Enriched Designs Research Articles

Thermal hydraulic modeling of solid fueled nuclear thermal propulsion reactors Part I: Development and verification

This paper focuses on the development and demonstration of a modern thermal–hydraulic engineering tool to design nuclear thermal propulsion reactors. Low enriched uranium nuclear thermal propulsion reactors are currently being invested to appease regulatory and proliferation concerns, and consequently rendering the previous highly enriched uranium designs inapplicable. Sparse experimental data from the previously designed highly enriched uranium designs may be non-ideal for benchmarking low-enriched uranium designs. Computational fluid dynamics codes provide an affordable and expeditious alternate route for the verification of thermal–hydraulic engineering tools. Verification of engineering tools is crucial as they will be implemented in coupled neutronic and thermal–hydraulic simulations to ascertain the thermal and safety margins of a given design. Extensive research was performed on the optimization and design of nuclear thermal propulsion reactors, but there is limited publicly available description of currently adopted thermal–hydraulic solution procedures used for the design of contemporary nuclear thermal propulsion reactors. More specifically, the modelling assumptions, geometric simplifications, correlations, and iterative procedures are not always well understood or documented. The purpose of this paper is to provide a clear explanation of our thermal hydraulic modelling approach, clarify the impacts of commonly used assumptions on engineering-based tools, and demonstrate the importance of thermal–hydraulic solutions on neutronics. These objectives are achieved through the newly developed ntpThermo computational tool. This tool is verified against the high-order computational fluid dynamics code OpenFoam, which serves as the reference solution following a successful validation against experimental data. The results indicate that the reduced order-modeling approach implemented in ntpThermo can provide valuable engineering design support and be used for coupled neutronic and thermal–hydraulic simulations.

The Inconvenient Truth About Convenience and Purposive Samples.

Most research is conducted on convenience and purposive samples that may be randomly or nonrandomly drawn. A convenience sample is the one that is drawn from a source that is conveniently accessible to the researcher. A purposive sample is the one whose characteristics are defined for a purpose that is relevant to the study. The findings of a study based on convenience and purposive sampling can only be generalized to the (sub)population from which the sample is drawn and not to the entire population. This article explains the concepts involved with the help of examples of both good and bad sampling practice. Database studies and studies with enriched designs are cited as special examples of convenience and purposive sampling. Issues related to the internal and external validity of convenience and purposive samples are explained. The importance of good sampling techniques in the design and interpretation of research is understated; this must change.

Evaluation of non-linear-mixed-effect modeling to reduce the sample sizes of pediatric trials in type 2 diabetes mellitus.

Recruitment for pediatric trials in Type II Diabetes Mellitus (T2DM) is very challenging, necessitating the exploration of new approaches for reducing the sample sizes of pediatric trials. This work aimed at assessing if a longitudinal Non-Linear-Mixed-Effect (NLME) analysis of T2DM trial could be more powerful and thus require fewer patients than two standard statistical analyses commonly used as primary or sensitivity efficacy analysis: Last-Observation-Carried-Forward (LOCF) followed by (co)variance (AN(C)OVA) analysis at the evaluation time-point, and Mixed-effects Model Repeated Measures (MMRM) analysis. Standard T2DM efficacy studies were simulated, with glycated hemoglobin (HbA1c) as the main endpoint, 24weeks' study duration, 2 arms, assuming a placebo and a treatment effect, exploring three different scenarios for the evolution of HbA1c, and accounting for a dropout phenomenon. 1000 trials were simulated, then analyzed using the 3 analyses, whose powers were compared. As expected, the longitudinal modeling MMRM analysis was found to be more powerful than the LOCF + ANOVA analysis at week 24. The NLME analysis gave slightly more accurate drug-effect estimations than the two other methods, however it tended to slightly overestimate the magnitude of the drug effect, and it was more powerful than the MMRM analysis only in some scenarios of slow HbA1c decrease. The gain in power afforded by NLME was more apparent when two additional assessments enriched the design; however, the gain was not systematic for all scenarios. Finally, this work showed that NLME analyses may help to reduce significantly the required sample sizes in T2DM pediatric studies, but only for enriched designs and slow HbA1c decrease.

