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Abstract Background:BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes. Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. Results: The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies. Cancer Epidemiol Biomarkers Prev; 24(1); 308–16. ©2014 AACR.

ScopeWe reevaluated previously reported associations between variants in pathways of one‐carbon (1‐C) (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake.Methods and resultsOdds ratios (OR) for 446 genetic variants were estimated among 13 410 OC cases and 22 635 controls, and among 2281 cases and 3444 controls with folate information. Following multiple testing correction, the most significant main effect associations were for dihydropyrimidine dehydrogenase (DPYD) variants rs11587873 (OR = 0.92; p = 6 × 10−5) and rs828054 (OR = 1.06; p = 1 × 10−4). Thirteen variants in the pyrimidine metabolism genes, DPYD, DPYS, PPAT, and TYMS, also interacted significantly with folate in a multivariant analysis (corrected p = 9.9 × 10−6) but collectively explained only 0.2% of OC risk. Although no other associations were significant after multiple testing correction, variants in SHMT1 in 1‐C transfer, previously reported with OC, suggested lower risk at higher folate (pinteraction = 0.03–0.006).ConclusionVariation in pyrimidine metabolism genes, particularly DPYD, which was previously reported to be associated with OC, may influence risk; however, stratification by folate intake is unlikely to modify disease risk appreciably in these women. SHMT1 SNP‐by‐folate interactions are plausible but require further validation. Polymorphisms in selected genes in purine metabolism were not associated with OC.

Context Studies that investigate research questions that have already been resolved represent a waste of resources. However, the failure to collect sufficient evidence to resolve a given question results in ambiguity. Objectives The present study was conducted to reanalyse the results of a meta‐analysis of simulation‐based education ( SBE ) to determine: (i) whether researchers continue to replicate research studies after the answer to a research question has become known, and (ii) whether researchers perform enough replications to definitively answer important questions. Methods A systematic search of multiple databases to May 2011 was conducted to identify original research evaluating SBE for health professionals in comparison with no intervention or any active intervention, using skill outcomes. Data were extracted by reviewers working in duplicate. Data synthesis involved a cumulative meta‐analysis to illuminate patterns of evidence by sequentially adding studies according to a variable of interest (e.g. publication year) and re‐calculating the pooled effect size with each addition. Cumulative meta‐analysis by publication year was applied to 592 comparative studies using several thresholds of ‘sufficiency’, including: statistical significance; stable effect size classification and magnitude (Hedges’ g ± 0.1), and precise estimates (confidence intervals of less than ± 0.2). Results Among studies that compared the outcomes of SBE with those of no intervention, evidence supporting a favourable effect of SBE on skills existed as early as 1973 (one publication) and further evidence confirmed a quantitatively large effect of SBE by 1997 (28 studies). Since then, a further 404 studies were published. Among studies comparing SBE with non‐simulation instruction, the effect initially favoured non‐simulation training, but the addition of a third study in 1997 brought the pooled effect to slightly favour simulation, and by 2004 (14 studies) this effect was statistically significant (p < 0.05) and the magnitude had stabilised (small effect). A further 37 studies were published after 2004. By contrast, evidence from studies evaluating repetition continued to show borderline statistical significance and wide confidence intervals in 2011. Conclusions Some replication is necessary to obtain stable estimates of effect and to explore different contexts, but the number of studies of SBE often exceeds the minimum number of replications required.

