than effects on gross endpoints such as hatching success and time to hatch suggesting potential value for these endpoints as early indicators of ecologically relevant stress. These results provide important insight into the effects of a common fungicide on important endpoints for organismal energetics and life history. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

    Science.gov (United States)

    Thompson, Christopher Glen; Becker, Betsy Jane

    2014-01-01

    A common assumption in meta-analysis is that effect sizes are independent. When correlated effect sizes are analyzed using traditional univariate techniques, this assumption is violated. This research assesses the impact of dependence arising from treatment-control studies with multiple endpoints on homogeneity measures "Q" and…

  16. Applied survival analysis using R

    CERN Document Server

    Moore, Dirk F

    2016-01-01

    Applied Survival Analysis Using R covers the main principles of survival analysis, gives examples of how it is applied, and teaches how to put those principles to use to analyze data using R as a vehicle. Survival data, where the primary outcome is time to a specific event, arise in many areas of biomedical research, including clinical trials, epidemiological studies, and studies of animals. Many survival methods are extensions of techniques used in linear regression and categorical data, while other aspects of this field are unique to survival data. This text employs numerous actual examples to illustrate survival curve estimation, comparison of survivals of different groups, proper accounting for censoring and truncation, model variable selection, and residual analysis. Because explaining survival analysis requires more advanced mathematics than many other statistical topics, this book is organized with basic concepts and most frequently used procedures covered in earlier chapters, with more advanced topics...

  17. Assessing single and joint effects of chemicals on the survival and reproduction of Folsomia candida (Collembola) in soil

    International Nuclear Information System (INIS)

    Amorim, M.J.B.; Pereira, C.; Menezes-Oliveira, V.B.; Campos, B.; Soares, A.M.V.M.; Loureiro, S.

    2012-01-01

    Chemicals are often found in the environment as complex mixtures. There has been a large effort in the last decade to assess the combined effect of chemicals, using the conceptual models of Concentration Addition and Independent Action, but also including synergistic, antagonistic, dose-level and dose–ratio dependent deviations from these models. In the present study, single and mixture toxicity of atrazine, dimethoate, lindane, zinc and cadmium were studied in Folsomia candida, assessing survival and reproduction. Different response patterns were observed for the different endpoints and synergistic patterns were observed when pesticides were present. Compared with the previously tested Enchytraeus albidus and Porcellionides pruinosus, the mixture toxicity pattern for F. candida was species specific. The present study highlights the importance of studying toxicity of chemicals mixtures due to the observed potentiation of effects and confirms that for an adequate ecologically relevant risk assessment different organisms and endpoints should be included. - Highlights: ► Folsomia candida (Collembola) were exposed to binary mixtures of atrazine, dimethoate, lindane, zinc and cadmium. ► Synergistic response patterns were often observed when pesticides were present in the mixtures. ► Response patterns upon mixture exposure differed within endpoints (survival vs. reproduction) in some cases. ► As to single chemical toxicity, response patterns for mixture exposures seem to be also species specific. - Exposure to chemical mixtures in Folsomia candida showed potentiation of effects. Mixture toxicity patterns differ among species and endpoint measured.

  18. Teaching secondary mathematics

    CERN Document Server

    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

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

    International Nuclear Information System (INIS)

    Esperanza, Marta; Cid, Ángeles; Herrero, Concepción; Rioboo, Carmen

    2015-01-01

    Highlights: • Mitochondrial membrane potential constituted the most sensitive parameter assayed. • Several genotoxicity methods were applied for first time in ecotoxicological studies. • Oxidative DNA base damage (8-OHdG) was induced by paraquat exposure. • Cells with DNA strand breakage and subG1-nuclei increased in treated cultures. • Typical apoptosis hallmarks were observed in microalgal cells exposed to paraquat. - Abstract: Since recent evidence has demonstrated that many types of chemicals exhibit oxidative and/or genotoxic potential on living organisms, reactive oxygen species (ROS) formation and DNA damage are currently the best accepted paradigms to assess the potential hazardous biological effects of a wide range of contaminants. The goal of this study was to evaluate the sensitivity of different cytotoxicity and genotoxicity responses on the model microalga Chlamydomonas reinhardtii exposed to the prooxidant herbicide paraquat. In addition to the growth endpoint, cell viability, mitochondrial membrane potential and presence of reactive oxygen species (ROS) were assayed as potential markers of cytotoxicity using flow cytometry (FCM). To study the effects of paraquat on C. reinhardtii DNA, several genotoxicity approaches were implemented for the first time in an ecotoxicological study on microalgae. Oxidative DNA base damage was analysed by measuring the oxidative DNA lesion 8-OHdG by FCM. DNA fragmentation was analysed by different methods: comet assay, and cell cycle analysis by FCM, with a particular focus on the presence of subG1-nuclei. Finally, effects on morphology of nuclei were monitored through DAPI staining. The evaluation of these endpoints showed that several physiological and biochemical parameters reacted to oxidative stress disturbances with greater sensitivity than integrative parameters such as growth rates or cell viability. The experiments revealed concentration-dependent cytotoxicity (ROS formation, depolarization of

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

    Energy Technology Data Exchange (ETDEWEB)

    Esperanza, Marta; Cid, Ángeles; Herrero, Concepción; Rioboo, Carmen, E-mail: carmen.rioboo@udc.es

    2015-08-15

    Highlights: • Mitochondrial membrane potential constituted the most sensitive parameter assayed. • Several genotoxicity methods were applied for first time in ecotoxicological studies. • Oxidative DNA base damage (8-OHdG) was induced by paraquat exposure. • Cells with DNA strand breakage and subG1-nuclei increased in treated cultures. • Typical apoptosis hallmarks were observed in microalgal cells exposed to paraquat. - Abstract: Since recent evidence has demonstrated that many types of chemicals exhibit oxidative and/or genotoxic potential on living organisms, reactive oxygen species (ROS) formation and DNA damage are currently the best accepted paradigms to assess the potential hazardous biological effects of a wide range of contaminants. The goal of this study was to evaluate the sensitivity of different cytotoxicity and genotoxicity responses on the model microalga Chlamydomonas reinhardtii exposed to the prooxidant herbicide paraquat. In addition to the growth endpoint, cell viability, mitochondrial membrane potential and presence of reactive oxygen species (ROS) were assayed as potential markers of cytotoxicity using flow cytometry (FCM). To study the effects of paraquat on C. reinhardtii DNA, several genotoxicity approaches were implemented for the first time in an ecotoxicological study on microalgae. Oxidative DNA base damage was analysed by measuring the oxidative DNA lesion 8-OHdG by FCM. DNA fragmentation was analysed by different methods: comet assay, and cell cycle analysis by FCM, with a particular focus on the presence of subG1-nuclei. Finally, effects on morphology of nuclei were monitored through DAPI staining. The evaluation of these endpoints showed that several physiological and biochemical parameters reacted to oxidative stress disturbances with greater sensitivity than integrative parameters such as growth rates or cell viability. The experiments revealed concentration-dependent cytotoxicity (ROS formation, depolarization of

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

    Directory of Open Access Journals (Sweden)

    Coppey L

    2018-04-01

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

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

    Science.gov (United States)

    Allen, John C; Thumboo, Julian; Lye, Weng Kit; Conaghan, Philip G; Chew, Li-Ching; Tan, York Kiat

    2018-03-01

    To determine whether novel methods of selecting joints through (i) ultrasonography (individualized-ultrasound [IUS] method), or (ii) ultrasonography and clinical examination (individualized-composite-ultrasound [ICUS] method) translate into smaller rheumatoid arthritis (RA) clinical trial sample sizes when compared to existing methods utilizing predetermined joint sites for ultrasonography. Cohen's effect size (ES) was estimated (ES^) and a 95% CI (ES^L, ES^U) calculated on a mean change in 3-month total inflammatory score for each method. Corresponding 95% CIs [nL(ES^U), nU(ES^L)] were obtained on a post hoc sample size reflecting the uncertainty in ES^. Sample size calculations were based on a one-sample t-test as the patient numbers needed to provide 80% power at α = 0.05 to reject a null hypothesis H 0 : ES = 0 versus alternative hypotheses H 1 : ES = ES^, ES = ES^L and ES = ES^U. We aimed to provide point and interval estimates on projected sample sizes for future studies reflecting the uncertainty in our study ES^S. Twenty-four treated RA patients were followed up for 3 months. Utilizing the 12-joint approach and existing methods, the post hoc sample size (95% CI) was 22 (10-245). Corresponding sample sizes using ICUS and IUS were 11 (7-40) and 11 (6-38), respectively. Utilizing a seven-joint approach, the corresponding sample sizes using ICUS and IUS methods were nine (6-24) and 11 (6-35), respectively. Our pilot study suggests that sample size for RA clinical trials with ultrasound endpoints may be reduced using the novel methods, providing justification for larger studies to confirm these observations. © 2017 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.

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

    Science.gov (United States)

    López Ariste, A.; Aulanier, G.; Schmieder, B.; Sainz Dalda, A.

    2006-09-01

    The 3D magnetic field topology of solar filaments/prominences is strongly debated, because it is not directly measureable in the corona. Among various prominence models, several are consistent with many observations, but their related topologies are very different. We conduct observations to address this paradigm. We measure the photospheric vector magnetic field in several small flux concentrations surrounding a filament observed far from disc center. Our objective is to test for the presence/absence of magnetic dips around/below the filament body/barb, which is a strong constraint on prominence models, and that is still untested by observations. Our observations are performed with the THEMIS/MTR instrument. The four Stokes parameters are extracted, from which the vector magnetic fields are calculated using a PCA inversion. The resulting vector fields are then deprojected onto the photospheric plane. The 180° ambiguity is then solved by selecting the only solution that matches filament chirality rules. Considering the weakness of the resulting magnetic fields, a careful analysis of the inversion procedure and its error bars was performed, to avoid over-interpretation of noisy or ambiguous Stokes profiles. Thanks to the simultaneous multi-wavelength THEMIS observations, the vector field maps are coaligned with the Hα image of the filament. By definition, photospheric dips are identifiable where the horizontal component of the magnetic field points from a negative toward a positive polarity. Among six bipolar regions analyzed in the filament channel, four at least display photospheric magnetic dips, i.e. bald patches. For barbs, the topology of the endpoint is that of a bald patch located next to a parasitic polarity, not of an arcade pointing within the polarity. The observed magnetic field topology in the photosphere tends to support models of prominence based on magnetic dips located within weakly twisted flux tubes. Their underlying and lateral extensions form

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

    Energy Technology Data Exchange (ETDEWEB)

    Boveri, M.; Pazos, P.; Gennari, A.; Casado, J.; Hartung, T.; Prieto, P. [ECVAM, Inst. for Health and Consumer Protection, Joint Research Centre, European Commission, Ispra (Italy)

    2004-04-01

    The human colorectal adenocarcinoma cell line Caco-2 is a widely used in vitro model of the intestinal barrier. Cadmium chloride (CdCl{sub 2}) is a highly toxic metal compound, ubiquitous in the biosphere, able to enter the food chain and to reach the intestinal epithelium, causing structural and functional damages. The aim of this work was to characterise cadmium toxicity in Caco-2 cells and, in particular, to compare the sensitivity of different endpoints revealing damage both on the epithelial barrier and at the cellular or molecular level. After 24-h exposure of the cells to CdCl{sub 2}, lactate dehydrogenase (LDH) leakage showed cadmium-induced cell toxicity, significant from 25 {mu}M CdCl{sub 2} and above, and analysis of different cell death pathways indicated the presence of necrosis after treatment with 50 {mu}M CdCl{sub 2}. At the molecular level, we observed an increase in the protective protein heat shock protein 70 (HSP70), starting at 10 {mu}M CdCl{sub 2}. At the barrier level, transepithelial electrical resistance (TEER) decreased while paracellular permeability (PCP) significantly increased after the treatment, showing an EC{sub 50} of 6 and 16 {mu}M CdCl{sub 2}, respectively, and indicating the loss of barrier integrity. In conclusion, our data reveal that CdCl{sub 2} toxicity in Caco-2 cells can be detected at the barrier level at very low concentrations; also, HSP70 was shown to be a sensitive marker for detecting in vitro cadmium-induced toxicity. (orig.)

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

    Directory of Open Access Journals (Sweden)

    Brian K Chu

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

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

    Science.gov (United States)

    Farkas, Bence; Kardos, Péter; Orosz, Szabolcs; Tarnawa, István; Csekő, Csongor; Lévay, György; Farkas, Sándor; Lendvai, Balázs; Kovács, Péter

    2015-11-02

    The trigeminovascular system has a pivotal role in the pathomechanism of migraine. The aim of the present study was to further develop existing models of migraine making them more suitable for testing the effects of compounds with presumed antimigraine activity in anaesthetised rats. Simultaneous recording of ongoing activity of spontaneously active neurons in the trigeminocervical complex as well as their discharges evoked by electrical stimulation of the dura mater via activation of A- and C-sensory fibres were carried out. Effects of sumatriptan, propranolol and topiramate were evaluated prior to and after application of a mixture containing inflammatory mediators on the dura. Propranolol (10 mg/kg s.c) and topiramate (30 mg/kg s.c.) resulted in a tendency to decrease the level of both spontaneous and evoked activity, while sumatriptan (1 mg/kg s.c.) did not exhibit any effect on recorded parameters. Application of an inflammatory soup to the dura mater boosted up spontaneous activity, which could be significantly attenuated by propranolol and topiramate but not by sumatriptan. In addition, all compounds prevented the delayed increase of spontaneous firing. In contrast to the ongoing activity, evoked responses were not augmented by inflammatory mediators. Nevertheless, inhibitory effect of propranolol and topiramate was evident when considering A- or C-fibre responses. Findings do not support the view that electrically evoked responses are useful for the measurement of trigeminal sensitization. It is proposed however, that inhibition of enhanced firing (immediate and/or delayed) evoked by inflammatory mediators as an endpoint have higher predictive validity regarding the clinical effectiveness of compounds. Copyright © 2015 Elsevier B.V. All rights reserved.

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

    Energy Technology Data Exchange (ETDEWEB)

    Hinton, T.G.; Congdon, J.; Scott, D. [Univ. of Georgia, Aiken, SC (US). Savannah River Ecology Lab.; Rowe, C. [Univ. of Puerto Rico, San Juan (PR); Bedford, J.; Whicker, W. [Colorado State Univ., Fort Collins, CO (US)

    1998-06-01

    'The goal of this report is to establish a protocol for assessing risks to non-human populations exposed to environmental stresses typically found on many DOE sites. The authors think that they can achieve this by using novel biological dosimeters in controlled, manipulative dose/effects experiments, and by coupling changes in metabolic rates and energy allocation patterns to meaningful population response variables (such as age-specific survivorship, reproductive output, age at maturity and longevity). This research is needed to determine the relevancy of sublethal cellular damage to the performance of individuals and populations exposed to chronic, low-level radiation, and radiation with concomitant exposure to chemicals. They believe that a scientifically defensible endpoint for measuring ecological risks can only be determined once its understood the extent to which molecular damage from contaminant exposure is detrimental at the individual and population levels of biological organization. The experimental facility will allow them to develop a credible assessment tool for appraising ecological risks, and to evaluate the effects of radionuclide/chemical synergisms on non-human species. This report summarizes work completed midway of a 3-year project that began in November 1996. Emphasis to date has centered on three areas: (1) developing a molecular probe to measure stable chromosomal aberrations known as reciprocal translocations, (2) constructing an irradiation facility where the statistical power inherent in replicated mesocosms can be used to address the response of non-human organisms to exposures from low levels of radiation and metal contaminants, and (3) quantifying responses of organisms living in contaminated mesocosms and field sites.'

