Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.

BACKGROUND Although the Affordable Care Act has been successful in expanding Medicaid to >17 million people, insurance alone may not translate into access to health care. Even among the insured, substantial barriers to accessing services inhibit health care utilization. OBJECTIVES We examined the effect of selected barriers to health care access and the magnitude of those barriers on health care utilization. RESEARCH DESIGN Data come from a 2008 survey of adult enrollees in Minnesota's public health care programs. We used multivariate logistic regression to estimate the effects of perceived patient, provider, and system-level barriers on past year delayed, foregone, and lack of preventive care. SUBJECTS A total of 2194 adults enrolled in Minnesota Health Care Programs who were mostly female (66%), high school graduates (76%), unemployed (62%), and living in metro areas (67%) were included in the analysis. RESULTS Reporting problems across all barriers increased the odds of delayed care from 2 times for provider-related barriers (OR=2.0; 95% CI, 1.2-3.3) to >6 times for access barriers (OR=6.2; 95% CI, 3.8-10.2) and foregone care from 2.6 times for family/work barriers (OR=2.6; 95% CI, 1.3-5.1) to >7 times for access barriers (OR=7.1; 95% CI, 3.9-13.1). Perceived discrimination was the only barrier consistently associated with all 3 utilization outcomes. CONCLUSIONS Multiple types of barriers are associated with delayed and foregone care. System-level barriers and discrimination have the greatest effect on health care seeking behavior.

Systematic reviews (SRs) have the potential to contribute uniquely to the evaluation of sex and gender differences (termed "sex effects"). This article describes the reporting of sex effects by SRs on interventions for depression, type 2 diabetes mellitus, and chronic pain conditions (chronic low back pain, knee osteoarthritis, and fibromyalgia). It includes SRs published since 1 October 2009 that evaluate medications, behavioral interventions, exercise, quality improvement, and some condition-specific treatments. The reporting of sex effects by primary randomized, controlled trials is also examined. Of 313 eligible SRs (86 for depression, 159 for type 2 diabetes mellitus, and 68 for chronic pain), few (n = 29) reported sex effects. Most SRs reporting sex effects used metaregression, whereas 9 SRs used subgroup analysis or individual-patient data meta-analysis. The proportion of SRs reporting the sex distribution of primary studies varied from a low of 31% (n = 8) for low back pain to a high of 68% (n = 23) for fibromyalgia. Primary randomized, controlled trials also infrequently reported sex effects, and most lacked an adequate sample size to examine them. Therefore, all SRs should report the proportion of women enrolled in primary studies and evaluate sex effects using appropriate methods whenever power is adequate.

2-Phenethyl isothiocyanate (PEITC), a natural product found as a conjugate in watercress and other cruciferous vegetables, is an inhibitor of the metabolic activation and lung carcinogenicity of the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in F344 rats and A/J mice. We carried out a clinical trial to determine whether PEITC also inhibits the metabolic activation of NNK in smokers. Cigarette smokers were recruited and asked to smoke cigarettes containing deuterium-labeled [pyridine-D4]NNK for an acclimation period of at least 1 week. Then subjects were randomly assigned to one of two arms: PEITC followed by placebo, or placebo followed by PEITC. During the 1-week treatment period, each subject took PEITC (10 mg in 1 mL of olive oil, 4 times per day). There was a 1-week washout period between the PEITC and placebo periods. The NNK metabolic activation ratio [pyridine-D4]hydroxy acid/total [pyridine-D4]NNAL was measured in urine samples to test the hypothesis that PEITC treatment modified NNK metabolism. Eighty-two smokers completed the study and were included in the analysis. Overall, the NNK metabolic activation ratio was reduced by 7.7% with PEITC treatment (P = 0.023). The results of this trial, while modest in effect size, provide a basis for further investigation of PEITC as an inhibitor of lung carcinogenesis by NNK in smokers. Cancer Prev Res; 9(5); 396-405. ©2016 AACR.

PURPOSE To evaluate cancer incidence among Minnesota taconite mining workers. METHODS We evaluated cancer incidence between 1988 and 2010 in a cohort of 40,720 Minnesota taconite mining workers used between 1937 and 1983. Standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) were estimated by comparing numbers of incident cancers with frequencies in the Minnesota Cancer Surveillance System. SIRs for lung cancer by histologic subtypes were also estimated. We adjusted for out-of-state migration and conducted a probabilistic bias analysis for smoking-related cancers. RESULTS A total of 5700 cancers were identified, including 51 mesotheliomas and 973 lung cancers. The SIRs for lung cancer and mesothelioma were 1.3 (95% CI = 1.2-1.4) and 2.4 (95% CI = 1.8-3.2), respectively. Stomach, laryngeal, and bladder cancers were also elevated. However, adjusting for potential confounding by smoking attenuated the estimates for lung (SIR = 1.1, 95% CI = 1.0-1.3), laryngeal (SIR = 1.2, 95% CI = 0.8-1.6), oral (SIR = 0.9, 95% CI = 0.7-1.2), and bladder cancers (SIR = 1.0, 95% CI = 0.8-1.1). CONCLUSIONS Taconite workers may have an increased risk for certain cancers. Lifestyle and work-related factors may play a role in elevated morbidity. The extent to which mining-related exposures contribute to disease burden is being investigated.

