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1.
Modelling PK/QT relationships from Phase I dose‐escalation trials for drug combinations and developing quantitative risk assessments of clinically relevant QT prolongations 下载免费PDF全文
In current industry practice, it is difficult to assess QT effects at potential therapeutic doses based on Phase I dose‐escalation trials in oncology due to data scarcity, particularly in combinations trials. In this paper, we propose to use dose‐concentration and concentration‐QT models jointly to model the exposures and effects of multiple drugs in combination. The fitted models then can be used to make early predictions for QT prolongation to aid choosing recommended dose combinations for further investigation. The models consider potential correlation between concentrations of test drugs and potential drug–drug interactions at PK and QT levels. In addition, this approach allows for the assessment of the probability of QT prolongation exceeding given thresholds of clinical significance. The performance of this approach was examined via simulation under practical scenarios for dose‐escalation trials for a combination of two drugs. The simulation results show that invaluable information of QT effects at therapeutic dose combinations can be gained by the proposed approaches. Early detection of dose combinations with substantial QT prolongation is evaluated effectively through the CIs of the predicted peak QT prolongation at each dose combination. Furthermore, the probability of QT prolongation exceeding a certain threshold is also computed to support early detection of safety signals while accounting for uncertainty associated with data from Phase I studies. While the prediction of QT effects is sensitive to the dose escalation process, the sensitivity and limited sample size should be considered when providing support to the decision‐making process for further developing certain dose combinations. Copyright © 2016 John Wiley & Sons, Ltd. 相似文献
2.
Joris Van Damme Anne Hublet Bart De Clercq Emmanuel Kuntsche Lea Maes Els Clays 《Journal of American college health : J of ACH》2017,65(8):558-566
Objective: Drinking alcohol during the exams can affect academic performance and future career options, but is rarely investigated. Drinking motives, sociodemographics and personality characteristics are investigated in nonabstainers and weekly drinkers during the exams. Participants: 7,181 Belgian university students who anonymously responded to an email invitation to an online survey. Methods: Logistic regressions and mixed design analysis of variance on cross-sectional data. Results: One-third of the students continued drinking during the exams, with 40% drinking weekly. Nonabstainers were mainly men, elder, internally motivated when drinking, and housed with parents or independently. Weekly drinkers were similar, except mainly housed in student apartments or independently. Personality characteristics were nonsignificant. All drinking motives were less pronounced during the exams, with smaller differences for internal motives. Conclusions: Mainly linked to internal drinking motives, drinking during the exams in higher education is underestimated. The characteristics and motives of students doing so can be used in future interventions. 相似文献
3.
Kaatje Els Bollaerts Winy Messens Laurent Delhalle Marc Aerts Yves Van der Stede Jeroen Dewulf Sophie Quoilin Dominiek Maes Koen Mintiens Koen Grijspeerdt 《Risk analysis》2009,29(6):820-840
A quantitative microbial risk assessment (QMRA) according to the Codex Alimentarius Principles is conducted to evaluate the risk of human salmonellosis through household consumption of fresh minced pork meat in Belgium. The quantitative exposure assessment is carried out by building a modular risk model, called the METZOON-model, which covers the pork production from farm to fork. In the METZOON-model, the food production pathway is split up in six consecutive modules: (1) primary production, (2) transport and lairage, (3) slaughterhouse, (4) postprocessing, (5) distribution and storage, and (6) preparation and consumption. All the modules are developed to resemble as closely as possible the Belgian situation, making use of the available national data. Several statistical refinements and improved modeling techniques are proposed. The model produces highly realistic results. The baseline predicted number of annual salmonellosis cases is 20,513 ( SD 9061.45). The risk is estimated higher for the susceptible population (estimate 4.713 × 10−5 ; SD 1.466 × 10−5 ) compared to the normal population (estimate 7.704 × 10−6 ; SD 5.414 × 10−6 ) and is mainly due to undercooking and to a smaller extent to cross-contamination in the kitchen via cook's hands. 相似文献
4.
OBJECTIVE: This pilot project assessed the effectiveness of an intervention to increase knowledge and reduce risky behaviors related to cumulative trauma disorders (CTD) in office workers. STUDY DESIGN: All 124 employees from the administrative offices of a health maintenance organization were invited to participate. Subjects were followed across time using an identification number. Data were collected via questionnaire in June 1994 (pretest1) (N=84), August 1994 (pretest II) (N= 63) and September 1995 (posttest) (N=40). The yearlong intervention focused on functional activities to prevent CTD. RESULTS: of chi-square analyses for the 40 subjects who completed all surveys indicated this intervention significantly increased overall knowledge of CTD (p =.002). Significant changes in self-reported hand/wrist (p =.016) and neck/shoulder (p =.003) posture were also found. CONCLUSIONS: This study is a first step in identifying effective educational interventions to increase knowledge and reduce risk factors related to CTD in office workers. 相似文献
5.