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

    Science.gov (United States)

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

    2013-01-01

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

  9. Nuclear War Survival Skills

    Energy Technology Data Exchange (ETDEWEB)

    Kearny, C.H.

    2002-06-24

    The purpose of this book is to provide Americans with information and instructions that will significantly increase their chances of surviving a possible nuclear attack. It brings together field-tested instructions that, if followed by a large fraction of Americans during a crisis that preceded an attack, could save millions of lives. The author is convinced that the vulnerability of our country to nuclear threat or attack must be reduced and that the wide dissemination of the information contained in this book would help achieve that objective of our overall defense strategy.

  10. Survival after blood transfusion

    DEFF Research Database (Denmark)

    Kamper-Jørgensen, Mads; Ahlgren, Martin; Rostgaard, Klaus

    2008-01-01

    of transfusion recipients in Denmark and Sweden followed for up to 20 years after their first blood transfusion. Main outcome measure was all-cause mortality. RESULTS: A total of 1,118,261 transfusion recipients were identified, of whom 62.0 percent were aged 65 years or older at the time of their first...... the SMR remained significantly 1.3-fold increased. CONCLUSION: The survival and relative mortality patterns among blood transfusion recipients were characterized with unprecedented detail and precision. Our results are relevant to assessments of the consequences of possible transfusion-transmitted disease...... as well as for cost-benefit estimation of new blood safety interventions....

  11. Survival curves for irradiated cells

    International Nuclear Information System (INIS)

    Gibson, D.K.

    1975-01-01

    The subject of the lecture is the probability of survival of biological cells which have been subjected to ionising radiation. The basic mathematical theories of cell survival as a function of radiation dose are developed. A brief comparison with observed survival curves is made. (author)

  12. Survival analysis of colorectal cancer patients with tumor recurrence using global score test methodology

    Energy Technology Data Exchange (ETDEWEB)

    Zain, Zakiyah, E-mail: zac@uum.edu.my; Ahmad, Yuhaniz, E-mail: yuhaniz@uum.edu.my [School of Quantitative Sciences, Universiti Utara Malaysia, UUM Sintok 06010, Kedah (Malaysia); Azwan, Zairul, E-mail: zairulazwan@gmail.com, E-mail: farhanaraduan@gmail.com, E-mail: drisagap@yahoo.com; Raduan, Farhana, E-mail: zairulazwan@gmail.com, E-mail: farhanaraduan@gmail.com, E-mail: drisagap@yahoo.com; Sagap, Ismail, E-mail: zairulazwan@gmail.com, E-mail: farhanaraduan@gmail.com, E-mail: drisagap@yahoo.com [Surgery Department, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, 56000 Bandar Tun Razak, Kuala Lumpur (Malaysia); Aziz, Nazrina, E-mail: nazrina@uum.edu.my

    2014-12-04

    Colorectal cancer is the third and the second most common cancer worldwide in men and women respectively, and the second in Malaysia for both genders. Surgery, chemotherapy and radiotherapy are among the options available for treatment of patients with colorectal cancer. In clinical trials, the main purpose is often to compare efficacy between experimental and control treatments. Treatment comparisons often involve several responses or endpoints, and this situation complicates the analysis. In the case of colorectal cancer, sets of responses concerned with survival times include: times from tumor removal until the first, the second and the third tumor recurrences, and time to death. For a patient, the time to recurrence is correlated to the overall survival. In this study, global score test methodology is used in combining the univariate score statistics for comparing treatments with respect to each survival endpoint into a single statistic. The data of tumor recurrence and overall survival of colorectal cancer patients are taken from a Malaysian hospital. The results are found to be similar to those computed using the established Wei, Lin and Weissfeld method. Key factors such as ethnic, gender, age and stage at diagnose are also reported.

  13. Secondary amenorrhea (image)

    Science.gov (United States)

    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 ...

  14. Survival Analysis of Patients with End Stage Renal Disease

    Science.gov (United States)

    Urrutia, J. D.; Gayo, W. S.; Bautista, L. A.; Baccay, E. B.

    2015-06-01

    This paper provides a survival analysis of End Stage Renal Disease (ESRD) under Kaplan-Meier Estimates and Weibull Distribution. The data were obtained from the records of V. L. MakabaliMemorial Hospital with respect to time t (patient's age), covariates such as developed secondary disease (Pulmonary Congestion and Cardiovascular Disease), gender, and the event of interest: the death of ESRD patients. Survival and hazard rates were estimated using NCSS for Weibull Distribution and SPSS for Kaplan-Meier Estimates. These lead to the same conclusion that hazard rate increases and survival rate decreases of ESRD patient diagnosed with Pulmonary Congestion, Cardiovascular Disease and both diseases with respect to time. It also shows that female patients have a greater risk of death compared to males. The probability risk was given the equation R = 1 — e-H(t) where e-H(t) is the survival function, H(t) the cumulative hazard function which was created using Cox-Regression.

  15. Nuclear war survival skills

    International Nuclear Information System (INIS)

    Kearney, C.H.

    1979-09-01

    This book includes chapters on psychological preparations, warning and communications, and evacuation. It describes the building of expedient shelters, their ventilation and cooling, the purification and storage of adequate water, the processing and cooking of whole grains and legumes, fallout meters, protection against fires and carbon monoxide, and expedient furnishings for shelters. Other chapters cover sanitation and preventive medicine, medical advice for nuclear survivors lacking the help of doctors, improvised footwear and clothing, and advice on minimum preparations that can be made at low cost and should be made before a crisis arises. One appendix of the handbook gives detailed, field-tested instructions for building six types of earth-covered expedient fallout shelters, with criteria to guide the choice of which shelter to build. Others contain instructions for making an efficient shelter-ventilating pump and a homemade fallout meter that is accurate and dependable with inexpensive materials found in most households. This report is primarily a compilation and summary of civil defense measures and inventions developed at ORNL over the past 14 years and field-tested in six states, from Florida to Utah. It is the first comprehensive handbook of survival information for use by untrained citizens who want to improve their chances of surviving a possible nuclear attack. Sections may be easily excerpted and reproduced for mass distribution through news media

  16. Towards secondary fingerprint classification

    CSIR Research Space (South Africa)

    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...

  17. Secondary Fire Analysis.

    Science.gov (United States)

    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

  18. The RENAISSANCE (AIO-FLOT5) trial: effect of chemotherapy alone vs. chemotherapy followed by surgical resection on survival and quality of life in patients with limited-metastatic adenocarcinoma of the stomach or esophagogastric junction - a phase III trial of the German AIO/CAO-V/CAOGI.

    Science.gov (United States)

    Al-Batran, Salah-Eddin; Goetze, Thorsten O; Mueller, Daniel W; Vogel, Arndt; Winkler, Michael; Lorenzen, Sylvie; Novotny, Alexander; Pauligk, Claudia; Homann, Nils; Jungbluth, Thomas; Reissfelder, Christoph; Caca, Karel; Retter, Steffen; Horndasch, Eva; Gumpp, Julia; Bolling, Claus; Fuchs, Karl-Hermann; Blau, Wolfgang; Padberg, Winfried; Pohl, Michael; Wunsch, Andreas; Michl, Patrick; Mannes, Frank; Schwarzbach, Matthias; Schmalenberg, Harald; Hohaus, Michael; Scholz, Christian; Benckert, Christoph; Knorrenschild, Jorge Riera; Kanngießer, Veit; Zander, Thomas; Alakus, Hakan; Hofheinz, Ralf-Dieter; Roedel, Claus; Shah, Manish A; Sasako, Mitsuru; Lorenz, Dietmar; Izbicki, Jakob; Bechstein, Wolf O; Lang, Hauke; Moenig, Stefan P

    2017-12-28

    Historical data indicate that surgical resection may benefit select patients with metastatic gastric and gastroesophageal junction cancer. However, randomized clinical trials are lacking. The current RENAISSANCE trial addresses the potential benefits of surgical intervention in gastric and gastroesophageal junction cancer with limited metastases. This is a prospective, multicenter, randomized, investigator-initiated phase III trial. Previously untreated patients with limited metastatic stage (retroperitoneal lymph node metastases only or a maximum of one incurable organ site that is potentially resectable or locally controllable with or without retroperitoneal lymph nodes) receive 4 cycles of FLOT chemotherapy alone or with trastuzumab if Her2+. Patients without disease progression after 4 cycles are randomized 1:1 to receive additional chemotherapy cycles or surgical resection of primary and metastases followed by subsequent chemotherapy. 271 patients are to be allocated to the trial, of which at least 176 patients will proceed to randomization. The primary endpoint is overall survival; main secondary endpoints are quality of life assessed by EORTC-QLQ-C30 questionnaire, progression free survival and surgical morbidity and mortality. Recruitment has already started; currently (Feb 2017) 22 patients have been enrolled. If the RENAISSANCE concept proves to be effective, this could potentially lead to a new standard of therapy. On the contrary, if the outcome is negative, patients with gastric or GEJ cancer and metastases will no longer be considered candidates for surgical intervention. The article reports of a health care intervention on human participants and is registered on October 12, 2015 under ClinicalTrials.gov Identifier: NCT02578368 ; EudraCT: 2014-002665-30.

  19. Impact of Secondary Prevention on Mortality after a First Ischemic Stroke in Puerto Rico.

    Science.gov (United States)

    Rojas, Maria E; Marsh, Wallace; Felici-Giovanini, Marcos E; Rodríguez-Benitez, Rosa J; Zevallos, Juan C

    2017-03-01

    The objective of this study was to evaluate the impact of the prescription of secondary prevention therapies on mortality in Puerto Rican patients hospitalized with a first ischemic stroke. This was a retrospective secondary data analysis of the 2007 and 2009 Puerto Rico Stroke Registry electronic database. Information was obtained from the medical charts of patients discharged with ICD-9 codes 434 and 436 from 20 hospitals located in Puerto Rico. Descriptive analyses were conducted for demographics and comorbidities. Chi2 statistics compared the proportion of patients prescribed secondary prevention therapy and the proportion of patients not prescribed secondary prevention therapy. Lastly, survival rates were calculated from 2007 up to and including December 2010. The mean age of the 3,965 patients was 70 (±14) years. Secondary prevention therapy was prescribed to only 1% of the patients. The most frequent comorbidities were hypertension (85%), diabetes (52%), and hyperlipidemia (25%). The case fatality rate for patients prescribed secondary prevention therapy was 16%, compared to 26% for patients not prescribed secondary prevention therapy (p<0.01). The mean survival for stroke patients prescribed secondary preventions was 450 days (95% CI;182−718), compared to 266 days (95% CI; 244−287) for those not prescribed secondary prevention therapy (p = 0.175). A low percentage of patients with a first ischemic stroke were prescribed secondary prevention therapy. While not statistically significant, survival analysis suggests that secondary prevention therapy decreased mortality in patients with a stroke.

  20. Lack of Bystander Effects From High LET Radiation For Early Cytogenetic Endpoints.

    Energy Technology Data Exchange (ETDEWEB)

    Groesser, Torsten; Cooper, Brian; Rydberg, Bjorn

    2008-05-07

    The aim of this work was to study radiation-induced bystander effects for early cytogenetic end points in various cell lines using the medium transfer technique after exposure to high- and low-LET radiation. Cells were exposed to 20 MeV/ nucleon nitrogen ions, 968 MeV/nucleon iron ions, or 575 MeV/nucleon iron ions followed by transfer of the conditioned medium from the irradiated cells to unirradiated test cells. The effects studied included DNA double-strand break induction, {gamma}-H2AX focus formation, induction of chromatid breaks in prematurely condensed chromosomes, and micronucleus formation using DNA repair-proficient and -deficient hamster and human cell lines (xrs6, V79, SW48, MO59K and MO59J). Cell survival was also measured in SW48 bystander cells using X rays. Although it was occasionally possible to detect an increase in chromatid break levels using nitrogen ions and to see a higher number of {gamma}-H2AX foci using nitrogen and iron ions in xrs6 bystander cells in single experiments, the results were not reproducible. After we pooled all the data, we could not verify a significant bystander effect for any of these end points. Also, we did not detect a significant bystander effect for DSB induction or micronucleus formation in these cell lines or for clonogenic survival in SW48 cells. The data suggest that DNA damage and cytogenetic changes are not induced in bystander cells. In contrast, data in the literature show pronounced bystander effects in a variety of cell lines, including clonogenic survival in SW48 cells and induction of chromatid breaks and micronuclei in hamster cells. To reconcile these conflicting data, it is possible that the epigenetic status of the specific cell line or the precise culture conditions and medium supplements, such as serum, may be critical for inducing bystander effects.

  1. Incidence and survival in non-hereditary amyloidosis in Sweden

    Directory of Open Access Journals (Sweden)

    Hemminki Kari

    2012-11-01

    Full Text Available Abstract Background Amyloidosis is a heterogeneous disease caused by deposition of amyloid fibrils in organs and thereby interfering with physiological functions. Hardly any incidence data are available and most survival data are limited to specialist clinics. Methods Amyloidosis patients were identified from the Swedish Hospital Discharge and Outpatients Registers from years 2001 through 2008. Results The incidence of non-hereditary amyloidosis in 949 patients was 8.29 per million person-years and the diagnostic age with the highest incidence was over 65 years. Secondary systemic amyloidosis showed an incidence of 1 per million and a female excess and the largest number of subsequent rheumatoid arthritis deaths; the median survival was 4 years. However, as rheumatoid arthritis deaths also occurred in other diagnostic subtypes, the incidence of secondary systemic amyloidosis was likely to be about 2.0 per million. The median survival of patients with organ-limited amyloidosis was 6 years. Most myeloma deaths occurred in patients diagnosed with unspecified or ‘other’ amyloidosis. These subtypes probably accounted for most of immunoglobulin light chain (AL amyloidosis cases; the median survival time was 3 years. Conclusions The present diagnostic categorization cannot single out AL amyloidosis in the Swedish discharge data but, by extrapolation from myeloma cases, an incidence of 3.2 per million could be ascribed to AL amyloidosis. Similarly, based on rheumatoid arthritis death rates, an incidence of 2.0 could be ascribed to secondary systemic amyloidosis.

  2. Evaluation of surviving fraction using nonclonogenic staining densitometry method

    International Nuclear Information System (INIS)

    Nishiguchi, Iku; Ogawa, Koichi; Ito, Hisao; Hashimoto, Shozo

    1994-01-01

    This study was performed to compare our nonclonogenic survival assay (densitometry assay, DM assay) with the widely used clonogenic assay. The established cell lines (HaLa, RMUG, IMR, GOTO) were grown in F 10 medium. The cells were spread in 24-well plates, irradiated with different doses, cultured for about one week and stained with crystal violet after the culture period. Taking the transparent images of the stained well on the light source with the CCD camera, the images were collected with the matrix size 64 x 64, and the integrated optical density of the entire surface of each well was determined by computer with our original program. As the number of cells in the well is reflected by its staining density, the surviving fraction was calculated as the fraction of growth in the irradiated wells relative to controls. The survival curves obtained by the densitometry method showed good correlations with those obtained by clonogenic assay. It is possible to predict intrinsic radiosensitivity with this assay, even if the cells do not form good colonies. However, this method is based on measurements in cultures which depend on the metabolism and growth kinetics of the irradiated cells. Cells should grow exponetially in the same manner in any well to obtain a result similar to that of clonogenic assay, although growth kinetics may be altered by irradiation. This, the endpoint must be strictly standardized. (author)

  3. Investment activities in the U.S. secondary woodworking industry

    Science.gov (United States)

    Matthew Bumgardner; Urs Buehlmann; Karen. Koenig

    2017-01-01

    The U.S. secondary woodworking industry has shown signs of improvement after the steep losses in sales volume associated with the housing crisis that began in 2007. Employment in several sectors has begun to increase, suggesting that companies that survived the downturn are positioning to increase sales growth. It is likely that investment plans to improve firm-level...

