Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies LRRC4C, LHX5-AS1 and nominates ancestry-specific loci PTPRK , GRB14 , and KIAA0825 as novel risk loci for Alzheimer's disease: the Alzheimer's Disease Genetics Consortium.

Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in non-European ancestry groups in genome-wide association studies (GWAS). We constructed and analyzed a multi-ancestry GWAS dataset in the Alzheimer's Disease (AD) Genetics Consortium (ADGC) to test for novel shared and ancestry-specific AD susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6,728 African American, 8,899 Hispanic (HIS), and 3,232 East Asian individuals, performing within-ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. We identified 13 loci with cross-ancestry associations including known loci at/near CR1 , BIN1 , TREM2 , CD2AP , PTK2B , CLU , SHARPIN , MS4A6A , PICALM , ABCA7 , APOE and two novel loci not previously reported at 11p12 ( LRRC4C ) and 12q24.13 ( LHX5-AS1 ). Reflecting the power of diverse ancestry in GWAS, we observed the SHARPIN locus using 7.1% the sample size of the original discovering single-ancestry GWAS (n=788,989). We additionally identified three GWS ancestry-specific loci at/near ( PTPRK ( P =2.4×10 -8 ) and GRB14 ( P =1.7×10 -8 ) in HIS), and KIAA0825 ( P =2.9×10 -8 in NHW). Pathway analysis implicated multiple amyloid regulation pathways (strongest with P adjusted =1.6×10 -4 ) and the classical complement pathway ( P adjusted =1.3×10 -3 ). Genes at/near our novel loci have known roles in neuronal development ( LRRC4C, LHX5-AS1 , and PTPRK ) and insulin receptor activity regulation ( GRB14 ). These findings provide compelling support for using traditionally-underrepresented populations for gene discovery, even with smaller sample sizes.

Identification and early anticoagulation in patients with atrial fibrillation in the emergency department.

BACKGROUND: Emergency departments (ED) in the United States see more than half a million atrial fibrillation visits a year, however guideline recommended anticoagulation is prescribed in <55% of eligible patients. OBJECTIVE: The purpose of this study was to measure guideline recommended anticoagulation prescribing in patients with nonvalvular atrial fibrillation (NVAF) presenting to the ED, with the goal of closing any treatment gap established. METHODS: We conducted an observational, prospective cohort study in consecutive patients presenting to the ED with a diagnosis of NVAF. CHA2DS2-VASc and HAS-BLED scores were calculated and used as predefined criteria to establish guideline-based oral anticoagulation compliance in comparing routine care (baseline cohort) versus a multidisciplinary team approach. Transition of Care (TOC) services and follow-up were also provided in the multidisciplinary cohort. The primary endpoint was to compare the proportion of patients on guideline based oral anticoagulant (OAC) therapy at admission and discharge between the groups. RESULTS: In the Baseline Cohort (BC) (n = 99), 62.3% of patients with a moderate-high risk of stroke (CHA2DS2-VASc score ≥ 2) were discharged on guideline-based OAC therapy versus 87.8% in the Multidisciplinary Team Cohort (MTC) (n = 131), a 25.5% overall improvement for appropriate anticoagulation (p-value <.001, 95% CI (0.14-0.37)). CONCLUSIONS: A multidisciplinary team approach with TOC services for the identification and early intervention of NVAF patients at risk of stroke in the ED can significantly improve the percentage of moderate to high-risk patients that are discharged home with guideline based OAC.

Patients transplanted for nonalcoholic steatohepatitis are at increased risk for postoperative cardiovascular events.