Els van Wijngaarden Carlo Leget Anne Goossensen 《International Journal of Social Research Methodology》2018,21(3):317-331
This article focuses on research ethics in highly intimate research with possible impact on life and death. In order to stimulate an open-ended dialogue about research ethics, we reflect on four ethical challenges that came up during our research into older people with a wish to die. Drawing on our experiences, we discuss (1) the possibly confirming influence of our research on the death wish (moral experience of whether or not to disregard responsibility); (2) the suggested duty to intervene (moral experience of whether or not to compromise the person’s autonomy); (3) the researcher’s authority and power over the data (moral experience of threatening a person’s self-narrative) and (4) the dilemma of intimacy (moral experience of encountering the tragic). For guidance in addressing these challenges, we draw upon work on research ethics from phenomenological and care ethics scholars, as well as from those writing about relational ethics in health research. We suggest that being open about ethical uneasiness is important, because in most cases of a grey area, there are only open-ended answers needing an enquiring mind, rather than clear and fixed guidelines. Acknowledgement of ethical uneasiness and open-ended reflexivity are indispensable to constitute a morally good research practice. 相似文献
6.
Manoochehr Babanezhad Stijn Vansteelandt Els Goetghebeur 《Journal of statistical planning and inference》2010
Over the past decades, various principles for causal effect estimation have been proposed, all differing in terms of how they adjust for measured confounders: either via traditional regression adjustment, by adjusting for the expected exposure given those confounders (e.g., the propensity score), or by inversely weighting each subject's data by the likelihood of the observed exposure, given those confounders. When the exposure is measured with error, this raises the question whether these different estimation strategies might be differently affected and whether one of them is to be preferred for that reason. In this article, we investigate this by comparing inverse probability of treatment weighted (IPTW) estimators and doubly robust estimators for the exposure effect in linear marginal structural mean models (MSM) with G-estimators, propensity score (PS) adjusted estimators and ordinary least squares (OLS) estimators for the exposure effect in linear regression models. We find analytically that these estimators are equally affected when exposure misclassification is independent of the confounders, but not otherwise. Simulation studies reveal similar results for time-varying exposures and when the model of interest includes a logistic link. 相似文献
7.
Christiane Timmerman Els Vanderwaeren Maurice Crul 《The International migration review》2003,37(4):1065-1090
A growing proportion of second‐generation Moroccan and Turkish youngsters in Belgium are moving on to higher secondary education and beyond. This trend is greater among Moroccan youngsters than among their Turkish peers. Turkish girls in particular are still married off at a young age, which inevitably affects their educational opportunities. Despite higher participation rates for youngsters from immigrant backgrounds, the educational gap with Belgian pupils and students remains wide. This is largely attributable to differences in socioeconomic background. It appears that the concentration of second‐generation immigrant pupils in certain schools is also a major explanatory factor. Despite their increased participation in education, second‐generation immigrants are still not well represented in the labor market and they are, moreover, employed mostly in less favorable segments of that market. An interesting development among second‐generation immigrants is the polarization that is taking place in relation to the significance of Islam. A growing number of second‐generation youngsters are opting for a more secular way of life, while an increasingly large group is choosing Islamist ideologies or at least a more conscious form of Islam. For young people of the second generation, who often have little to hold on to socially, Islamism can provide a transparent, supportive, and all‐embracing frame of reference. 相似文献
8.
Els Schellekens 《Intercultural Education》2001,12(3):339-347
This article looks at the development of the educational kit This Is Me that is aimed at four- to six-year-olds. The kit, created in 1995, aims to help children develop their own identity, a positive self-image, mutual acceptance and mutual respect. The target group of this intercultural education tool is young children. In addition to describing the aims and contents of this tool, we also evaluate how these materials are being used. 相似文献
9.
Nieuwenhuijsen ER 《Work (Reading, Mass.)》2004,23(3):215-224
The purpose of this evidence-based study is to investigate the impact of a multi-component intervention on health behavior change among office/computer workers in preventing repetitive strain injuries. Forty office workers employed in an administrative office in Michigan participated in this project. The subjects completed a comprehensive questionnaire at three different times in 1994 and 1995. The intervention took place between time 2 and time 3 and included posters, e-mail tips, mini-workshops, and activities of a Wellness Ergonomic Team. A theoretical model was tested to identify factors influencing healthy behaviors. Study findings revealed positive behavior change for 62% of the participants. The factors most strongly related to health behavior change appear to be self-efficacy, the intention to change one's behavior, and perceived health status. Better understanding of health behavior change coupled with ergonomic modifications is a significant step toward the prevention of repetitive strain injuries resulting from computer use. 相似文献
10.
Els Goetghebeur & Krista Lapp 《Journal of the Royal Statistical Society. Series C, Applied statistics》1998,46(3):351-364
The causal effect of a treatment is estimated at different levels of treatment compliance, in a placebo-controlled trial on the reduction of blood pressure. The structural nested mean model makes no direct assumptions on selected treatment compliance levels and placebo prognosis but relies on the randomization assumption and a parametric form for causal effects. It can be seen as a regression model for unpaired data, where pre- and post-randomization covariables are treated differently. The causal parameters are found as solutions to estimating equations involving estimated placebo response and treatment compliance based on base-line covariates for all subjects. Our example considers a linear effect of the percentage of prescribed dose taken on achieved diastolic blood pressure reduction. We propose an exploration of structural model checks. In the example, this reveals an interaction between the causal effect of active dose taken and the base-line body weight of the patient. 相似文献