  4. Effectiveness of Transformational Leadership Style in Secondary Schools in Nigeria

    Science.gov (United States)

    Money, Veronica. O.

    2017-01-01

    Education is the engine of national growth. A population of well educated citizens increases national economic competitiveness. To survive and develop in any nation, the education industry must grow. Secondary schools in Nigeria are headed by Principal. They are regarded as the Chief Executive of the school and are held accountable for all that…

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

    International Nuclear Information System (INIS)

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

    2003-01-01

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

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

    Science.gov (United States)

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

    2017-05-01

    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.

  7. Surviving Sepsis Campaign

    DEFF Research Database (Denmark)

    Rhodes, Andrew; Evans, Laura E; Alhazzani, Waleed

    2017-01-01

    OBJECTIVE: To provide an update to "Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012." DESIGN: A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings...... (for those committee members attending the conference). A formal conflict-of-interest (COI) policy was developed at the onset of the process and enforced throughout. A stand-alone meeting was held for all panel members in December 2015. Teleconferences and electronic-based discussion among subgroups......, and evidence profiles were generated. Each subgroup generated a list of questions, searched for best available evidence, and then followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence from high to very low...

  8. Surviving Sepsis Campaign

    DEFF Research Database (Denmark)

    Rhodes, Andrew; Evans, Laura E; Alhazzani, Waleed

    2017-01-01

    OBJECTIVE: To provide an update to "Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012". DESIGN: A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings...... (for those committee members attending the conference). A formal conflict-of-interest (COI) policy was developed at the onset of the process and enforced throughout. A stand-alone meeting was held for all panel members in December 2015. Teleconferences and electronic-based discussion among subgroups......, and evidence profiles were generated. Each subgroup generated a list of questions, searched for best available evidence, and then followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence from high to very low...

  9. Surviving relatives after suicide

    DEFF Research Database (Denmark)

    Nørrelykke, Helle; Cohrt, Pernille

    and that suicide has become a subject of research, prevention and treatment. Auxiliary Strategies In the 1990s there have been established the Centre for Suicide Research and the Centre for Prevention of Suicide in Denmark and there has been drafted a national policy document which focuses on the need......We would like to focus on the surviving relatives after suicides, because it is generally accepted that it is especially difficult to recover after the loss from suicide and because we know as a fact that one suicide affects five persons on average. Every year approximately 700 people commit...... suicide in Denmark. This means that at least 400 people undergo the trauma it is when one of their near relatives commits suicide. We also know that the loss from suicide involves a lot of conflicting feelings - like anger, shame, guilt and loss and that the lack of therapy/treatment of these difficult...

  10. Quantitative interpretation of heavy ion effects: Comparison of different systems and endpoints

    Science.gov (United States)

    Kiefer, J.

    For a quantitative interpretation of biological heavy ion action the following parameters have to be taken into account: variations of energy depositions in microscopical sites, the dependence of primary lesion formation on local energy density and changes in repairability. They can be studied in objects of different size and with different sensitivities. Results on survival and mutation induction in yeast and in mammalian cells will be compared with theoretical predictions. It is shown that shouldered survival curves of diploid yeast can be adequately described if the final slope is adjusted according to the varying production of primary lesions. This is not the case for mammalian cells where the experiments show a rapid loss of the shoulder with LET, contrary to theoretical expectations. This behaviour is interpreted to mean that the repairability of heavy ion lesions is different in the two systems. Mutation induction is theoretically expected to decrease with higher LET. This is found in yeast but not in mammalian cells where it actually increases. These results suggest a higher rate of misrepair in mammalian cells.

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

    Science.gov (United States)

    Manfra, Loredana; Canepa, Sara; Piazza, Veronica; Faimali, Marco

    2016-01-01

    Swimming speed alteration and mortality assays with the marine crustacean Artemia franciscana were carried out. EC50 and LC50 values after 24-48h exposures were calculated for two reference toxicants, copper sulphate pentahydrate (CuSO4·5H2O) and Sodium Dodecyl Sulphate (SDS), and an ecotoxicological concern organic compound, Diethylene Glycol (DEG). Different end-points have been evaluated, in order to point out their sensitivity levels. The swimming speed alteration (SSA) was compared to mortality values and also to the hatching rate inhibition (literature data). SSA resulted to be more sensitive than the mortality and with a sensitivity comparable to (or even higher than) the hatching rate endpoint. Copyright © 2015 Elsevier Inc. All rights reserved.

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

    Science.gov (United States)

    Mangoni, Arduino A; Pilotto, Alberto

    2016-01-01

    Older patients with various degrees of frailty and disability, a key population target of pharmacological interventions in acute and chronic disease states, are virtually neglected in pre-marketing studies assessing the efficacy and safety of investigational drugs. Moreover, aggressively pursuing established therapeutic targets in old age, e.g. blood pressure, serum glucose or cholesterol concentrations, is not necessarily associated with the beneficial effects, and the acceptable safety, reported in younger patient cohorts. Measures of self-reported health and functional status might represent additional, more meaningful, therapeutic end-points in the older population, particularly in patients with significant frailty and relatively short life expectancy, e.g. in the presence of cancer and/or neurodegenerative disease conditions. Strategies enhancing early knowledge about key pharmacological characteristics of investigational drugs targeting older adults are discussed, together with the rationale for incorporating non-traditional, patient-centred, end-points in this ever-increasing group.

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

    Science.gov (United States)

    Toropov, Andrey A; Toropova, Alla P

    2014-06-01

    The experimental data on the bacterial reverse mutation test on C60 nanoparticles (TA100) is examined as an endpoint. By means of the optimal descriptors calculated with the Monte Carlo method a mathematical model of the endpoint has been built up. The model is the mathematical function of (i) dose (g/plate); (ii) metabolic activation (i.e. with S9 mix or without S9 mix); and (iii) illumination (i.e. dark or irradiation). The statistical quality of the model is the following: n=10, r(2)=0.7549, q(2)=0.5709, s=7.67, F=25 (Training set); n=5, r(2)=0.8987, s=18.4 (Calibration set); and n=5, r(2)=0.6968, s=10.9 (Validation set). Copyright © 2013 Elsevier Ltd. All rights reserved.

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

    International Nuclear Information System (INIS)

    Liu Xiaohui

    2010-01-01

    A recent study indicates that the α 2 α s 2 order QED processes of Υ→J/ψ+X decay are compatible with those of QCD processes. However, in the endpoint region, the nonrelativistic QED calculation breaks down since the collinear degrees of freedom are missing under the framework of this effective theory. In this paper we apply the soft-collinear effective theory (SCET) to study the color-singlet QED process at the kinematic limit. Within this approach we are able to sum the kinematic logarithms by running operators using the renormalization group equations of soft-collinear effective theory, which will lead to a dramatic change in the momentum distribution near the endpoint and the spectrum shape consistent with the experimental results.

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

    Science.gov (United States)

    Horemans, Nele; Van Hees, May; Saenen, Eline; Van Hoeck, Arne; Smolders, Valérie; Blust, Ronny; Vandenhove, Hildegarde

    2016-01-01

    Uranium (U) toxicity is known to be highly dependent on U speciation and bioavailability. To assess the impact of uranium on plants, a growth inhibition test was set up in the freshwater macrophyte Lemna minor. First growth media with different compositions were tested in order to find a medium fit for testing U toxicity in L. minor. Following arguments were used for medium selection: the ability to sustain L. minor growth, a high solubility of U in the medium and a high percentage of the more toxic U-species namely UO2(2+). Based on these selection criteria a with a low phosphate concentration of 0.5 mg L(-1) and supplemented with 5 mM MES (2-(N-morpholino)ethanesulfonic acid) to ensure pH stability was chosen. This medium also showed highest U toxicity compared to the other tested media. Subsequently a full dose response curve for U was established by exposing L. minor plants to U concentrations ranging from 0.05 μM up to 150 μM for 7 days. Uranium was shown to adversely affect growth of L. minor in a dose dependent manner with EC10, EC30 and EC50 values ranging between 1.6 and 4.8 μM, 7.7-16.4 μM and 19.4-37.2 μM U, respectively, depending on the growth endpoint. Four different growth related endpoints were tested: frond area, frond number, fresh weight and dry weight. Although differences in relative growth rates and associated ECx-values calculated on different endpoints are small (maximal twofold difference), frond area is recommended to be used to measure U-induced growth effects as it is a sensitive growth endpoint and easy to measure in vivo allowing for measurements over time. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

    Science.gov (United States)

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

    2017-11-01

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

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

    OpenAIRE

    Nuno H Franco; Margarida Correia-Neves; I Anna S Olsson

    2012-01-01

    Public concern on issues such as animal welfare or the scientific validity and clinical value of animal research is growing, resulting in increasing regulatory demands for animal research. Abiding to the most stringent animal welfare standards, while having scientific objectives as the main priority, is often challenging. To do so, endpoints of studies involving severe, progressive diseases need to be established considering how early in the disease process the scientific objectives can be ac...

  18. Secondary metabolites from Ganoderma.

    Science.gov (United States)

    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.

  19. Pulmonary arterial hypertension secondary to chronic thromboemboli

    International Nuclear Information System (INIS)

    Crysikopoulos, H.; Forrest, J.V.; Olson, L.K.; Roberts, A.C.

    1989-01-01

    The authors report their experience in 150 patients with pulmonary arterial hypertension secondary to chronic pulmonary embolism (CPE). Plain film findings are variable, commonly nonspecific. Occasionally nonuniformity of pulmonary perfusion or truncation of central pulmonary arteries suggest CPE. Multiple, large, unmatched perfusion defects are the most common scintigraphic observations. CT can exclude conditions mimicking CPE, particularly fibrosing mediastinitis. Pulmonary arteriography depicts the location and distribution of emboli. CPE is becoming an increasingly important entity to recognize because of available surgical treatment. Thromboendarterectomy may improve functional status and survival. The diagnosis should be considered in any patient with pulmonary arterial hypertension

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

    Science.gov (United States)

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

    2015-11-01

    No standard time or pharmacopoeia disintegration test method for orodispersible films (ODFs) exists. The USP disintegration test for tablets and capsules poses significant challenges for end-point determination when used for ODFs. We tested a newly developed disintegration test unit (DTU) against the USP disintegration test. The DTU is an accessory to the USP disintegration apparatus. It holds the ODF in a horizontal position, allowing top-view of the ODF during testing. A Gauge R&R study was conducted to assign relative contributions of the total variability from the operator, sample or the experimental set-up. Precision was compared using commercial ODF products in different media. Agreement between the two measurement methods was analysed. The DTU showed improved repeatability and reproducibility compared to the USP disintegration system with tighter standard deviations regardless of operator or medium. There is good agreement between the two methods, with the USP disintegration test giving generally longer disintegration times possibly due to difficulty in end-point determination. The DTU provided clear end-point determination and is suitable for quality control of ODFs during product developmental stage or manufacturing. This may facilitate the development of a standardized methodology for disintegration time determination of ODFs. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:3893-3903, 2015. Copyright © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

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

    Science.gov (United States)

    Tao, Tao; Wyer, Robert S; Zheng, Yuhuang

    2017-03-01

    We propose a two-process conceptualization of numerical information processing to describe how people form impressions of a score that is described along a bounded scale. According to the model, people spontaneously categorize a score as high or low. Furthermore, they compare the numerical discrepancy between the score and the endpoint of the scale to which it is closer, if they are not confident of their categorization, and use implications of this comparison as a basis for judgment. As a result, their evaluation of the score is less extreme when the range of numbers along the scale is large (e.g., from 0 to 100) than when it is small (from 0 to 10). Six experiments support this two-process model and demonstrate its generalizability. Specifically, the magnitude of numbers composing the scale has less impact on judgments (a) when the score being evaluated is extreme, (b) when individuals are unmotivated to engage in endpoint comparison processes (i.e., they are low in need for cognition), and (c) when they are unable to do so (i.e., they are under cognitive load). Moreover, the endpoint to which individuals compare the score can depend on their regulatory focus. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

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

    Science.gov (United States)

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

    2016-10-01

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

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

    Science.gov (United States)

    Ulker, Ozge Cemiloglu; Kaymak, Yesim; Karakaya, Asuman

    2014-01-01

    Balsam of Peru and fragrance mix are commonly used in cosmetic products. Allergy to fragrance is the most common cause of cosmetic contact dermatitis. In the present study, ex vivo local lymph node assay-5-bromo-2'-deoxyuridine (LLNA-BrdU) was used to evaluate the dermal sensitization potential of these cosmetic mixtures. The stimulation index values and estimated concentration (EC3) values were calculated and the potency classification was found for each mixture. At the same time, in order to measure the irritant effect without having to use additional animals, a combination of ex vivo LLNA-BrdU and the irritancy assay was conducted. Th1 [interleukin (IL)-2, interferon-γ] and Th2 cytokine (IL-4, IL-5) releases from lymph node cell culture were investigated as non-radioactive endpoints. According to the results of ex vivo LLNA-BrdU assays, EC3 values were found to be 3.09% (moderate) for balsam of Peru and 4.44% (moderate) for fragrance mix. Cytokine analysis results indicate that both Th1 and Th2 cytokines are involved in the regulation of murine contact allergy and can be considered as useful endpoints. In conclusion, according to our results, fragrance mix and balsam of Peru can be considered as moderate sensitizers; however, in high concentrations, both of them have irritation properties. The cytokines investigated can be considered as the endpoints of the ex vivo LLNA-BrdU assay. © 2014 S. Karger AG, Basel.

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

    Science.gov (United States)

    Single, Andrew; Beetham, Henry; Telford, Bryony J; Guilford, Parry; Chen, Augustine

    2015-12-01

    Cell viability assays fulfill a central role in drug discovery studies. It is therefore important to understand the advantages and disadvantages of the wide variety of available assay methodologies. In this study, we compared the performance of three endpoint assays (resazurin reduction, CellTiter-Glo, and nuclei enumeration) and two real-time systems (IncuCyte and xCELLigence). Of the endpoint approaches, both the resazurin reduction and CellTiter-Glo assays showed higher cell viabilities when compared directly to stained nuclei counts. The IncuCyte and xCELLigence real-time systems were comparable, and both were particularly effective at tracking the effects of drug treatment on cell proliferation at sub-confluent growth. However, the real-time systems failed to evaluate contrasting cell densities between drug-treated and control-treated cells at full growth confluency. Here, we showed that using real-time systems in combination with endpoint assays alleviates the disadvantages posed by each approach alone, providing a more effective means to evaluate drug toxicity in monolayer cell cultures. Such approaches were shown to be effective in elucidating the toxicity of synthetic lethal drugs in an isogenic pair of MCF10A breast cell lines. © 2015 Society for Laboratory Automation and Screening.