Objectives Debriefing is a common feature of technology‐enhanced simulation ( TES ) education. However, evidence for its effectiveness remains unclear. We sought to characterise how debriefing is reported in the TES literature, identify debriefing features that are associated with improved outcomes, and evaluate the effectiveness of debriefing when combined with TES . Methods We systematically searched databases, including MEDLINE , EMBASE and Scopus, and reviewed previous bibliographies for original comparative studies investigating the use of TES with debriefing in training health care providers. Reviewers, in duplicate, evaluated study quality and abstracted information on instructional design, debriefing and outcomes. Effect sizes ( ES ) were pooled using random‐effects meta‐analysis. Results From 10 903 potentially eligible studies, we identified 177 studies (11 511 learners) that employed debriefing as part of TES . Key characteristics of debriefing (e.g. duration, educator presence and characteristics, content, structure/method, timing, use of video) were usually incompletely reported. A meta‐analysis of four studies demonstrated that video‐assisted debriefing has negligible and non‐significant effects for time skills ( ES = 0.10) compared with non‐video‐assisted debriefing. Meta‐analysis demonstrated non‐significant effects in favour of expert modelling with short debriefing in comparison with long debriefing (ES range = 0.21–0.74). Among studies comparing terminal with concurrent debriefing, results were variable depending on outcome measures and the context of training (e.g. medical resuscitation versus technical skills). Eight additional studies revealed insight into the roles of other debriefing‐related factors (e.g. multimedia debriefing, learner‐led debriefing, debriefing duration, content of debriefing). Among studies that compared simulation plus debriefing with no intervention, pooled ES s were favourable for all outcomes (ES range = 0.28–2.16). Conclusions Limited evidence suggests that video‐assisted debriefing yields outcomes similar to those of non‐video‐assisted debriefing. Other debriefing design features show mixed or non‐significant results. As debriefing characteristics are usually incompletely reported, future debriefing research should describe all the key debriefing characteristics along with their associated descriptors.

Background— Patients undergo major physical and psychological changes after implantation of a left ventricular assist device as destination therapy (DT). We sought to qualitatively study outcomes and attitudes of patients after DT. Methods and Results— Ambulatory outpatients with DT at our institution were invited to be interviewed between June and August 2011. In-person interviews were audio-recorded, transcribed, and analyzed qualitatively using thematic analysis. The study included 12 patients (11 men) from the Midwestern United States with a median age of 71.5 years (range, 33–78 years). Interviews were conducted at a median (range) time of 1.37 (0.43–5.04) years after DT implantation. Most patients were white (n=11), married (n=10), and Christian (n=10). We identified 6 themes commonly discussed by the interviewees: preparedness planning, new lease on life, optimizing support networks, systemic limitations, reflections on time, and communication matters. Analysis revealed that most patients saw DT as their only choice, despite other alternatives. Conclusions— Ambulatory patients reported varied experiences after DT but commonly reported gratitude for improved functional status and a perception of improved symptom burden. Recommendations for improving post-DT care include developing patient support systems, systematizing education for community providers, and expanding respite services.

BACKGROUND AND OBJECTIVE: Pediatrics has embraced technology-enhanced simulation (TES) as an educational modality, but its effectiveness for pediatric education remains unclear. The objective of this study was to describe the characteristics and evaluate the effectiveness of TES for pediatric education. METHODS: This review adhered to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) standards. A systematic search of Medline, Embase, CINAHL, ERIC, Web of Science, Scopus, key journals, and previous review bibliographies through May 2011 and an updated Medline search through October 2013 were conducted. Original research articles in any language evaluating the use of TES for educating health care providers at any stage, where the content solely focuses on patients 18 years or younger, were selected. Reviewers working in duplicate abstracted information on learners, clinical topic, instructional design, study quality, and outcomes. We coded skills (simulated setting) separately for time and nontime measures and similarly classified patient care behaviors and patient effects. RESULTS: We identified 57 studies (3666 learners) using TES to teach pediatrics. Effect sizes (ESs) were pooled by using a random-effects model. Among studies comparing TES with no intervention, pooled ESs were large for outcomes of knowledge, nontime skills (eg, performance in simulated setting), behaviors with patients, and time to task completion (ES = 0.80–1.91). Studies comparing the use of high versus low physical realism simulators showed small to moderate effects favoring high physical realism (ES = 0.31–0.70). CONCLUSIONS: TES for pediatric education is associated with large ESs in comparison with no intervention. Future research should include comparative studies that identify optimal instructional methods and incorporate pediatric-specific issues into educational interventions.