Citations

Abstract Mammographic density measures adjusted for age and body mass index (BMI) are heritable predictors of breast cancer risk, but few mammographic density-associated genetic variants have been identified. Using data for 10,727 women from two international consortia, we estimated associations between 77 common breast cancer susceptibility variants and absolute dense area, percent dense area and absolute nondense area adjusted for study, age, and BMI using mixed linear modeling. We found strong support for established associations between rs10995190 (in the region of ZNF365), rs2046210 (ESR1), and rs3817198 (LSP1) and adjusted absolute and percent dense areas (all P < 10−5). Of 41 recently discovered breast cancer susceptibility variants, associations were found between rs1432679 (EBF1), rs17817449 (MIR1972-2: FTO), rs12710696 (2p24.1), and rs3757318 (ESR1) and adjusted absolute and percent dense areas, respectively. There were associations between rs6001930 (MKL1) and both adjusted absolute dense and nondense areas, and between rs17356907 (NTN4) and adjusted absolute nondense area. Trends in all but two associations were consistent with those for breast cancer risk. Results suggested that 18% of breast cancer susceptibility variants were associated with at least one mammographic density measure. Genetic variants at multiple loci were associated with both breast cancer risk and the mammographic density measures. Further understanding of the underlying mechanisms at these loci could help identify etiologic pathways implicated in how mammographic density predicts breast cancer risk. Cancer Res; 75(12); 2457–67. ©2015 AACR.

SummaryData from the National LymphoCare Study (a prospective, multicentre registry that enrolled follicular lymphoma (FL) patients from 2004 to 2007) were used to determine disease characteristics, treatment patterns, outcomes and prognosis for elderly FL (eFL) patients. Of 2650 FL patients, 209 (8%) were aged >80 years; these eFL patients more commonly had grade 3 disease, less frequently received chemoimmunotherapy and anthracyclines, and had lower response rates when compared to younger patients. With a median follow‐up of 6.9 years, 5‐year overall survival (OS) for eFL patients was 59%; 38% of deaths were lymphoma‐related. No treatment produced superior OS among eFL patients. In multivariate Cox models, anaemia, B‐symptoms and male sex predicted worse OS (P < 0·01); a prognostic index of these factors (0, 1 or ≥2 present) predicted OS [hazard ratio (95% CI): ≥2 vs. 0, 4·72 (2·38–9·33); 1 vs. 0, 2·63 (1·39–4·98)], with a higher concordance index (0·63) versus the Follicular Lymphoma International Prognostic Index (0·55). The index was validated in an independent cohort. In the largest prospective US‐based eFL cohort, no optimal therapy was identified and nearly 40% of deaths were lymphoma‐related, representing baseline outcomes in the modern era.

Introduction: A dramatic increase in the number of pediatric orthopaedic fellows being trained has led to concerns that there may be an oversupply of pediatric orthopaedists. The purpose of this study was to determine whether this perception is accurate and whether the practice expectations of recent pediatric fellowship graduates are being met by surveying recent pediatric fellowship graduates about their early practice experiences. Methods: A 36-question survey approved by the Pediatric Orthopaedic Society of North America (POSNA) leadership was electronically distributed to 120 recent graduates of pediatric orthopaedic fellowships; 81 responses were ultimately obtained (67.5% response rate). Results: Almost all (91%) of the respondents were very or extremely satisfied with their fellowship experience. Half of the respondents had at least 1 job offer before they entered their fellowships. After completion of fellowships, 35% received 1 job offer and 62.5% received ≥2 job offers; only 2.5% did not receive a job offer. Most reported a practice consisting almost entirely of pediatric orthopaedics, and 93.5% thought this was in line with their expectations; 87% indicated satisfaction with their current volume of pediatric orthopaedics, and 85% with the complexity of their pediatric orthopaedic cases. Despite the high employment percentages and satisfaction with practice profiles, nearly a third (28%) of respondents replied that too many pediatric orthopaedists are being trained. Conclusions: Positive messages from this survey include the satisfaction of graduates with their fellowship training, the high percentage of graduates who readily found employment, and the satisfaction of graduates with their current practice environments; this indicates that the pediatric orthopaedic job environment is not completely saturated and there are continued opportunities for graduating pediatric fellows despite the increased number of fellows being trained. Although not determined by this study, it may be that the stable demand for pediatric orthopaedic services is being driven by the expansion of the scope of practice as well as subspecialization within the practice of pediatric orthopaedics.