  5. Neoadjuvant plus adjuvant bevacizumab in early breast cancer (NSABP B-40 [NRG Oncology]): secondary outcomes of a phase 3, randomised controlled trial.

    Science.gov (United States)

    Bear, Harry D; Tang, Gong; Rastogi, Priya; Geyer, Charles E; Liu, Qing; Robidoux, André; Baez-Diaz, Luis; Brufsky, Adam M; Mehta, Rita S; Fehrenbacher, Louis; Young, James A; Senecal, Francis M; Gaur, Rakesh; Margolese, Richard G; Adams, Paul T; Gross, Howard M; Costantino, Joseph P; Paik, Soonmyung; Swain, Sandra M; Mamounas, Eleftherios P; Wolmark, Norman

    2015-09-01

    NSABP B-40 was a 3 × 2 factorial trial testing whether adding capecitabine or gemcitabine to docetaxel followed by doxorubicin plus cyclophosphamide neoadjuvant chemotherapy would improve outcomes in women with operable, HER2-negative breast cancer and whether adding neoadjuvant plus adjuvant bevacizumab to neoadjuvant chemotherapy regimens would also improve outcomes. As reported previously, addition of neoadjuvant bevacizumab increased the proportion of patients achieving a pathological complete response, which was the primary endpoint. We present secondary patient outcomes, including disease-free survival, a specified endpoint by protocol, and data for distant recurrence-free interval, and overall survival, which were not prespecified endpoints but were collected prospectively. In this randomised controlled trial (NSABP B-40), we enrolled women aged 18 years or older, with operable, HER2-non-amplified invasive adenocarcinoma of the breast, 2 cm or greater in diameter by palpation, clinical stage T1c-3, cN0, cN1, or cN2a, without metastatic disease and diagnosed by core needle biopsy. Patients received one of three docetaxel-based neoadjuvant regimens for four cycles: docetaxel alone (100 mg/m(2)) with addition of capecitabine (825 mg/m(2) oral twice daily days 1-14, 75 mg/m(2) docetaxel) or with addition of gemcitabine (1000 mg/m(2) days 1 and 8 intravenously, 75 mg/m(2) docetaxel), all followed by neoadjuvant doxorubicin and cyclophosphamide (60 mg/m(2) and 600 mg/m(2) intravenously) every 3 weeks for four cycles. Those randomly assigned to bevacizumab groups were to receive bevacizumab (15 mg/kg, every 3 weeks for six cycles) with neoadjuvant chemotherapy and postoperatively for ten doses. Randomisation was done (1:1:1:1:1:1) via a biased-coin minimisation procedure to balance the characteristics with respect to clinical nodal status, clinical tumour size, hormone receptor status, and age. Intent-to-treat analyses were done for disease-free survival and

  6. On the relationship between tumour growth rate and survival in non-small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Hitesh B. Mistry

    2017-11-01

    Full Text Available A recurrent question within oncology drug development is predicting phase III outcome for a new treatment using early clinical data. One approach to tackle this problem has been to derive metrics from mathematical models that describe tumour size dynamics termed re-growth rate and time to tumour re-growth. They have shown to be strong predictors of overall survival in numerous studies but there is debate about how these metrics are derived and if they are more predictive than empirical end-points. This work explores the issues raised in using model-derived metric as predictors for survival analyses. Re-growth rate and time to tumour re-growth were calculated for three large clinical studies by forward and reverse alignment. The latter involves re-aligning patients to their time of progression. Hence, it accounts for the time taken to estimate re-growth rate and time to tumour re-growth but also assesses if these predictors correlate to survival from the time of progression. I found that neither re-growth rate nor time to tumour re-growth correlated to survival using reverse alignment. This suggests that the dynamics of tumours up until disease progression has no relationship to survival post progression. For prediction of a phase III trial I found the metrics performed no better than empirical end-points. These results highlight that care must be taken when relating dynamics of tumour imaging to survival and that bench-marking new approaches to existing ones is essential.

  7. Network survivability performance (computer diskette)

    Science.gov (United States)

    1993-11-01

    File characteristics: Data file; 1 file. Physical description: 1 computer diskette; 3 1/2 in.; high density; 2.0MB. System requirements: Mac; Word. This technical report has been developed to address the survivability of telecommunications networks including services. It responds to the need for a common understanding of, and assessment techniques for network survivability, availability, integrity, and reliability. It provides a basis for designing and operating telecommunication networks to user expectations for network survivability.

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

    Directory of Open Access Journals (Sweden)

    Grassi Luigi

    2009-05-01

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

  9. Depression and Liver Transplant Survival.

    Science.gov (United States)

    Meller, William; Welle, Nicole; Sutley, Kristen; Thurber, Steven

    Patients who underwent liver transplantation and experienced clinical depression have heretofore evinced lower survival rates when compared to nondepressed counterparts. To investigate the hypothesis that transplant patients who seek and obtain medical treatment for depression would circumvent the prior reduced survival findings. A total of 765 patients with liver transplants were scrutinized for complications following transplantation. Further, 104 patients experienced posttransplant depression as manifested by diagnosis and treatment by medical personnel. Survival analyses were conducted comparing hazard and survival curves for these selected individuals and the remainder of transplant patients. Contrary to prior data and consistent with the aforementioned hypothesis, median survival durations, survival curves, and hazard functions (controlling for age and prolonged posttransplant survival for the depressed patients were better. The improved survival for the depressed patients may simply be related to an amelioration of depressed symptoms via antidepressant medications. However, this interpretation would only be congruent with reduced hazard, not elevated survival, beyond the norm (median) for other transplant participants. Assuming the reliability and generalization of our findings, perhaps a reasonable and compelling interpretation is that combined with the effectiveness of antidepressant medications, the seeking and receiving treatment for depression is a type of proxy measure of a more global pattern of adherence to recommended posttransplant medical regimens. Copyright © 2017 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.

  10. Ship Systems Survivability Test Site

    Data.gov (United States)

    Federal Laboratory Consortium — Area for testing survivability of shipboard systems to include electrical, communications, and fire suppression. Multipurpose test range for supporting gun firing,...

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  12. Surviving a Suicide Attempt

    Directory of Open Access Journals (Sweden)

    Ahmed Al-Harrasi

    2016-09-01

    Full Text Available Suicide is a global phenomenon in all regions of the world affecting people of all age groups. It has detrimental consequences on patients, their families, and the community as a whole. There have been numerous risk factors described for suicide including mental illness, stressful life situations, loss of social support, and general despair. The association of suicide with Islam has not been extensively studied. The common impression from clinical practice is that being a practicing Muslim reduces the risk of suicide. Another factor associated with suicide is starting a patient on antidepressants. However, this has been questioned recently. This report describes a middle-aged man with depression and multiple social stressors who survived a serious suicide attempt. The discussion will focus on the factors that lead him to want to end his life and the impact of the assumed protective factors such as religious belief and family support on this act of self-harm. Such patients can be on the edge when there is an imbalance between risk factors (such as depression, insomnia, and psychosocial stressors and protective factors (like religious affiliation and family support. All physicians are advised to assess the suicide risk thoroughly in patients with depression regardless of any presumed protective factor.

  13. Survival and weak chaos.

    Science.gov (United States)

    Nee, Sean

    2018-05-01

    Survival analysis in biology and reliability theory in engineering concern the dynamical functioning of bio/electro/mechanical units. Here we incorporate effects of chaotic dynamics into the classical theory. Dynamical systems theory now distinguishes strong and weak chaos. Strong chaos generates Type II survivorship curves entirely as a result of the internal operation of the system, without any age-independent, external, random forces of mortality. Weak chaos exhibits (a) intermittency and (b) Type III survivorship, defined as a decreasing per capita mortality rate: engineering explicitly defines this pattern of decreasing hazard as 'infant mortality'. Weak chaos generates two phenomena from the normal functioning of the same system. First, infant mortality- sensu engineering-without any external explanatory factors, such as manufacturing defects, which is followed by increased average longevity of survivors. Second, sudden failure of units during their normal period of operation, before the onset of age-dependent mortality arising from senescence. The relevance of these phenomena encompasses, for example: no-fault-found failure of electronic devices; high rates of human early spontaneous miscarriage/abortion; runaway pacemakers; sudden cardiac death in young adults; bipolar disorder; and epilepsy.

  14. A survival programme

    International Nuclear Information System (INIS)

    Vester, F.

    1978-01-01

    The book is a non-speculative information source on ecological problems and their possible solutions. It is a 'programme' from a twofold point of view: it determines political and scientific-technological objectives and it transfers knowledge by mental steps with techniques of programmed instruction. Thus emphasis is laid on detailed problems, especially by conscionsly challenged redundancies, and, on the other hand, a greater context is presented. Selected facts are examined under their different aspects, interactions and control circuits are described. Each chapter will speak for itself after the introduction has been read but is related to other chapters by cross references, illustrative material, a glossary and a comprehensive list of references. The 'Survival Programme' is a realistic and challenging discussion with the problem of 'Ecology in the Industrial Age'. It adresses scientists from various disciplines but also offers itself as a compendium to laymen in search of information, members of citizens initiatives and responsible representants of the political and industrial world. (orig./HP) [de

  15. Dynamics of secondary forests

    NARCIS (Netherlands)

    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

  16. Two secondary drops

    Indian Academy of Sciences (India)

    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.

  17. [Primary and secondary encopresis].

    Science.gov (United States)

    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.

  18. [Secondary thrombotic microangiopathies].

    Science.gov (United States)

    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.

  19. Secondary coolant purification system

    International Nuclear Information System (INIS)

    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

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

    Science.gov (United States)

    Niehaus, Ines; Dintsios, Charalabos-Markos

    2018-03-26

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

  1. Improved survival of baby boomer women with early-stage uterine cancer: A Surveillance, Epidemiology and End Results (SEER) Study.

    Science.gov (United States)

    Elshaikh, Mohamed A; Ruterbusch, Julie; Cote, Michele L; Cattaneo, Richard; Munkarah, Adnan R

    2013-11-01

    To study the prognostic impact of baby boomer (BB) generation on survival end-points of patients with early-stage endometrial carcinoma (EC). Data were obtained from the SEER registry between 1988-2009. Inclusion criteria included women who underwent hysterectomy for stage I-II EC. Patients were divided into two birth cohorts: BB (women born between 1946 and 1964) and pre-boomers (PB) (born between 1926 and 1945). A total of 30,956 patients were analyzed. Considering that women in the PB group were older than those of the BB generation, the statistical analysis was limited to women 50-59 years of age at the time of diagnosis (n=11,473). Baby boomers had a significantly higher percentage of endometrioid histology (pgeneration compared to the PB generation (p=0.0003) with a trend for improved uterine cancer-specific survival (p=0.0752). On multivariate analysis, birth cohort (BB vs. PB) was not a significant predictor of survival end-points. Factors predictive of survival included: tumor grade, FIGO stage, African-American race, and increased number of dissected LN. Our study suggests that the survival of BB women between 50-60 years of age is better compared to women in the PB generation. As more BB patients are diagnosed with EC, further research is warranted.

  2. Obesity adversely affects survival in pancreatic cancer patients.

    Science.gov (United States)

    McWilliams, Robert R; Matsumoto, Martha E; Burch, Patrick A; Kim, George P; Halfdanarson, Thorvardur R; de Andrade, Mariza; Reid-Lombardo, Kaye; Bamlet, William R

    2010-11-01

    Higher body-mass index (BMI) has been implicated as a risk factor for developing pancreatic cancer, but its effect on survival has not been thoroughly investigated. The authors assessed the association of BMI with survival in a sample of pancreatic cancer patients and used epidemiologic and clinical information to understand the contribution of diabetes and hyperglycemia. A survival analysis using Cox proportional hazards by usual adult BMI was performed on 1861 unselected patients with pancreatic adenocarcinoma; analyses were adjusted for covariates that included clinical stage, age, and sex. Secondary analyses incorporated self-reported diabetes and fasting blood glucose in the survival model. BMI as a continuous variable was inversely associated with survival from pancreatic adenocarcinoma (hazard ratio [HR], 1.019 for each increased unit of BMI [kg/m2], PFasting blood glucose and diabetes did not affect the results. Higher BMI is associated with decreased survival in pancreatic cancer. Although the mechanism of this association remains undetermined, diabetes and hyperglycemia do not appear to account for the observed association. Copyright © 2010 American Cancer Society.

  3. Global Activities and Plant Survival

    DEFF Research Database (Denmark)

    Bandick, Roger

    2014-01-01

    the highest exit rates. Moreover, the exit rates of globally engaged plants seem to be unaffected by increased foreign presence, whereas there appears to be a negative impact on the survival rates of non-exporting non-MNE plants. Finally, the result reveals that the survival ratio of plants of acquired...

  4. Radionuclide blood cell survival studies

    International Nuclear Information System (INIS)

    Bentley, S.A.; Miller, D.T.

    1986-01-01

    Platelet and red cell survival studies are reviewed. The use of 51 Cr and di-isopropylfluoridate labelled with tritium or 32 P is discussed for red cell survival study and 51 Cr and 111 In-oxine are considered as platelet labels. (UK)

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

    Directory of Open Access Journals (Sweden)

    Quail Deborah

    2010-07-01

    Full Text Available Abstract Background Factors Influencing Depression Endpoints Research (FINDER is a 6-month, prospective, observational study carried out in 12 European countries aimed at investigating health-related quality of life (HRQoL in outpatients receiving treatment for a first or new depressive episode. The Italian HRQoL data at 6 months is described in this report, and the factors associated with HRQoL changes were determined. Methods Data were collected at baseline, 3 and 6 months of treatment. HRQoL was measured using components of the 36-item Short Form Health Survey (SF-36; mental component summary (MCS, physical component summary (PCS and the European Quality of Life-5 Dimensions (EQ-5D; visual analogue scale (VAS and health status index (HSI. The Hospital Anxiety and Depression Scale (HADS was adopted to evaluate depressive symptoms, while somatic and painful physical symptoms were assessed by using the 28-item Somatic Symptom Inventory (SSI-28 and a VAS. Results Of the initial 513 patients, 472 completed the 3-month observation and 466 the 6-month observation. The SF-36 and EQ-5D mean (± SD scores showed HRQoL improvements at 3 months and a further smaller improvement at 6 months, with the most positive effects for SF-36 MCS (baseline 22.0 ± 9.2, 3 months 34.6 ± 10.0; 6 months 39.3 ± 9.5 and EQ-5D HSI (baseline 0.4 ± 0.3; 3 months 0.7 ± 0.3; 6 months 0.7 ± 0.2. Depression and anxiety symptoms (HADS-D mean at baseline 13.3 ± 4.2; HADS-A mean at baseline 12.2 ± 3.9 consistently decreased during the first 3 months (8.7 ± 4.3; 7.5 ± 3.6 and showed a further positive change at 6 months (6.9 ± 4.3; 5.8 ± 3.4. Somatic and painful symptoms (SSI and VAS significantly decreased, with the most positive changes in the SSI-28 somatic item (mean at baseline 2.4 ± 0.7; mean change at 3 months: -0.5; 95% CI -0.6 to -0.5; mean change at 6 months: -0.7; 95% CI -0.8 to -0.7; in 'interference of overall pain with daily activities' (mean at baseline 45

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

    Directory of Open Access Journals (Sweden)

    Maarten J. Bijlsma

    2016-04-01

    Full Text Available Abstract Background To determine the clinical effectiveness of statins on cardiovascular mortality in practice, observational studies are needed. Control for confounding is essential in any observational study. Falsification end-points may be useful to determine if bias is present after adjustment has taken place. Methods We followed starters on statin therapy in the Netherlands aged 46 to 100 years over the period 1996 to 2012, from initiation of statin therapy until cardiovascular mortality or censoring. Within this group (n = 49,688, up to 16 years of follow-up, we estimated the effect of adherence to statin therapy (0 = completely non-adherent, 1 = fully adherent on ischemic heart diseases and cerebrovascular disease (ICD10-codes I20-I25 and I60-I69 as well as respiratory and endocrine disease mortality (ICD10-codes J00-J99 and E00-E90 as falsification end points, controlling for demographic factors, socio-economic factors, birth cohort, adherence to other cardiovascular medications, and diabetes using time-varying Cox regression models. Results Falsification end-points indicated that a simpler model was less biased than a model with more controls. Adherence to statins appeared to be protective against cardiovascular mortality (HR: 0.70, 95 % CI 0.61 to 0.81. Conclusions Falsification end-points helped detect overadjustment bias or bias due to competing risks, and thereby proved to be a useful technique in such a complex setting.