Miradas cruzadas. Notas sobre arquitecturas nórdicas y arquitectos viajeros entre Japón y Europa

The research starts from the idea that traditional Japanese architecture has played an important role in the development of modern architecture in Europe, especially in the case of domestic architecture. The objective is to summarize this fact, widely studied in the United States due to the work of Frank Lloyd Wright. However, this fact has only been partially analysed about Europe, especially during the second half of the 20th century and in relation to the Nordic countries. How did Nordic architects find inspiration in the East? What drew them to your tectonic culture? How did they apply the Japanese aesthetic to their own designs? While sometimes only formal elements were used, without much more depth, in other cases, the principles of Orientalism, Sukiya architecture or the Villa Katsura as a reference, enriched domestic architecture designs. Such is the case of Jørn Utzon, Halldor Gunnløgsson, Arne Korsmo or Sverre Fehn, among others; who were the leaders of a current of modern Eastern syncretism, which owes its origins to the vision of the Central European pioneers who visited Japan, to the influence of Erik Gunnar Asplund and, above all, to the legacy of Tetsuro Yoshida.

Auxiliary variable-enriched biomarker-stratified design.

Clinical trials in the era of precision medicine require assessment of biomarkers to identify appropriate subgroups of patients for targeted therapy. In a biomarker-stratified design (BSD), biomarkers are measured on all patients and used as stratification variables. However, such a trial can be both inefficient and costly, especially when the prevalence of the subgroup of primary interest is low and the cost of assessing the biomarkers is high. Efficiency can be improved and costs reduced by using enriched biomarker-stratified designs, in which patients of primary interest, typically the biomarker-positive patients, are oversampled. We consider a special type of enrichment design, an auxiliary variable-enriched design (AEBSD), in which enrichment is based on some inexpensive auxiliary variable that is positively correlated with the true biomarker. The proposed AEBSD reduces the total cost of the trial compared with a standard BSD when the prevalence rate of true biomarker positivity is small and the positive predictive value (PPV) of the auxiliary biomarker is larger than the prevalence rate. In addition, for an AEBSD, we can immediately randomize the patients selected in the screening process without waiting for the result of the true biomarker test, reducing the treatment waiting time. We propose an adaptive Bayesian method to adjust the assumed PPV while the trial is ongoing. Numerical studies and an example illustrate the approach. An R package is available.

Comparison of effect sizes between enriched and nonenriched trials of analgesics for chronic musculoskeletal pain: a systematic review.

To investigate the use of an enriched study design on the estimates of treatment effect in analgesic trials for chronic musculoskeletal pain. Database searches were conducted from 2004 to 2014. We included randomized placebo-controlled trials evaluating pain medications for chronic musculoskeletal pain. Methodological quality was assessed using the PEDro scale. The estimates of treatment effect on pain and adverse events were compared between enriched and nonenriched designs. Metaregression was used to assess the association between the effect size estimate and the study design controlling for analgesic dose and methodological quality. We included 108 trials, of which 99 were included in the meta-analysis (n=44 171). There were no overall differences in effect sizes between enriched and nonenriched designs for pain intensity. There was a significant difference for a reduction in any adverse events favouring enriched designs for opioids, but not for other analgesics or the outcome serious adverse events. There was an association between effect size and methodological quality, with failure to blind the outcome assessor and failure to use intention-to-treat analysis being associated with larger effect sizes. There is no evidence that the use of an enriched study design changes the treatment effect size estimate for pain. There is some evidence that clinical trials that employ enriched designs report a reduced risk of adverse events in trials for chronic musculoskeletal pain, but it is unclear whether enriched designs influence estimates of serious adverse events. Features of trial design and study quality were associated with treatment effect estimates.

Exposure enriched outcome dependent designs for longitudinal studies of gene-environment interaction.