Background— In asymptomatic patients with severe aortic stenosis, guidelines recommend left ventricular ejection fraction (LVEF) of <50% as the threshold for referral for aortic valve replacement. We investigated the importance of LVEF on long-term outcome after aortic valve replacement in symptomatic and asymptomatic patients with severe aortic stenosis. Methods and Results— We retrospectively identified 2017 patients with severe aortic stenosis (aortic valve area<1 cm 2 , mean gradient≥40 mm Hg, or indexed aortic valve area<0.6 cm 2 /m 2 ) who underwent surgical aortic valve replacement from January 1995 to June 2009. Patients were divided into 4 groups depending on preoperative LVEF (<50% in 300 [15%] patients, 50%–59% in 331 [17%], 60%–69% in 908 [45%], and ≥70% in 478 [24%]). During follow-up of 5.3±4.4 years, 1056 (52%) patients died. A decrease in mortality was observed with increasing LVEF, P <0.0001; 5-year mortality estimates (95% confidence interval) were 0.41 (0.35–0.47), LVEF<50%; 0.35 (0.29–0.41), LVEF 50% to 59%; 0.26 (0.23–0.29), LVEF 60% to 69%; and 0.22 (0.18–0.26), LVEF≥70%. Compared with patients with LVEF≥60%, patients with LVEF 50% to 59% had increased mortality (hazard ratio [HR], 1.58; P <0.001), with similar risk increase in both symptomatic (HR, 1.56; P <0.001) and asymptomatic patients (HR, 1.58; P =0.006). Correcting for risk factors, LV mass index, aortic valve area, and stroke volume index, LVEF was independently predictive of mortality (HR, 0.88 per 10%; P <0.001). When this analysis was repeated in the subset of 1333 patients without history of coronary artery disease, LVEF remained associated with mortality (HR, 0.90 per 10%; P =0.009). Conclusions— LVEF is a powerful predictor of outcome in patients with severe aortic stenosis undergoing aortic valve replacement, independent of the presence of valve-related symptoms.

A central principle of justice is that similar cases should be decided in similar ways. In pediatrics, however, there are cases in which 2 infants have similar diagnoses and prognoses, but their parents request different treatments. In this Ethics Rounds, we present such a situation that occurred in a single NICU. Three physician-ethicists analyze the issues.

ABSTRACT Background: Sleep deprivation and fatigue have been associated with medical errors, clinical performance decrements, and reduced quality of life for both practicing physicians and medical students. Greater understanding of the impact of sleep quantity on clinical reasoning could improve patient care. The purpose of our pilot study was to examine relationships between clinical reasoning (assessed by functional magnetic resonance imaging) and sleep time (measured in different ways by actigraphy) while answering multiple-choice questions (MCQs) from licensing agencies. Methods: Residents and faculty were administered a clinical reasoning exercise (MCQs from licensing bodies) during functional magnetic resonance imaging. Usual sleep patterns were sampled with actigraphy. Covariate analysis was used to examine the relationship between sleep duration (mean sleep, minimum sleep, maximum sleep) and brain activity during clinical reasoning (solving MCQs from licensing bodies). Results: The mean sleep time over the duration of monitoring for the group was 7.19 hours (SD 0.66) with a range of 6.1 to 8.1 hours (internal medicine faculty 7.1 hours, SD 0.41; internal medicine residents 7.27 hours, SD 0.92). There was a negative relationship between activation in the prefrontal cortex and minimum sleep time while reflecting on MCQs. Conclusion: Our findings provide evidence that the quantity of sleep can modulate brain activity while completing a clinically meaningful task that should be confirmed in larger studies. Our findings suggest that the construct of sleepiness may be more complex than appreciated by many and that the most important of these sleep measures in terms of outcomes remains to be determined.

Abstract Background: Genome-wide association studies have identified multiple genetic variants associated with prostate cancer risk which explain a substantial proportion of familial relative risk. These variants can be used to stratify individuals by their risk of prostate cancer. Methods: We genotyped 25 prostate cancer susceptibility loci in 40,414 individuals and derived a polygenic risk score (PRS). We estimated empirical odds ratios (OR) for prostate cancer associated with different risk strata defined by PRS and derived age-specific absolute risks of developing prostate cancer by PRS stratum and family history. Results: The prostate cancer risk for men in the top 1% of the PRS distribution was 30.6 (95% CI, 16.4–57.3) fold compared with men in the bottom 1%, and 4.2 (95% CI, 3.2–5.5) fold compared with the median risk. The absolute risk of prostate cancer by age of 85 years was 65.8% for a man with family history in the top 1% of the PRS distribution, compared with 3.7% for a man in the bottom 1%. The PRS was only weakly correlated with serum PSA level (correlation = 0.09). Conclusions: Risk profiling can identify men at substantially increased or reduced risk of prostate cancer. The effect size, measured by OR per unit PRS, was higher in men at younger ages and in men with family history of prostate cancer. Incorporating additional newly identified loci into a PRS should improve the predictive value of risk profiles. Impact: We demonstrate that the risk profiling based on SNPs can identify men at substantially increased or reduced risk that could have useful implications for targeted prevention and screening programs. Cancer Epidemiol Biomarkers Prev; 24(7); 1121–9. ©2015 AACR.