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

    Science.gov (United States)

    Benjamin, Daniel K; Miller, Wiliam C; Benjamin, Daniel K; Ryder, Robert W; Weber, David J; Walter, Emmanuel; McKinney, Ross E

    2003-11-07

    HIV adversely affects growth in children. Pediatric AIDS Clinical Trial Group (PACTG) protocols often use weight velocity [changes in weight z-score for age (WAZ)] as a part of the composite endpoint for phase II and III clinical trials. However, WAZ and height velocity (HAZ) have not been critically compared for their utility as part of the composite endpoint. HAZ and WAZ were compared to predict laboratory and clinical progression of HIV in a retrospective cohort study of HIV-infected children with data from PACTG Protocol 300. In both bivariable and multivariable analyses, changes in HAZ were more closely linked to subsequent progression than WAZ. Children with improved HAZ were somewhat less likely to exhibit virological failure [odds ratio (OR), 0.76; 95% confidence interval (CI) 0.51-1.14], than children with improved WAZ (OR, 1.45; 95% CI, 0.99,2.11). Children who had improved HAZ were less likely to exhibit immunological failure (OR, 0.7; 95% CI, 0.49-1.00), than children with improved WAZ (OR, 1.13; 95% CI, 0.82-1.57). Children who had improved HAZ were less likely to have other forms of clinical progression of HIV (OR, 0.55; 95% CI, 0.31-0.99), than children who had improved WAZ (OR, 1.0; 95% CI, 1.58-1.94). Increases in HAZ were associated with reduced risk of subsequent clinical progression and subsequent immune reconstitution and weakly associated with declines in HIV RNA. Changes in WAZ were not associated with laboratory outcomes relevant to pediatric HIV infection. Height velocity should be considered as a component of a composite clinical endpoint in future PACTG trials.

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

    Directory of Open Access Journals (Sweden)

    Sandria Godwin

    2016-06-01

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

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

    Science.gov (United States)

    Godwin, Sandria; Maughan, Curtis; Chambers, Edgar

    2016-01-01

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

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

    Science.gov (United States)

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

    2005-08-15

    The new OECD guideline 429 (skin sensitization: local lymph node assay) is based upon a protocol, which utilises the incorporation of radioactivity into DNA as a measure for cell proliferation in vivo. The guideline also enables the use of alternative endpoints in order to assess draining lymph node (LN) cell proliferation. Here we describe the first round of an inter-laboratory validation of alternative endpoints in the LLNA conducted in seven laboratories. The validation study was managed and supervised by the Swiss Agency for Therapeutic Products, Swissmedic. Statistical analyses of all data were performed by an independent centre at the University of Bern, Department of Statistics. Ear-draining, LN weight and cell count were used to assess proliferation instead of radioactive labeling of lymph node cells. In addition, the acute inflammatory skin reaction was measured by ear swelling and weight of circular biopsies of the ears to identify skin irritating properties of the test items. Hexylcinnamaldehyde (HCA) and three blinded test items were applied to female, 8--10 weeks old NMRI and BALB/c mice. Results were sent via the independent study coordinator to the statistician. The results of this first round showed that the alternative endpoints of the LLNA are sensitive and robust parameters. The use of ear weights added an important parameter assessing the skin irritation potential, which supports the differentiation of pure irritative from contact allergenic potential. There were absolute no discrepancies between the categorisation of the three test substances A--C determined by each single participating laboratories. The results highlighted also that many parameters do have an impact on the strength of the responses. Therefore, such parameters have to be taken into consideration for the categorisation of compounds due to their relative sensitizing potencies.

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

    Science.gov (United States)

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

    2005-08-15

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

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

    International Nuclear Information System (INIS)

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

    2005-01-01

    The new OECD guideline 429 (skin sensitization: local lymph node assay) is based upon a protocol, which utilises the incorporation of radioactivity into DNA as a measure for cell proliferation in vivo. The guideline also enables the use of alternative endpoints in order to assess draining lymph node (LN) cell proliferation. Here we describe the first round of an inter-laboratory validation of alternative endpoints in the LLNA conducted in seven laboratories. The validation study was managed and supervised by the Swiss Agency for Therapeutic Products, Swissmedic. Statistical analyses of all data were performed by an independent centre at the University of Bern, Department of Statistics. Ear-draining, LN weight and cell count were used to assess proliferation instead of radioactive labeling of lymph node cells. In addition, the acute inflammatory skin reaction was measured by ear swelling and weight of circular biopsies of the ears to identify skin irritating properties of the test items. Hexylcinnamaldehyde (HCA) and three blinded test items were applied to female, 8-10 weeks old NMRI and BALB/c mice. Results were sent via the independent study coordinator to the statistician. The results of this first round showed that the alternative endpoints of the LLNA are sensitive and robust parameters. The use of ear weights added an important parameter assessing the skin irritation potential, which supports the differentiation of pure irritative from contact allergenic potential. There were absolute no discrepancies between the categorisation of the three test substances A-C determined by each single participating laboratories. The results highlighted also that many parameters do have an impact on the strength of the responses. Therefore, such parameters have to be taken into consideration for the categorisation of compounds due to their relative sensitizing potencies

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

    Science.gov (United States)

    Godwin, Sandria; Maughan, Curtis; Chambers, Edgar

    2016-06-23

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

  14. [Survival analysis with competing risks: estimating failure probability].

    Science.gov (United States)

    Llorca, Javier; Delgado-Rodríguez, Miguel

    2004-01-01

    To show the impact of competing risks of death on survival analysis. We provide an example of survival time without chronic rejection after heart transplantation, where death before rejection acts as a competing risk. Using a computer simulation, we compare the Kaplan-Meier estimator and the multiple decrement model. The Kaplan-Meier method overestimated the probability of rejection. Next, we illustrate the use of the multiple decrement model to analyze secondary end points (in our example: death after rejection). Finally, we discuss Kaplan-Meier assumptions and why they fail in the presence of competing risks. Survival analysis should be adjusted for competing risks of death to avoid overestimation of the risk of rejection produced with the Kaplan-Meier method.

  15. Marketing child survival.

    Science.gov (United States)

    Grant, J P

    1984-01-01

    Growth monitoring charts, packets of oral rehydration salts (ORS), and vaccines, are inexpensive, life-saving, growth-protecting technologies which can enable parents to protect their children against the worst effects of poverty. Similarly, a matrix of current and easily understandable information about pregnancy, breast feeding, weaning, feeding during and immediately after illness, child spacing, and preparing and using home-made oral rehydration solutions, also could empower parents to protect the lives and the health of their children. The question arises as to how can these technologies and this information be put at the disposal of millions of families in the low-income world. The initial task of the Child Survival and Development Revolution is the communication of what is now possible, yet little is known about how to communicate information whose principal value is to the poor. There are 2 large-scale precedents: the Green Revolution, which in many instances succeeded in putting into the hands of thousands of small and large farmers the techniques and the knowledge which enabled them to double and treble the yields from their lands; and the campaign to put the knowledge and the means of family planning at the disposal of many millions of people. There are 2 lessons to be learned from these precedents: they have shown that the way to promote a people's technology and to put information at the disposal of the majority is by mobilizing all possible resources and working through all possible channels both to create the demand and to meet it; and neither the Green Revolution nor the family planning movement rally took off until they were viewed as political and economic priorities and given the full support of the nation's political leadership. Nowhere are these 2 lessons more clearly illustrated than in present-day Indonesia. Because the campaign for family planning was given high personal and political priority by the President, and because 85% of all family

  16. Secondary hypertension in adults.

    Science.gov (United States)

    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.

  17. Secondary combined suicide pact.

    Science.gov (United States)

    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.

  18. THE SECONDARY EXTINCTION CORRECTION

    Energy Technology Data Exchange (ETDEWEB)

    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)

  19. Secondary Breast Augmentation.

    Science.gov (United States)

    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.

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

    International Nuclear Information System (INIS)

    Mishima, K.; Yamashita, K.

    2011-01-01

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

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

    DEFF Research Database (Denmark)

    Hobolth, Asger; Stone, Eric

    2009-01-01

    computational finance to human genetics and genomics. A common theme among these diverse applications is the need to simulate sample paths of a CTMC conditional on realized data that is discretely observed. Here we present a general solution to this sampling problem when the CTMC is defined on a discrete....... In doing so, we show that no method dominates the others across all model specifications, and we give explicit proof of which method prevails for any given Q, T, and endpoints. Finally, we introduce and compare three applications of CTMCs to demonstrate the pitfalls of choosing an inefficient sampler....

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

    International Nuclear Information System (INIS)

    Sala, Miquel; Faria, Melissa; Sarasúa, Ignacio; Barata, Carlos; Bonada, Núria; Brucet, Sandra; Llenas, Laia; Ponsá, Sergio; Prat, Narcís; Soares, Amadeu M.V.M.

    2016-01-01

    The rivers and streams of the world are becoming saltier due to human activities. In spite of the potential damage that salt pollution can cause on freshwater ecosystems, this is an issue that is currently poorly managed. Here we explored intraspecific differences in the sensitivity of freshwater fauna to two major ions (Cl"− and SO_4"2"−) using the net-spinning caddisfly Hydropsyche exocellata Dufour 1841 (Trichoptera, Hydropsychidae) as a model organism. We exposed H. exocellata to saline solutions (reaching a conductivity of 2.5 mS cm"−"1) with Cl"−:SO_4"2"− ratios similar to those occurring in effluents coming from the meat, mining and paper industries, which release dissolved salts to rivers and streams in Spain. We used two different populations, coming from low and high conductivity streams. To assess toxicity, we measured sub-lethal endpoints: locomotion, symmetry of the food-capturing nets and oxidative stress biomarkers. According to biomarkers and net building, the population historically exposed to lower conductivities (B10) showed higher levels of stress than the population historically exposed to higher conductivities (L102). However, the differences between populations were not strong. For example, net symmetry was lower in the B10 than in the L102 only 48 h after treatment was applied, and biomarkers showed a variety of responses, with no discernable pattern. Also, treatment effects were rather weak, i.e. only some endpoints, and in most cases only in the B10 population, showed a significant response to treatment. The lack of consistent differences between populations and treatments could be related to the high salt tolerance of H. exocellata, since both populations were collected from streams with relatively high conductivities. The sub-lethal effects tested in this study can offer an interesting and promising tool to monitor freshwater salinization by combining physiological and behavioural bioindicators. - Highlights: • We assessed Cl

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

    Energy Technology Data Exchange (ETDEWEB)

    Sala, Miquel [Centre Tecnològic Forestal de Catalunya - CTFC, Solsona, Catalunya (Spain); Faria, Melissa [CESAM, Departamento de Biologia, Universidade de Aveiro, 3810-193 Aveiro (Portugal); Sarasúa, Ignacio [Technische Universität München, Munich, Bayern (Germany); Barata, Carlos [Institute of Environmental Assessment and Water Research (IDAEA-CSIC), Barcelona (Spain); Bonada, Núria [Grup de Recerca Freshwater Ecology and Management (FEM), Departament d' Ecologia, Facultat de Biologia, Universitat de Barcelona (UB), Diagonal 643, 08028 Barcelona, Catalonia (Spain); Grup de Recerca Freshwater Ecology and Management (FEM), Departament d' Ecologia, Facultat de Biologia, Institut de Recerca de la Biodiversitat (IRBio), Universitat de Barcelona - UB, Diagonal 643, 08028 Barcelona, Catalonia (Spain); Brucet, Sandra [Aquatic Ecology Group, BETA Tecnio Centre, University of Vic - Central University of Catalonia, Vic, Catalonia (Spain); Catalan Institution for Research and Advanced Studies, ICREA, Barcelona 08010 (Spain); Llenas, Laia; Ponsá, Sergio [Aquatic Ecology Group, BETA Tecnio Centre, University of Vic - Central University of Catalonia, Vic, Catalonia (Spain); Prat, Narcís [Grup de Recerca Freshwater Ecology and Management (FEM), Departament d' Ecologia, Facultat de Biologia, Universitat de Barcelona (UB), Diagonal 643, 08028 Barcelona, Catalonia (Spain); Soares, Amadeu M.V.M. [CESAM, Departamento de Biologia, Universidade de Aveiro, 3810-193 Aveiro (Portugal); and others

    2016-10-01

    The rivers and streams of the world are becoming saltier due to human activities. In spite of the potential damage that salt pollution can cause on freshwater ecosystems, this is an issue that is currently poorly managed. Here we explored intraspecific differences in the sensitivity of freshwater fauna to two major ions (Cl{sup −} and SO{sub 4}{sup 2−}) using the net-spinning caddisfly Hydropsyche exocellata Dufour 1841 (Trichoptera, Hydropsychidae) as a model organism. We exposed H. exocellata to saline solutions (reaching a conductivity of 2.5 mS cm{sup −1}) with Cl{sup −}:SO{sub 4}{sup 2−} ratios similar to those occurring in effluents coming from the meat, mining and paper industries, which release dissolved salts to rivers and streams in Spain. We used two different populations, coming from low and high conductivity streams. To assess toxicity, we measured sub-lethal endpoints: locomotion, symmetry of the food-capturing nets and oxidative stress biomarkers. According to biomarkers and net building, the population historically exposed to lower conductivities (B10) showed higher levels of stress than the population historically exposed to higher conductivities (L102). However, the differences between populations were not strong. For example, net symmetry was lower in the B10 than in the L102 only 48 h after treatment was applied, and biomarkers showed a variety of responses, with no discernable pattern. Also, treatment effects were rather weak, i.e. only some endpoints, and in most cases only in the B10 population, showed a significant response to treatment. The lack of consistent differences between populations and treatments could be related to the high salt tolerance of H. exocellata, since both populations were collected from streams with relatively high conductivities. The sub-lethal effects tested in this study can offer an interesting and promising tool to monitor freshwater salinization by combining physiological and behavioural bioindicators

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2008-12-11

    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

  5. Secondary victims of rape

    DEFF Research Database (Denmark)

    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...