Joint effects of genetic and environmental factors have been increasingly recognized in the development of many complex human diseases. Despite the popularity of case-control and case-only designs, longitudinal cohort studies that can capture time-varying outcome and exposure information have long been recommended for gene-environment (G×E) interactions. To date, literature on sampling designs for longitudinal studies of G×E interaction is quite limited. We therefore consider designs that can prioritize a subsample of the existing cohort for retrospective genotyping on the basis of currently available outcome, exposure, and covariate data. In this work, we propose stratified sampling based on summaries of individual exposures and outcome trajectories and develop a full conditional likelihood approach for estimation that adjusts for the biased sample. We compare the performance of our proposed design and analysis with combinations of different sampling designs and estimation approaches via simulation. We observe that the full conditional likelihood provides improved estimates for the G×E interaction and joint exposure effects over uncorrected complete-case analysis, and the exposure enriched outcome trajectory dependent design outperforms other designs in terms of estimation efficiency and power for detection of the G×E interaction. We also illustrate our design and analysis using data from the Normative Aging Study, an ongoing longitudinal cohort study initiated by the Veterans Administration in 1963. Copyright © 2017 John Wiley & Sons, Ltd.

Topical lidocaine for neuropathic pain in adults.

Lidocaine is a local anaesthetic that is sometimes used on the skin to treat neuropathic pain. To assess the analgesic efficacy of topical lidocaine for chronic neuropathic pain in adults, and to assess the associated adverse events. We searched CENTRAL, MEDLINE, and EMBASE from inception to 1 July 2014, together with the reference lists of retrieved papers and other reviews. We also searched ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal to identify additional published or unpublished data. We included randomised, double-blind studies of at least two weeks' duration comparing any formulation of topical lidocaine with placebo or another active treatment in chronic neuropathic pain. Participants were adults aged 18 and over. We included only full journal publication articles. Two review authors independently extracted efficacy and adverse event data, and examined issues of study quality. We performed analysis using three tiers of evidence. First tier evidence derived from data meeting current best standards and subject to minimal risk of bias (outcome equivalent to substantial pain intensity reduction, intention-to-treat analysis without imputation for dropouts; at least 200 participants in the comparison, 8 to 12 weeks' duration, parallel design); second tier evidence from data that failed to meet one or more of these criteria and that we considered at some risk of bias but with adequate numbers in the comparison; and third tier evidence from data involving small numbers of participants that we considered very likely to be biased or used outcomes of limited clinical utility, or both. We included 12 studies (508 participants) in comparisons with placebo or an active control. Six studies enrolled participants with moderate or severe postherpetic neuralgia, and the remaining studies enrolled different, or mixed, neuropathic pain conditions, including trigeminal neuralgia and postsurgical or post-traumatic neuralgia. Four different formulations were used: 5% medicated patch, 5% cream, 5% gel, and 8% spray. Most studies used a cross-over design, and two used a parallel-group design. Two studies used enriched enrolment with randomised withdrawal. Seven studies used multiple doses, with one to four-week treatment periods, and five used single applications. We judged all of the studies at high risk of bias because of small size or incomplete outcome assessment, or both.There was no first or second tier evidence, and no pooling of data was possible for efficacy outcomes. Only one multiple-dose study reported our primary outcome of participants with ≥ 50% or ≥ 30% pain intensity reduction. Three single-dose studies reported participants who were pain-free at a particular time point, or had a 2-point (of 10) reduction in pain intensity. The two enriched enrolment, randomised withdrawal studies reported time to loss of efficacy. In all but one study, third tier (very low quality) evidence indicated that lidocaine was better than placebo for some measure of pain relief. Pooling multiple-dose studies across conditions demonstrated no clear evidence of an effect of lidocaine on the incidence of adverse events or withdrawals, but there were few events and the withdrawal phase of enriched enrolment designs is not suitable to assess the true impact of adverse events (very low quality evidence). This review found no evidence from good quality randomised controlled studies to support the use of topical lidocaine to treat neuropathic pain, although individual studies indicated that it was effective for relief of pain. Clinical experience also supports efficacy in some patients. Several large ongoing studies, of adequate duration, with clinically useful outcomes should provide more robust conclusions about both efficacy and harm.