OBJECTIVE To examine the association between employment duration, elongate mineral particle (EMP) exposure, silica exposure and the risk of lung cancer in the taconite mining industry. METHODS We conducted a nested case-control study of lung cancer within a cohort of Minnesota taconite iron mining workers employed by any of the mining companies in operation in 1983. Lung cancer cases were identified by vital records and cancer registry data through 2010. Two age-matched controls were selected from risk sets of cohort members alive and lung cancer free at the time of case diagnosis. Calendar time-specific exposure estimates were made for every job and were used to estimate workers' cumulative exposures. ORs and 95% CIs were estimated using conditional logistic regression. We evaluated total lung cancer risk and risk of histological subtype by total work duration and by cumulative EMP, and silica exposure by quartile of the exposure distribution. RESULTS A total of 1706 cases and 3381 controls were included in the analysis. After adjusting for work in haematite mining, asbestos exposure and sex, the OR for total duration of employment was 0.99 (95% CI 0.96 to 1.01). The ORs for quartile 4 versus 1 of EMP and silica exposure were 0.82 (95% CI 0.57 to 1.19) and 0.97 (95% CI 0.70 to 1.35), respectively. The risk of each histological subtype of lung cancer did not change with increasing exposure. CONCLUSIONS This study suggests that the estimated taconite mining exposures do not increase the risk of developing lung cancer.

The consequences of alcohol use disorder (AUD) and suicide create immense health disparities among Alaska Native people. The People Awakening project is a long-term collaboration between Alaska Native (AN) communities and university researchers seeking to foster health equity through development of positive solutions to these disparities. These efforts initiated a research relationship that identified individual, family, and community protective factors from AUD and suicide. AN co-researchers next expressed interest in translating these findings into intervention. This led to development of a strengths-based community intervention that is the focus of the special issue. The intervention builds these protective factors to prevent AUD and suicide risk within AN youth, and their families and communities. This review provides a critical examination of existing literature and a brief history of work leading to the intervention research. These work efforts portray a shared commitment of university researchers and community members to function as co-researchers, and to conduct research in accord with local Yup'ik cultural values. This imperative allowed the team to navigate several tensions we locate in a convergence of historical and contemporary ecological contextual factors inherent in AN tribal communities with countervailing constraints imposed by Western science.

OBJECTIVE Medical school curricula intended to promote empathy varies widely. Even the most effective curricula leave a significant group of students untouched. Pre-existing student factors influence their response to learning experiences. We examined the individual predictors of first semester medical students' attitudes toward the value of physician empathy in clinical encounters. METHODS First year students (n=4732) attending a stratified random sample of 49 US medical schools completed an online questionnaire that included measures of dispositional characteristics, attitudes and beliefs, self-concept and well-being. RESULTS Discomfort with uncertainty, close-mindedness, dispositional empathy, elitism, medical authoritarianism, egalitarianism, self-concept and well-being all independently predicted first year medical students' attitudes toward the benefit of physician empathy in clinical encounters. CONCLUSION Students vary on their attitude toward the value of physician empathy when they start medical school. The individual factors that predict their attitudes toward empathy may also influence their response to curricula promoting empathic care. PRACTICE IMPLICATIONS Curricula in medical school promoting empathic care may be more universally effective if students' preexisting attitudes are taken into account. Messages about the importance of physician empathy may need to be framed in ways that are consistent with the beliefs and prior world-views of medical students.

BACKGROUND AND PURPOSE: Many studies use medical record review for ascertaining outcomes. One large, longitudinal study, the Women's Health Initiative (WHI), ascertains strokes using participant self-report and subsequent physician review of medical records. This is resource-intensive. Herein, we assess whether Medicare data can reliably assess stroke events in the WHI. METHODS: Subjects were WHI participants with fee-for-service Medicare. Four stroke definitions were created for Medicare data using discharge diagnoses in hospitalization claims: definition 1, stroke codes in any position; definition 2, primary position stroke codes; and definitions 3 and 4, hemorrhagic and ischemic stroke codes, respectively. WHI data were randomly split into training (50%) and test sets. A concordance matrix was used to examine the agreement between WHI and Medicare stroke diagnosis. A WHI stroke and a Medicare stroke were considered a match if they occurred within +/-7 days of each other. Refined analyses excluded Medicare events when medical records were unavailable for comparison. RESULTS: Training data consisted of 24 428 randomly selected participants. There were 577 WHI strokes and 557 Medicare strokes using definition 1. Of these, 478 were a match. With regard to algorithm performance, specificity was 99.7%, negative predictive value was 99.7%, sensitivity was 82.8%, positive predictive value was 85.8%, and kappa=0.84. Performance was similar for test data. Whereas specificity and negative predictive value exceeded 99%, sensitivity ranged from 75% to 88% and positive predictive value ranged from 80% to 90% across stroke definitions. CONCLUSIONS: Medicare data seem useful for population-based stroke research; however, performance characteristics depend on the definition selected.