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

    International Nuclear Information System (INIS)

    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)

  7. Corticosteroid Treatment Influences TA-Proteinuria and Renal Survival in IgA Nephropathy.

    Directory of Open Access Journals (Sweden)

    Cristina Sarcina

    Full Text Available The clinical course of IgA nephropathy (IgAN and its outcome are extremely variable. Proteinuria at baseline has been considered one of the most important risk factors. More recently, mean proteinuria of follow-up (time-average proteinuria: TAp was described as a stronger marker of renal survival, suggesting to consider it as a marker of disease activity and response to treatment. We evaluated predictors of renal survival in IgAN patients with different degrees of renal dysfunction and histological lesions, focusing on the role of the therapy in influencing TAp. We performed a retrospective analysis of three prospective, randomized, clinical trials enrolling 325 IgAN patients from 1989 to 2005. Patients were divided into 5 categories according to TAp. The primary endpoint of the 100% increase of serum creatinine occurred in 54 patients (16.6% and renal survival was much better in groups having lower TAp. The median follow up was 66.6 months (range 12 to 144. The primary endpoint of the 100% increase of serum creatinine occurred in 54 patients (16,6% and renal survival was much better in groups having lower TA proteinuria. At univariate analysis plasma creatinine and 24h proteinuria, systolic (SBP and diastolic (DBP blood pressure during follow-up and treatment with either steroid (CS or steroid plus azathioprine (CS+A were the main factors associated with lower TAp and renal survival. At multivariate analysis, female gender, treatment with S or S+A, lower baseline proteinuria and SBP during follow-up remained as the only variables independently influencing TAp. In conclusion, TA-proteinuria is confirmed as one of the best outcome indicators, also in patients with a severe renal insufficiency. A 6-month course of corticosteroids seems the most effective therapy to reduce TAp.

  8. Neutron-energy-dependent cell survival and oncogenic transformation.

    Science.gov (United States)

    Miller, R C; Marino, S A; Martin, S G; Komatsu, K; Geard, C R; Brenner, D J; Hall, E J

    1999-12-01

    Both cell lethality and neoplastic transformation were assessed for C3H10T1/2 cells exposed to neutrons with energies from 0.040 to 13.7 MeV. Monoenergetic neutrons with energies from 0.23 to 13.7 MeV and two neutron energy spectra with average energies of 0.040 and 0.070 MeV were produced with a Van de Graaff accelerator at the Radiological Research Accelerator Facility (RARAF) in the Center for Radiological Research of Columbia University. For determination of relative biological effectiveness (RBE), cells were exposed to 250 kVp X rays. With exposures to 250 kVp X rays, both cell survival and radiation-induced oncogenic transformation were curvilinear. Irradiation of cells with neutrons at all energies resulted in linear responses as a function of dose for both biological endpoints. Results indicate a complex relationship between RBEm and neutron energy. For both survival and transformation, RBEm was greatest for cells exposed to 0.35 MeV neutrons. RBEm was significantly less at energies above or below 0.35 MeV. These results are consistent with microdosimetric expectation. These results are also compatible with current assessments of neutron radiation weighting factors for radiation protection purposes. Based on calculations of dose-averaged LET, 0.35 MeV neutrons have the greatest LET and therefore would be expected to be more biologically effective than neutrons of greater or lesser energies.

  9. Very Early PSA Response to Abiraterone in mCRPC Patients: A Novel Prognostic Factor Predicting Overall Survival.

    Science.gov (United States)

    Facchini, Gaetano; Caffo, Orazio; Ortega, Cinzia; D'Aniello, Carmine; Di Napoli, Marilena; Cecere, Sabrina C; Della Pepa, Chiara; Crispo, Anna; Maines, Francesca; Ruatta, Fiorella; Iovane, Gelsomina; Pisconti, Salvatore; Montella, Maurizio; Berretta, Massimiliano; Pignata, Sandro; Cavaliere, Carla

    2016-01-01

    Abiraterone Acetate (AA) is approved for the treatment of mCRPC after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated and for treatment of mCRPC progressed during or after docetaxel-based chemotherapy regimen. The aim of this study is to evaluate the role of early PSA decline for detection of therapy success or failure in mCRPC patients treated with AA in post chemotherapy setting. We retrospectively evaluated 87 patients with mCRPC treated with AA. Serum PSA levels were evaluated after 15, 90 days and then monthly. The PSA flare phenomenon was evaluated, according to a confirmation value at least 1 week apart. The primary endpoint was to demonstrate that an early PSA decline correlates with a longer progression free survival (PFS) and overall survival (OS). The secondary endpoind was to demonstrate a correlation between better outcome and demographic and clinical patient characteristics. We have collected data of 87 patients between Sep 2011 and Sep 2014. Early PSA response (≥50% from baseline at 15 days) was found in 56% evaluated patients and confirmed in 29 patients after 90 days. The median PFS was 5.5 months (4.6-6.5) and the median OS was 17.1 months (8.8-25.2). In early responders patients (PSA RR ≥ 50% at 15 days), we found a significant statistical advantage in terms of PFS at 1 year, HR 0.28, 95%CI 0.12-0.65, p = 0.003, and OS, HR 0.21 95% CI 0.06-0.72, p = 0.01. The results in PFS at 1 years and OS reached statistical significance also in the evaluation at 90 days. A significant proportion (78.6%) of patients achieved a rapid response in terms of PSA decline. Early PSA RR (≥50% at 15 days after start of AA) can provide clinically meaningful information and can be considered a surrogate of longer PFS and OS.

  10. Better midterm survival in women after transcatheter aortic valve implantation.

    Science.gov (United States)

    Takagi, Hisato; Umemoto, Takuya

    2017-08-01

    In previous meta-analyses demonstrating better midterm overall survival in women undergoing transcatheter aortic valve implantation (TAVI), unadjusted risk and odds ratios were combined. To determine whether female gender is independently associated with better survival after TAVI, we performed a meta-analysis pooling adjusted hazard ratios (HRs) based on multivariate Cox proportional hazard regression. MEDLINE and EMBASE were searched through September 2015 using PubMed and OVID. Studies considered for inclusion met the following criteria: the study population was patients undergoing TAVI; and main outcomes included midterm (mean or median ≥6 months) overall survival or all-cause mortality in women and men. An unadjusted and/or adjusted HR of all-cause mortality for women versus men was abstracted from each individual study. Of 1347 potentially relevant articles screened initially, 16 reports of eligible studies were identified and included. A primary meta-analysis of the 9 adjusted HRs demonstrated a significantly better midterm overall survival in women than men (N.=6891; HR=0.80; 95% confidence interval [CI]: 0.65 to 0.97; P=0.03). A secondary meta-analysis adding 5 statistically non-significant unadjusted HR also indicated better survival in women (N.=8645; HR=0.83; 95% CI: 0.72 to 0.96; P=0.01). Although statistical tests for the primary meta-analysis revealed funnel plot asymmetry in favor of women, the secondary meta-analysis produced a symmetrical funnel plot. Female gender may be independently associated with better midterm overall survival after TAVI.

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

    Science.gov (United States)

    This presentation describes development and application of a physiologically-based computational model that simulates the brain-pituitary-gonadal (BPG) axis and other endpoints important in reproduction such as concentrations of sex steroid hormones, 17-estradiol, testosterone, a...

  12. Hazardous waste transportation risk assessment for the US Department of Energy Environmental Restoration and Waste Management Programmatic Environmental Impact Statement -- human health endpoints

    International Nuclear Information System (INIS)

    Hartmann, H.M.; Policastro, A.J.; Lazaro, M.A.

    1994-01-01

    In this presentation, a quantitative methodology for assessing the risk associated with the transportation of hazardous waste (HW) is proposed. The focus is on identifying air concentrations of HW that correspond to specific human health endpoints

  13. Evaluation of Gene Expression Endpoints in the Context of a Xenopus laevis Metamorphosis-based Bioassay to Detect Thyroid Hormone Disruptors

    Science.gov (United States)

    This study accentuates the need to examine multiple tissues and provides critical information required for optimization of exposure regimens and endpoint assessments that focus on the detection of disruption in TH-regulatory systems.

  14. Pretreatment oral hygiene habits and survival of head and neck squamous cell carcinoma (HNSCC) patients.

    Science.gov (United States)

    Friemel, Juliane; Foraita, Ronja; Günther, Kathrin; Heibeck, Mathias; Günther, Frauke; Pflueger, Maren; Pohlabeln, Hermann; Behrens, Thomas; Bullerdiek, Jörn; Nimzyk, Rolf; Ahrens, Wolfgang

    2016-03-11

    The survival time of patients with head and neck squamous cell carcinoma (HNSCC) is related to health behavior, such as tobacco smoking and alcohol consumption. Poor oral health (OH), dental care (DC) and the frequent use of mouthwash have been shown to represent independent risk factors for head and neck cancerogenesis, but their impact on the survival of HNSCC patients has not been systematically investigated. Two hundred seventy-six incident HNSCC cases recruited for the ARCAGE study were followed through a period of 6-10 years. Interview-based information on wearing of dentures, gum bleeding, teeth brushing, use of floss and dentist visits were grouped into weighted composite scores, i.e. oral health (OH) and dental care (DH). Use of mouthwash was assessed as frequency per day. Also obtained were other types of health behavior, such as smoking, alcohol drinking and diet, appreciated as both confounding and study variables. Endpoints were progression-free survival, overall survival and tumor-specific survival. Prognostic values were estimated using Kaplan-Meier analysis and Cox proportional hazards regression models. A good dental care score, summarizing annual dental visits, daily teeth cleaning and use of floss was associated with longer overall survival time (p = .001). The results of the Cox regression models similarly suggested a higher risk of tumor progression and shortened overall survival in patients with poor dental care, but the results lost their statistical significance after other types of health behavior had been controlled for. Frequent use of mouthwash (≥ 2 times/day) significantly increased the risk of tumor-specific death (HR = 2.26; CI = 1.19-4.32). Alcohol consumption and tobacco smoking were dose-dependently associated with tumor progression and shorter overall survival. Frequent mouthwash use of ≥ 2 times/day seems to elevate the risk of tumor-specific death in HNSCC patients. Good dental care scores are associated with longer overall

  15. Population density, call-response interval, and survival of out-of-hospital cardiac arrest

    Directory of Open Access Journals (Sweden)

    Ogawa Toshio

    2011-04-01

    Full Text Available Abstract Background Little is known about the effects of geographic variation on outcomes of out-of-hospital cardiac arrest (OHCA. The present study investigated the relationship between population density, time between emergency call and ambulance arrival, and survival of OHCA, using the All-Japan Utstein-style registry database, coupled with geographic information system (GIS data. Methods We examined data from 101,287 bystander-witnessed OHCA patients who received emergency medical services (EMS through 4,729 ambulatory centers in Japan between 2005 and 2007. Latitudes and longitudes of each center were determined with address-match geocoding, and linked with the Population Census data using GIS. The endpoints were 1-month survival and neurologically favorable 1-month survival defined as Glasgow-Pittsburgh cerebral performance categories 1 or 2. Results Overall 1-month survival was 7.8%. Neurologically favorable 1-month survival was 3.6%. In very low-density (2 and very high-density (≥10,000/km2 areas, the mean call-response intervals were 9.3 and 6.2 minutes, 1-month survival rates were 5.4% and 9.1%, and neurologically favorable 1-month survival rates were 2.7% and 4.3%, respectively. After adjustment for age, sex, cause of arrest, first aid by bystander and the proportion of neighborhood elderly people ≥65 yrs, patients in very high-density areas had a significantly higher survival rate (odds ratio (OR, 1.64; 95% confidence interval (CI, 1.44 - 1.87; p Conclusion Living in a low-density area was associated with an independent risk of delay in ambulance response, and a low survival rate in cases of OHCA. Distribution of EMS centers according to population size may lead to inequality in health outcomes between urban and rural areas.

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

    Science.gov (United States)

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

    2017-05-01

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

  17. Cardiovascular disease incidence and survival

    DEFF Research Database (Denmark)

    Byberg, Stine; Agyemang, Charles; Zwisler, Ann Dorthe

    2016-01-01

    Studies on cardiovascular disease (CVD) incidence and survival show varying results between different ethnic groups. Our aim was to add a new dimension by exploring the role of migrant status in combination with ethnic background on incidence of-and survival from-CVD and more specifically acute...... of some types of cardiovascular disease compared to Danish-born. Family-reunified migrants on the other hand had lower rates of CVD. All migrants had better survival than Danish-born indicating that migrants may not always be disadvantaged in health....

  18. Stimulated human fibroblast cell survival

    International Nuclear Information System (INIS)

    Smith, B.P.; Gale, K.L.; Einspenner, M.; Greenstock, C.L.; Gentner, N.E.

    1992-01-01

    Techniques for cloning cultured mammalian cells have supported the most universally-accepted method for measuring the induction of lethality by geno-toxicants such as ionizing radiation: the 'survival of colony-forming ability (CFA)' assay. Since most cultured human cell lines exhibit plating efficiency (i.e. the percentage of cells that are capable of reproductively surviving and dividing to form visible colonies) well below 100%, such assays are in essence 'survival of plating efficiency' assays, since they are referred to the plating (or cloning) efficiency of control (i.e. unirradiated) cells. (author). 8 refs., 2 figs

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

    Science.gov (United States)

    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.

  20. Waterborne cadmium impacts immunocytotoxic and cytogenotoxic endpoints in green-lipped mussel, Perna canaliculus

    Energy Technology Data Exchange (ETDEWEB)

    Chandurvelan, Rathishri, E-mail: rch118@uclive.ac.nz [School of Biological Sciences, University of Canterbury, Private Bag 4800, Christchurch 8140 (New Zealand); Marsden, Islay D., E-mail: islay.marsden@canterbury.ac.nz [School of Biological Sciences, University of Canterbury, Private Bag 4800, Christchurch 8140 (New Zealand); Gaw, Sally, E-mail: sally.gaw@canterbury.ac.nz [Department of Chemistry, University of Canterbury, Private Bag 4800, Christchurch 8140 (New Zealand); Glover, Chris N., E-mail: chris.glover@canterbury.ac.nz [School of Biological Sciences, University of Canterbury, Private Bag 4800, Christchurch 8140 (New Zealand)

    2013-10-15

    damage in green-lipped mussels, an impact that may have implications such as reduced disease resistance and compromised survival. These data also suggest that immunocytotoxic and cytogenotoxic biomarkers would be a valuable addition to environmental monitoring programmes using green-lipped mussels.

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

    Directory of Open Access Journals (Sweden)

    Shah Mukim Uddin

    2015-03-01

    Full Text Available In recent years, many improvements have been made in foodborne pathogen detection methods to reduce the impact of food contamination. Several rapid methods have been developed with biosensor devices to improve the way of performing pathogen detection. This paper presents an automated endpoint detection system for amplicons generated by loop mediated isothermal amplification (LAMP on a microfluidic compact disk platform. The developed detection system utilizes a monochromatic ultraviolet (UV emitter for excitation of fluorescent labeled LAMP amplicons and a color sensor to detect the emitted florescence from target. Then it processes the sensor output and displays the detection results on liquid crystal display (LCD. The sensitivity test has been performed with detection limit up to 2.5 × 10−3 ng/µL with different DNA concentrations of Salmonella bacteria. This system allows a rapid and automatic endpoint detection which could lead to the development of a point-of-care diagnosis device for foodborne pathogens detection in a resource-limited environment.