Beyond Motivation: Job and Work Design for Development, Health, Ambidexterity, and More

Much research shows it is possible to design motivating work, which has positive consequences for individuals and their organizations. This article reviews research that adopts this motivational perspective on work design, and it emphasizes that it is important to continue to refine motivational theories. In light of continued large numbers of poor-quality jobs, attention must also be given to influencing practice and policy to promote the effective implementation of enriched work designs. Nevertheless, current and future work-based challenges mean that designing work for motivation is necessary but insufficient. This review argues that work design can be a powerful vehicle for learning and development, for maintaining and enhancing employees' physical and mental health, and for achieving control and flexibility simultaneously (for example, in the form of ambidexterity); all these outcomes are important given the challenges in today's workplaces. The review concludes by suggesting methodological directions.

Systematic review of efficacy and safety of buprenorphine versus fentanyl or morphine in patients with chronic moderate to severe pain

Objective:To systematically assess efficacy and safety of buprenorphine patch versus fentanyl patch in patients with chronic moderate to severe pain.Methods:Fifteen databases were searched up to December 2010. Randomised and quasi-randomised trials assessing the efficacy in patients with chronic pain were included. Quantitative methods for data synthesis were used and two network meta-analyses were conducted.Results:Fourteen unique trials (17 publications) were included. No head-to-head randomised trials of buprenorphine patch compared with fentanyl patch were identified. Therefore, less robust evidence from indirect comparisons was used. Results from a network meta-analysis of non-enriched designs (eight trials), using trials versus placebo and trials versus morphine for indirect comparisons, indicated that transdermal fentanyl, in comparison with transdermal buprenorphine, showed significantly more nausea (odds ratio [OR] 4.66, 95% confidence interval (CI) 1.07 to 20.39), a significantly higher number of treatment discontinuations due to adverse events (OR 5.94, 95% CI 1.78 to 19.87), and non-significant differences on all other outcomes, including pain measures. In comparison with morphine, transdermal buprenorphine had a significantly higher decrease of pain intensity (MD [mean difference] −16.20, 95% CI −28.92 to −3.48) while morphine caused more cases of constipation (OR 7.50, 95% CI 1.45 to 38.85) and a significantly higher number of treatment discontinuations due to adverse events (OR 5.80, 95% CI 1.68 to 20.11). All other outcomes showed non-significant differences between transdermal buprenorphine and morphine. The results were similar when also including six trials using enriched designs with the exception of more cases of vomiting for fentanyl (OR 17.32, 95% CI 4.43 to 67.71) and morphine (OR 15.85, 95% CI 3.92 to 64.13) compared to buprenorphine.Conclusions:The findings indicate comparability of transdermal buprenorphine and transdermal fentanyl for pain measures with significantly fewer adverse events (nausea and treatment discontinuation due to adverse events) caused by transdermal buprenorphine.

Betting on Biomarkers

In this issue, Johnson and colleagues (1) report on a study of ondansetron, a serotonin receptor antagonist, for alcohol-dependent patients. Had they conducted a standard randomized placebo-controlled trial, they would have found no statistically significant difference between treatment groups on the primary outcome measure and stopped there. That is, on average, their study participants were not significantly less likely to drink if they received ondansetron than if they received placebo.

CS06-02 - How fast antipsychotics work – implications for theory and practise

It has been traditionally accepted that antipsychotics have a 'delayed onset' of action with various authors claiming 2–3 weeks of delay. Data from the previous few years has contradicted this notion.The talk will review this data, identify its theoretical implications and implications for practise. In an initial meta-analysis of over 8,000 patient data it was shown that antipsychotic action is not delayed at all but evident in teh first week, this change is not non-specific sedation but a specific anti-'psychotic' effect, and is seen with all evaluated antipsychotics. In more recent studies we have been able to show that this effect is even discernable in the first 24 hours, is related to dopmaine D2 occupancy achieved early on, and early non-response is a very strong predictor of subsequent non-response.This early onset is not only an isolated improvement in psychosis-but, can also be seen on quality of life and social functionign indicators. These data raise interesting questions regarding the mechanism of improvement: they question the standard 'depolarisation block' hypothesis of antispychotic action-and suggest a simpler dopamine occupancy hypothesis instead; since change occurs early it is possible to map different trajectories and our most recent findigns show that drug-treated patients show a distinct trajectory from those observed in placebo-treated patients. Finally, these findings have implications for the design of clinical trials and clinical practise. In clinical trials it is possible to use early-response to devise adpative or enriched designs that are more clinically relevant - example of a recent such application will be discussed and at a clinical level it may be possible to reconsider the standard notion that an antipsychotic must be tried for 6 weeks before considering an alterative option.