  2. Allergenicity evaluation of fragrance mix and its ingredients by using ex vivo local lymph node assay-BrdU endpoints.

    Science.gov (United States)

    Ulker, Ozge Cemiloglu; Kaymak, Yesim; Karakaya, Asuman

    2014-03-01

    The present studies were performed to compare the differences between sensitization potency of fragrance mix and its ingredients (oak moss absolute, isoeugenol, eugenol, cinnamal, hydroxycitronellal, geraniol, cinnamic alcohol, alpha amyl cinnamal), by using ex vivo LLNA-BrdU ELISA. The SI and EC3 values were calculated and potency classification was found for the mixture and for each ingredients. TH1 cytokines (IL-2, IFN-γ) and TH2 cytokines (IL-4, IL-5) releases from lymph node cell culture were also investigated as contact sensitization endpoints. The EC3 values were calculated and the potency of contact sensitization were classified for fragrance mix, oak moss absolute, isoeugenol, eugenol, cinnamal, hydroxycitronellal, geraniol, cinnamic alcohol, alpha amyl cinnamal respectively: 4.4% (moderate), 3.4% (moderate), 0.88% (strong), 16.6% (weak), 1.91% (moderate), 9.77% (moderate), 13.1% (weak), 17.93% (weak), 7.74% (moderate). According to our results it should be concluded that exposure to fragrance mix does not constitute an evidently increased hazard compared to exposure to each of the eight fragrance ingredients separately. Cytokine analyses results indicate that both TH1 and TH2 cytokines are involved in the regulation of murine contact allergy and can be considered as useful endpoints. Copyright © 2014 Elsevier Ltd. All rights reserved.

  3. How Can Viral Dynamics Models Inform Endpoint Measures in Clinical Trials of Therapies for Acute Viral Infections?

    Directory of Open Access Journals (Sweden)

    Carolin Vegvari

    Full Text Available Acute viral infections pose many practical challenges for the accurate assessment of the impact of novel therapies on viral growth and decay. Using the example of influenza A, we illustrate how the measurement of infection-related quantities that determine the dynamics of viral load within the human host, can inform investigators on the course and severity of infection and the efficacy of a novel treatment. We estimated the values of key infection-related quantities that determine the course of natural infection from viral load data, using Markov Chain Monte Carlo methods. The data were placebo group viral load measurements collected during volunteer challenge studies, conducted by Roche, as part of the oseltamivir trials. We calculated the values of the quantities for each patient and the correlations between the quantities, symptom severity and body temperature. The greatest variation among individuals occurred in the viral load peak and area under the viral load curve. Total symptom severity correlated positively with the basic reproductive number. The most sensitive endpoint for therapeutic trials with the goal to cure patients is the duration of infection. We suggest laboratory experiments to obtain more precise estimates of virological quantities that can supplement clinical endpoint measurements.

  4. Testing of an End-Point Control Unit Designed to Enable Precision Control of Manipulator-Coupled Spacecraft

    Science.gov (United States)

    Montgomery, Raymond C.; Ghosh, Dave; Tobbe, Patrick A.; Weathers, John M.; Manouchehri, Davoud; Lindsay, Thomas S.

    1994-01-01

    This paper presents an end-point control concept designed to enable precision telerobotic control of manipulator-coupled spacecraft. The concept employs a hardware unit (end-point control unit EPCU) that is positioned between the end-effector of the Space Shuttle Remote Manipulator System and the payload. Features of the unit are active compliance (control of the displacement between the end-effector and the payload), to allow precision control of payload motions, and inertial load relief, to prevent the transmission of loads between the end-effector and the payload. This paper presents the concept and studies the active compliance feature using a simulation and hardware. Results of the simulation show the effectiveness of the EPCU in smoothing the motion of the payload. Results are presented from initial, limited tests of a laboratory hardware unit on a robotic arm testbed at the l Space Flight Center. Tracking performance of the arm in a constant speed automated retraction and extension maneuver of a heavy payload with and without the unit active is compared for the design speed and higher speeds. Simultaneous load reduction and tracking performance are demonstrated using the EPCU.

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

    International Nuclear Information System (INIS)

    Li, X.; Sawatsky, N.

    1995-01-01

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

  6. Causes of secondary headache (image)

    Science.gov (United States)

    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 ...

  7. Probabilistic Survivability Versus Time Modeling

    Science.gov (United States)

    Joyner, James J., Sr.

    2016-01-01

    This presentation documents Kennedy Space Center's Independent Assessment work completed on three assessments for the Ground Systems Development and Operations (GSDO) Program to assist the Chief Safety and Mission Assurance Officer during key programmatic reviews and provided the GSDO Program with analyses of how egress time affects the likelihood of astronaut and ground worker survival during an emergency. For each assessment, a team developed probability distributions for hazard scenarios to address statistical uncertainty, resulting in survivability plots over time. The first assessment developed a mathematical model of probabilistic survivability versus time to reach a safe location using an ideal Emergency Egress System at Launch Complex 39B (LC-39B); the second used the first model to evaluate and compare various egress systems under consideration at LC-39B. The third used a modified LC-39B model to determine if a specific hazard decreased survivability more rapidly than other events during flight hardware processing in Kennedy's Vehicle Assembly Building.

  8. The Survival of the Wisest

    Science.gov (United States)

    Salk, Jonas

    1975-01-01

    Suggests that humans differ from other living organisms in the ability to exercise learned behavior and the individual will, which may allow people to make the changes in values necessary to survive on this planet. (DW)

  9. Customer service skills for survival.

    Science.gov (United States)

    McAtee, L F

    1999-11-01

    As APICS practitioners, we all must share a common goal. How can we contribute to our company's success? Success can be measured in positive terms of market share, growth, profitability, return on investment, or some combination thereof. Each company must establish its own definition of success. For the purposes of this article, success will be equated to one word that we can all readily identify with: survival. What skills do we need to survive in the marketplace of the next millennium?

  10. Prolongation of islet allograft survival

    International Nuclear Information System (INIS)

    Lacy, P.E.; Davie, J.M.; Finke, E.H.; Scharp, D.W.

    1979-01-01

    Pretreatment of donor rats with irradiation and silica followed by in vitro culture of the islets for 1 to 2 days prolonged survival of allografts across a minor histocompatibility barrier if hand-picked, clean islets were used for transplantation. Pretreatment of donor rats with irradiation and silica in conjunction with a single injection of antilymphocyte serum (ALS) into the recipient produced a prolongation of survival of hand-picked islets transplanted across a major histocompatibility barrier

  11. Operational slack and venture survival

    OpenAIRE

    Azadegan, Arash; Patel, Pankaj; Parida, Vinit

    2013-01-01

    Slack can act as a double-edged sword. While it can buffer against environmental threats to help ensure business continuity, slack canalso be costly and reduce profitability. In this study, we focus on operational slack, the form related to the firm’s production processes. We investigate the role of operational slack on firm survival during its venture stage, when its survival is significantly challenged by environmental threats. Specifically, we explore how change in three types of environme...

  12. Secondary beams at GANIL

    International Nuclear Information System (INIS)

    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

  13. Secondary Vertex Finder Algorithm

    CERN Document Server

    Heer, Sebastian; The ATLAS collaboration

    2017-01-01

    If a jet originates from a b-quark, a b-hadron is formed during the fragmentation process. In its dominant decay modes, the b-hadron decays into a c-hadron via the electroweak interaction. Both b- and c-hadrons have lifetimes long enough, to travel a few millimetres before decaying. Thus displaced vertices from b- and subsequent c-hadron decays provide a strong signature for a b-jet. Reconstructing these secondary vertices (SV) and their properties is the aim of this algorithm. The performance of this algorithm is studied with tt̄ events, requiring at least one lepton, simulated at 13 TeV.

  14. SECONDARY (ENDOCRINE HYPERTENSION: LECTURE

    Directory of Open Access Journals (Sweden)

    M. Yu. Yukina

    2016-01-01

    Full Text Available Hypertension is a  very common disease with high morbidity and reduction in quality of life. Endocrine disorders are the most common cause of secondary hypertension affecting ~3% of the population. Primary aldosteronism can be the cause of endocrine hypertension more often than other endocrine disorders. Other less common causes of endocrine hypertension include Cushing syndrome, pheochromocytoma, thyroid disorders, and hyperparathyroidism. Endocrine hypertension is potentially curable if the underlying cause is identified and treated accordingly. Younger age at manifestation of resistance to multiple antihypertensive drugs, together with other clinical signs of an endocrine disorder, should raise the suspicion and prompt the appropriate evaluation.

  15. [Secondary osteoporosis in gynecology].

    Science.gov (United States)

    Taguchi, Y; Gorai, I

    1998-06-01

    Several diseases and medications are known to induce secondary osteoporosis. Among them, same situations are related to gynecological field. They include Turner's syndrome, anorexia nervosa, ovarian dysfunction, oophorectomy, GnRH agonist therapy, and osteoporosis associated with pregnancy. We briefly describe these secondary osteoporosis in this article as follows. Several studies have found osteoporosis to be a common complication of Turner's syndrome and hormone replacement therapy has been used as a possible management; in anorexic patient, low body weight, prolonged amenorrhea, early onset of anorexia nervosa, and hypercortisolism have been reported to be risks for bone demineralization; since oophorectomy which is a common intervention in gynecology leads osteoporosis, it is important to prevent osteoporosis caused by surgery as well as postmenopausal osteoporosis; GnRH agonist, which induces estrogen deficient state and affect bone mass, is commonly used as a management for endometriosis and leiomyoma of uterus; associated with pregnancy, post-pregnancy spinal osteoporosis and transient osteoporosis of the hip are clinically considered to be important and heparin therapy and magnesium sulfate therapy are commonly employed during pregnancy, affecting calcium homeostasis.

  16. Radioactive heavy ion secondary beams

    International Nuclear Information System (INIS)

    Bimbot, R.

    1987-01-01

    The production of secondary radioactive beams at GANIL using the LISE spectrometer is reviewed. The experimental devices, and secondary beam characteristics are summarized. Production of neutron rich secondary beams was studied for the systems Ar40 + Be at 44 MeV/u, and 018 + Be at 45 and 65 MeV/u. Partial results were also obtained for the system Ne22 + Ta at 45 MeV/u. Experiments using secondary beams are classified into two categories: those which correspond to fast transfer of nuclei from the production target to a well shielded observation point; and those in which the radioactive beam interacts with a secondary target

  17. The time dependent association of adrenaline administration and survival from out-of-hospital cardiac arrest.

    Science.gov (United States)

    Ewy, Gordon A; Bobrow, Bentley J; Chikani, Vatsal; Sanders, Arthur B; Otto, Charles W; Spaite, Daniel W; Kern, Karl B

    2015-11-01

    Recommended for decades, the therapeutic value of adrenaline (epinephrine) in the resuscitation of patients with out-of-hospital cardiac arrest (OHCA) is controversial. To investigate the possible time-dependent outcomes associated with adrenaline administration by Emergency Medical Services personnel (EMS). A retrospective analysis of prospectively collected data from a near statewide cardiac resuscitation database between 1 January 2005 and 30 November 2013. Multivariable logistic regression was used to analyze the effect of the time interval between EMS dispatch and the initial dose of adrenaline on survival. The primary endpoints were survival to hospital discharge and favourable neurologic outcome. Data from 3469 patients with witnessed OHCA were analyzed. Their mean age was 66.3 years and 69% were male. An initially shockable rhythm was present in 41.8% of patients. Based on a multivariable logistic regression model with initial adrenaline administration time interval (AATI) from EMS dispatch as the covariate, survival was greatest when adrenaline was administered very early but decreased rapidly with increasing (AATI); odds ratio 0.94 (95% Confidence Interval (CI) 0.92-0.97). The AATI had no significant effect on good neurological outcome (OR=0.96, 95% CI=0.90-1.02). In patients with OHCA, survival to hospital discharge was greater in those treated early with adrenaline by EMS especially in the subset of patients with a shockable rhythm. However survival rapidly decreased with increasing adrenaline administration time intervals (AATI). Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

  18. A surviving infant with sirenomelia (Mermaid syndrome) associated with absent bladder.

    Science.gov (United States)

    Stanton, Michael P; Penington, Elizabeth C; Hutson, John M

    2003-08-01

    The authors report a case of a surviving infant with sirenomelia (Mermaid syndrome). The child is now 4 years of age. The authors believe that this is only the fourth reported case of an infant with sirenomelia surviving beyond the neonatal period and the first associated with absent bladder. The abnormal distal aorta shown in this case supports the theory that sirenomelia is an extreme form of caudal dysgenesis rather than occurring secondary to vascular steal.

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

    Science.gov (United States)

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

    2015-07-21

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

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

    Science.gov (United States)

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

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

  1. Assessment of early response biomarkers in relation to long‐term survival in patients with HER2‐negative breast cancer receiving neoadjuvant chemotherapy plus bevacizumab: Results from the Phase II PROMIX trial

    Science.gov (United States)

    Kimbung, Siker; Markholm, Ida; Bjöhle, Judith; Lekberg, Tobias; von Wachenfeldt, Anna; Azavedo, Edward; Saracco, Ariel; Hellström, Mats; Veerla, Srinivas; Paquet, Eric; Bendahl, Pär‐Ola; Fernö, Mårten; Bergh, Jonas; Loman, Niklas

    2017-01-01

    Pathologic complete response (pCR) is a predictor for favorable outcome after neoadjuvant treatment in early breast cancer. Modulation of gene expression may also provide early readouts of biological activity and prognosis, offering the possibility for timely response‐guided treatment adjustment. The role of early transcriptional changes in predicting response to neoadjuvant chemotherapy plus bevacizumab was investigated. One‐hundred‐and‐fifty patients with large, operable and locally advanced HER2‐negative breast cancer received epirubicin and docetaxel, with the addition of bevacizumab. Patients underwent tumor biopsies at baseline, after Cycle 2 and at the time of surgery. The primary end point, pCR, and its relation with the secondary endpoints event‐free survival (EFS), overall survival (OS) and gene expression profiles, are reported. The pCR rate was 13% (95% CI 8.6–20.2), with significantly more pCRs among triple‐negative [28% (95% CI 14.8–45.4)] than among hormone receptor positive (HR+) tumors [9% (95% CI 4.6–16.3); (OR = 3.9 [CI = 1.5–10.3])]. pCR rates were not associated with EFS or OS. PAM50 subtypes significantly changed after Cycle 2 (p = 0.03) and an index of absolute changes in PAM50 correlations between these time‐points was associated with EFS [HR = 0.62 (CI = 0.3–1.1)]. In univariable analyses, signatures for angiogenesis, proliferation, estrogen receptor signaling, invasion and metastasis, and immune response, measured after Cycle 2, were associated with pCR in HR+ tumors. Evaluation of changes in molecular subtypes and other signatures early in the course of neoadjuvant treatment may be predictive of pCR and EFS. These factors may help guide further treatment and should be considered when designing neoadjuvant trials. PMID:28940389

  2. Analysis of cause-specific failure endpoints using simple proportions: an example from a randomized controlled clinical trial in early breast cancer

    International Nuclear Information System (INIS)

    Panzarella, Tony; Meakin, J. William

    1998-01-01

    Purpose: To describe a statistically valid method for analyzing cause-specific failure data based on simple proportions, that is easy to understand and apply, and outline under what conditions its implementation is well-suited. Methods and Materials: In the comparison of treatment groups, time to first failure (in any site) was analyzed first, followed by an analysis of the pattern of first failure, preferably at the latest complete follow-up time common to each group. Results: A retrospective analysis of time to contralateral breast cancer in 777 early breast cancer patients was undertaken. Patients previously treated by mastectomy plus radiation therapy to the chest wall and regional nodal areas were randomized to receive further radiation and prednisone (R+P), radiation alone (R), or no further treatment (NT). Those randomized to R+P had a statistically significantly delayed time to first failure compared to the group randomized to NT (p = 0.0008). Patients randomized to R also experienced a delayed time to first failure compared to NT, but the difference was not statistically significant (p 0.14). At 14 years from the date of surgery (the latest common complete follow-up time) the distribution of first failures was statistically significantly different between R+P and NT (p = 0.005), but not between R and NT (p = 0.09). The contralateral breast cancer first failure rate at 14 years from surgery was 7.2% for NT, 4.6% for R, and 3.7% for R+P. The corresponding Kaplan-Meier estimates were 13.2%, 8.2%, and 5.4%, respectively. Conclusion: Analyzing cause-specific failure data using methods developed for survival endpoints is problematic. We encourage the use of the two-step analysis strategy described when, as in the example presented, competing causes of failure are not likely to be statistically independent, and when a treatment comparison at a single time-point is clinically relevant and feasible; that is, all patients have complete follow-up to this point

  3. Progression-free survival results in postmenopausal Asian women: subgroup analysis from a phase III randomized trial of fulvestrant 500 mg vs anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON).