Development of enriched Gd-155 and Gd-157 burnable poison designs for a PWR core

In this study, a genetic algorithm developed by the authors was applied to design the optimal enriched Gd-155 and Gd-157 burnable poisons in a reference PWR TMI-1 core. The CASMO-4/TABLES/SIMULATE-3 package calculated the neutronic performance of the enriched UO 2/Gd 2O 3 fuel pin configurations. These configurations included different fractions of neutron absorbing isotopes Gd-155 and Gd-157, and 100 w/o enriched Gd-155 designs. Fuel cost analysis was performed to evaluate the economical benefits of these optimized enriched gadolinium designs. The break-even point for unit Gd-155 enrichment cost was determined to be around ∼$30/gram-Gd-155 with current unit cost scenario. The projected savings were 3.13% in gross and 2.08% in net compared to total fuel cycle cost of a reference TMI-1 core loading, if all of the 68 feed assemblies would be replaced with the optimized designs.

The proficiency trap: how to balance enriched job designs and the team's need for support

AbstractThe present study seeks to enlighten our understanding of ways to promote the performance of teams of professionals. Considering that job enrichment practices might block support for a team, and hence its performance, the study examined the moderating effects of cultural factors, namely individualism–collectivism and power distance, and the team leader's practices as a source of support in the job enrichment–team support relationship. Further, the study examined the mediating role of team support in improving the performance of professional teams. Results from 56 healthcare teams from different hospitals indicated that attempts to promote professionals' performance should consider at a minimum how to balance job enrichment practices and the team's need for support. The findings suggest that this balance could be achieved by emphasizing the support provided by the leader, and by strengthening the cultural values of low power distance and collectivism in the team. Copyright © 2004 John Wiley & Sons, Ltd.

Monotherapy comparative trials: placebos and suboptimal comparators

The superiority of a drug can be demonstrated using several comparative designs against either placebo, or a low dose of the study drug or standard anti-epileptic drug (AED). Firstly, the population could consist of inpatients admitted for presurgical monitoring. Although these trials are scientifically interpretable, and involve direct comparison of the study drug against placebo, they are, in general, too short in duration to be able to define clinical relevance. Secondly, patients with refractory epilepsy can participate in monotherapy substitution studies during which patients are randomised to one of at least two arms with the baseline AED subsequently tapered and discontinued. These patients are maintained on monotherapy for the rest of the trial. An enriched design can also be used in which patients successfully converted to a high dose of the study drug, are then randomised to either the high or low dose of the treatment. The ethics of such enriched designs is questionable. More recently, studies have been carried out in patients with new onset seizures. In such designs, patients are randomised to the study drug (possibly at different dosages), versus a placebo or pseudo-placebo control. Comparative trials in patients with newly-diagnosed epilepsy makes it more difficult to obtain significant differences due to the high number of patients needed and the usually lengthy time course of the study.

Statistical Issues in the Design and Analysis of Clinical Trials in Alzheimer's Disease

The nature and symptoms of Alzheimer's disease present unique issues and problems related to the design and analysis of clinical trials for assessing the efficacy of potential therapies. Based on the author's involvement with two multicenter studies in Alzheimer's patients, issues related to the design and analysis of such trials are discussed. Due to the progressive nature of the disease and the potential for carryover and withdrawal effects, crossover and enriched population designs are not recommended. Instead, parallel group comparisons are preferable. Since Alzheimer's disease has both cognitive and behavioral symptoms, both an objective cognitive test and a global assessment are recommended primary outcome variables. Other important design issues are specification of efficacy criteria, length of the double-blind treatment period, dose escalation, and follow-up of dropouts. With respect to statistical analysis, it is important to include all randomized patients in the analysis and to make every possi...