    Science.gov (United States)

    Noguchi, Shinzaburo; Ellis, Matthew J; Robertson, John F R; Thirlwell, Jackie; Fazal, Mehdi; Shao, Zhimin

    2018-05-01

    The international, phase III FALCON study (NCT01602380) in postmenopausal patients with hormone receptor-positive, locally advanced/metastatic breast cancer (LA/MBC) who had not received prior endocrine therapy, demonstrated statistically significant improvement in progression-free survival (PFS) for patients who received fulvestrant 500 mg vs anastrozole 1 mg. This subgroup analysis evaluated PFS in Asian (randomized in China, Japan, or Taiwan) and non-Asian patients from the FALCON study. Eligible patients (estrogen receptor- and/or progesterone receptor-positive LA/MBC; World Health Organization performance status 0-2; ≥ 1 measurable/non-measurable lesion[s]) were randomized. PFS was assessed via Response Evaluation Criteria in Solid Tumours version 1.1, surgery/radiotherapy for disease worsening, or death (any cause). Secondary endpoints included: objective response rate, clinical benefit rate, duration of response, and duration of clinical benefit. Consistency of effect across subgroups was assessed via hazard ratios and 95% confidence intervals (CIs) using a log-rank test. Adverse events (AEs) were evaluated. Of the 462 randomized patients, the Asian and non-Asian subgroups comprised 67 and 395 patients, respectively. In the Asian subgroup, median PFS was 16.6 and 15.9 months with fulvestrant and anastrozole, respectively (hazard ratio 0.81; 95% CI 0.44-1.50). In the non-Asian subgroup, median PFS was 16.5 and 13.8 months, respectively (hazard ratio 0.79; 95% CI 0.62-1.01). Secondary outcomes were numerically improved with fulvestrant vs anastrozole in both subgroups. AE profiles were generally consistent between Asian and non-Asian subgroups. Results of this subgroup analysis suggest that treatment effects in the Asian patient subgroup are broadly consistent with the non-Asian population.

  4. An application of the 'end-point' method to the minimum critical mass problem in two group transport theory

    International Nuclear Information System (INIS)

    Williams, M.M.R.

    2003-01-01

    A two group integral equation derived using transport theory, which describes the fuel distribution necessary for a flat thermal flux and minimum critical mass, is solved by the classical end-point method. This method has a number of advantages and in particular highlights the changing behaviour of the fissile mass distribution function in the neighbourhood of the core-reflector interface. We also show how the reflector thermal flux behaves and explain the origin of the maximum which arises when the critical size is less than that corresponding to minimum critical mass. A comparison is made with diffusion theory and the necessary and somewhat artificial presence of surface delta functions in the fuel distribution is shown to be analogous to the edge transients that arise naturally in transport theory

  5. Prediction of the relative toxicity of environmental toxins as a function of behavioral and non-behavioral endpoints

    International Nuclear Information System (INIS)

    Young, R.W.

    1979-01-01

    This study was conducted in order to examine the differential effects of behavioral and non-behavioral endpoints on the prediction of the relative toxicity of an environmental toxin. The effects of ionizing radiation were taken as the model for this evaluation. Forty rhesus monkeys were irradiated in groups of four at five different dose levels of high energy neuton and Bremsstrahlung radiations. Measures of behavioral performance, emesis and mortality were taken for each subject in order to test the hypotheses that behavioral indices would be more sensitive to gamma radiation than would physiological indices and that the physiological indices would be more sensitive to neutron radiations than would behavioral indices. The results supported these hypotheses

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

    International Nuclear Information System (INIS)

    Savage, J.R.K.

    1978-01-01

    A vital condition when chromosomal aberrations are to be used as a quantitative end-point (e.g. for constructing a dose response curve) is that a specific dose must produce a specific yield of aberrations under a given set of experimental conditions. In practice, there are very few cell systems where this condition is met. The majority show significant variations in observed yield with time between irradiation and sampling, indicative of variable radiosensitivity within the cell population. The profile of this yield time curve is determined by the cell-cycle kinetics and therefore is itself subject to modification by radiation through mitotic delay and perturbation. Thus in such heterogeneous populations, each increment of dose not only induces more aberrations, but at the same time modifies the recovered yield per cell. This has an obvious bearing upon the interpretation of the shape of any dose-response curve obtained

  7. The Medical Imaging & Technology Alliance conference on research endpoints appropriate for Medicare coverage of new PET radiopharmaceuticals.

    Science.gov (United States)

    Hillman, Bruce J; Frank, Richard A; Abraham, Brian C

    2013-09-01

    The outcomes of a 2011 Medical Imaging & Technology Alliance (MITA) conference helped shape considerations about what might be the most appropriate pathways for the regulatory and payment considerations of new PET radiopharmaceuticals. As follow-up to that conference, MITA convened a second conference of stakeholders to advise payers on what might be acceptable endpoints for clinical trials to support the coverage of novel PET agents. The conference involved experts on imaging and clinical research, providers of PET services, as well as representatives of interested medical societies, the PET industry, and the regulatory and payer communities. The principal outcome of their deliberations was that it was unrealistic to expect trials of new PET radiopharmaceuticals to directly demonstrate a health benefit. Rather, intermediate outcomes, such as a positive change in patient management, would be more efficient and appropriate.

  8. Transitions in Secondary Education

    DEFF Research Database (Denmark)

    Larsen, Britt Østergaard; Jensen, Leif; Pilegaard Jensen, Torben

    2014-01-01

    statistical model of educational progression. By using this method, we parcel educational attainment into a series of transitions and the model is able to control for educational selection and unobserved heterogeneity. We apply counterfactual analyses to allow a formal decomposition of the effects of social......The purpose of this article is to investigate educational choices and attainment of children who experience social problems during their upbringing. The study explores the extent to which social problems can help explain the gaps in entry and dropout rates in upper secondary education in Denmark...... between students from different socioeconomic backgrounds. Population-based registers are used to include information on family upbringing, e.g. alcohol abuse, criminality, use of psychopharmaca and out-of-home placement. We estimate a parsimonious version of Cameron and Heckman's (2001) dynamic...

  9. [Secondary orbital lymphoma].

    Science.gov (United States)

    Basanta, I; Sevillano, C; Álvarez, M D

    2015-09-01

    A case is presented of an 85 year-old Caucasian female with lymphoma that recurred in the orbit (secondary ocular adnexal lymphoma). The orbital tumour was a diffuse large B-cell lymphoma according to the REAL classification (Revised European-American Lymphoma Classification). Orbital lymphomas are predominantly B-cell proliferations of a variety of histological types, and most are low-grade tumours. Patients are usually middle-aged or elderly, and it is slightly more common in women. A palpable mass, proptosis and blepharoptosis are the most common signs of presentation. Copyright © 2011 Sociedad Española de Oftalmología. Published by Elsevier España, S.L.U. All rights reserved.

  10. HANARO secondary coolant management

    International Nuclear Information System (INIS)

    Kim, Seon Duk.

    1998-02-01

    In this report, the basic theory for management of water quality, environmental factors influencing to the coolant, chemicals and its usage for quality control of coolant are mentioned, and water balance including the loss rate by evaporation (34.3 m 3 /hr), discharge rate (12.665 m 3 /hr), concentration ratio and feed rate (54.1 m 3 /hr) are calculated at 20 MW operation. Also, the analysis data of HANSU Limited for HANARO secondary coolant (feed water and circulating coolant) - turbidity, pH, conductivity, M-alkalinity, Ca-hardness, chloride ion, total iron ion, phosphoric ion and conversion rate are reviewed. It is confirmed that the feed water has good quality and the circulating coolant has been maintained within the control specification in general, but some items exceeded the control specification occasionally. Therefore it is judged that more regular discharge of coolant is needed. (author). 6 refs., 17 tabs., 18 figs

  11. New secondary energy systems

    International Nuclear Information System (INIS)

    Schulten, R.

    1977-01-01

    As an introduction, the FRG's energy industry situation is described, secondary energy systems to be taken into consideration are classified, and appropriate market requirements are analyzed. Dealt with is district heating, i.e. the direct transport of heat by means of circulating media, and long-distance energy, i.e. the long-distance energy transport by means of chemical conversion in closed- or open-cycle systems. In closed-cycle systems heat is transported in the form of chemical latent energy. In contrast to this, chemical energy is transported in open-cycle systems in the form of fuel gases produced by coal gasification or by thermochemical water splitting. (GG) [de

  12. Second Primary Malignant Neoplasms and Survival in Adolescent and Young Adult Cancer Survivors.

    Science.gov (United States)

    Keegan, Theresa H M; Bleyer, Archie; Rosenberg, Aaron S; Li, Qian; Goldfarb, Melanie

    2017-11-01

    Although the increased incidence of second primary malignant neoplasms (SPMs) is a well-known late effect after cancer, few studies have compared survival after an SPM to survival of the same cancer occurring as first primary malignant neoplasm (PM) by age. To assess the survival impact of SPMs in adolescents and young adults (AYAs) (15-39 years) compared with that of pediatric (cancer in 13 Surveillance, Epidemiology and End Results regions in the United States diagnosed from 1992 to 2008 and followed through 2013. Data analysis was performed between June 2016 and January 2017. Five-year relative survival was calculated overall and for each cancer occurring as a PM or SPM by age at diagnosis. The impact of SPM status on cancer-specific death was examined using multivariable Cox proportional hazards regression. A total of 15 954 pediatric, 125 750 AYAs, and 878 370 older adult patients diagnosed as having 14 cancers occurring as a PM or SPM were included. Overall, 5-year survival after an SPM was 33.1% lower for children, 20.2% lower for AYAs, and 8.3% lower for older adults compared with a PM at the same age. For the most common SPMs in AYAs, the absolute difference in 5-year survival was 42% lower for secondary non-Hodgkin lymphoma, 19% for secondary breast carcinoma, 15% for secondary thyroid carcinoma, and 13% for secondary soft-tissue sarcoma. Survival by SPM status was significantly worse in younger vs older patients for thyroid, Hodgkin lymphoma, non-Hodgkin lymphoma, acute myeloid leukemia, soft-tissue sarcoma, and central nervous system cancer. Adolescents and young adults with secondary Hodgkin lymphoma (hazard ratio [95% CI], 3.5 [1.7-7.1]); soft-tissue sarcoma (2.8 [2.1-3.9]); breast carcinoma (2.1 [1.8-2.4]); acute myeloid leukemia (1.9 [1.5-2.4]); and central nervous system cancer (1.8 [1.2-2.8]) experienced worse survival compared with AYAs with the same PMs. The adverse impact of SPMs on survival is substantial for AYAs and may partially

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

    Science.gov (United States)

    Sala, Miquel; Faria, Melissa; Sarasúa, Ignacio; Barata, Carlos; Bonada, Núria; Brucet, Sandra; Llenas, Laia; Ponsá, Sergio; Prat, Narcís; Soares, Amadeu M V M; Cañedo-Arguelles, Miguel

    2016-10-01

    The rivers and streams of the world are becoming saltier due to human activities. In spite of the potential damage that salt pollution can cause on freshwater ecosystems, this is an issue that is currently poorly managed. Here we explored intraspecific differences in the sensitivity of freshwater fauna to two major ions (Cl(-) and SO4(2-)) using the net-spinning caddisfly Hydropsyche exocellata Dufour 1841 (Trichoptera, Hydropsychidae) as a model organism. We exposed H. exocellata to saline solutions (reaching a conductivity of 2.5mScm(-1)) with Cl(-):SO4(2-) ratios similar to those occurring in effluents coming from the meat, mining and paper industries, which release dissolved salts to rivers and streams in Spain. We used two different populations, coming from low and high conductivity streams. To assess toxicity, we measured sub-lethal endpoints: locomotion, symmetry of the food-capturing nets and oxidative stress biomarkers. According to biomarkers and net building, the population historically exposed to lower conductivities (B10) showed higher levels of stress than the population historically exposed to higher conductivities (L102). However, the differences between populations were not strong. For example, net symmetry was lower in the B10 than in the L102 only 48h after treatment was applied, and biomarkers showed a variety of responses, with no discernable pattern. Also, treatment effects were rather weak, i.e. only some endpoints, and in most cases only in the B10 population, showed a significant response to treatment. The lack of consistent differences between populations and treatments could be related to the high salt tolerance of H. exocellata, since both populations were collected from streams with relatively high conductivities. The sub-lethal effects tested in this study can offer an interesting and promising tool to monitor freshwater salinization by combining physiological and behavioural bioindicators. Copyright © 2016 Elsevier B.V. All rights

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

    Science.gov (United States)

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

    2005-01-26

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

  15. Predicting the outcome of oral food challenges with hen's egg through skin test end-point titration.

    Science.gov (United States)

    Tripodi, S; Businco, A Di Rienzo; Alessandri, C; Panetta, V; Restani, P; Matricardi, P M

    2009-08-01

    Oral food challenge (OFC) is the diagnostic 'gold standard' of food allergies but it is laborious and time consuming. Attempts to predict a positive OFC through specific IgE assays or conventional skin tests so far gave suboptimal results. To test whether skin test with titration curves predict with enough confidence the outcome of an oral food challenge. Children (n=47; mean age 6.2 +/- 4.2 years) with suspected and diagnosed allergic reactions to hen's egg (HE) were examined through clinical history, physical examination, oral food challenge, conventional and end-point titrated skin tests with HE white extract and determination of serum specific IgE against HE white. Predictive decision points for a positive outcome of food challenges were calculated through receiver operating characteristic (ROC) analysis for HE white using IgE concentration, weal size and end-point titration (EPT). OFC was positive (Sampson's score >or=3) in 20/47 children (42.5%). The area under the ROC curve obtained with the EPT method was significantly bigger than the one obtained by measuring IgE-specific antibodies (0.99 vs. 0.83, P<0.05) and weal size (0.99 vs. 0.88, P<0.05). The extract's dilution that successfully discriminated a positive from a negative OFC (sensitivity 95%, specificity 100%) was 1 : 256, corresponding to a concentration of 5.9 microg/mL of ovotransferrin, 22.2 microg/mL of ovalbumin, and 1.4 microg/mL of lysozyme. EPT is a promising approach to optimize the use of skin prick tests and to predict the outcome of OFC with HE in children. Further studies are needed to test w