UNLABELLED: Nonalcoholic steatohepatitis (NASH) is an independent predictor of coronary artery disease (CAD). Our aim was to compare the incidence of cardiovascular (CV) events between patients transplanted for NASH and alcohol (ETOH)-induced cirrhosis. This is a retrospective cohort study (August 1993 to March 2010) of 242 patients (115 NASH and 127 ETOH) with ≥12 months follow-up after liver transplantation (LT). Those with hepatocellular carcinoma or coexisting liver diseases were excluded. Kaplan-Meier's and Cox's proportional hazard analyses were conducted to compare survival. Logistic regression was used to calculate the likelihood of CV events, defined as death from any cardiac cause, myocardial infarction, acute heart failure, cardiac arrest, arrhythmia, complete heart block, and/or stroke requiring hospitalization <1 year after LT. Patients in the NASH group were older (58.4 versus 53.3 years) and were more likely to be female (45% versus 18%; P < 0.001). They were more likely to be morbidly obese (32% versus 9%), have dyslipidemia (25% versus 6%), or have hypertension (53% versus 38%; P < 0.01). On multivariate analysis, NASH patients were more likely to have a CV event <1 year after LT, compared to ETOH patients, even after controlling for recipient age, sex, smoking status, pretransplant diabetes, CV disease, and the presence of metabolic syndrome (26% versus 8%; odds ratio = 4.12; 95% confidence interval = 1.91-8.90). The majority (70%) of events occurred in the perioperative period, and the occurrence of a CV event was associated with a 50% overall mortality. However, there were no differences in patient, graft, or CV mortality between groups. CONCLUSIONS: CV complications are common after LT, and NASH patients are at increased risk independent of traditional cardiac risk factors, though this did not affect overall mortality.

Obesity classification in military personnel: a comparison of body fat, waist circumference, and body mass index measurements.

OBJECTIVE: The purpose of this study was to evaluate obesity classifications from body fat percentage (BF%), body mass index (BMI), and waist circumference (WC). METHODS: A total of 451 overweight/obese active duty military personnel completed all three assessments. RESULTS: Most were obese (men, 81%; women, 98%) using National Institutes of Health (NIH) BF% standards (men, >25%; women, >30%). Using the higher World Health Organization (WHO) BF >35% standard, 86% of women were obese. BMI (55.5% and 51.4%) and WC (21.4% and 31.9%) obesity rates were substantially lower for men and women, respectively (p < 0.05). BMI/WC were accurate discriminators for BF% obesity (theta for all comparisons >0.75, p < 0.001). Optimal cutoff points were lower than NIH/WHO standards; WC = 100 cm and BMI = 29 maximized sensitivity and specificity for men, and WC = 79 cm and BMI = 25.5 (NIH) or WC = 83 cm and BMI = 26 (WHO) maximized sensitivity and specificity for women. CONCLUSIONS: Both WC and BMI measures had high rates of false negatives compared to BF%. However, at a population level, WC/BMI are useful obesity measures, demonstrating fair-to-high discriminatory power.

Weight management using the internet a randomized controlled trial.

BACKGROUND: Most weight-loss research targets obese individuals who desire large weight reductions. However, evaluation of weight-gain prevention in overweight individuals is also critical as most Americans become obese as a result of a gradual gain of 1-2 pounds per year over many years. METHOD: This study evaluated the efficacy of an Internet-based program for weight-loss and weight-gain prevention with a two-group, prospective, randomized controlled trial. A military medical research center with a population of 17,000 active-duty military personnel supplied 446 overweight individuals (222 men; 224 women) with a mean age of 34 years and a mean BMI of 29. Recruitment and study participation occurred 2003-2005 and data were analyzed in 2006. Participants were randomly assigned to receive the 6-month behavioral Internet treatment (BIT, n=227) or usual care (n=224). Change in body weight, BMI, percent body fat, and waist circumference; presented as group by time interactions, were measured. RESULTS: After 6 months, completers who received BIT lost 1.3 kg while those assigned to usual care gained 0.6 kg (F((df=366))=24.17; I<0.001). Results were similar for the intention-to-treat model. BIT participants also had significant changes in BMI (-0.5 vs +0.2 kg/m(2); F((df=366))=24.58); percent body fat (-0.4 vs +0.6%; F((df=366))=10.45); and waist circumference (-2.1 vs -0.4 cm; F((df=366))=17.09); p<0.001 for all. CONCLUSIONS: Internet-based weight-management interventions result in small amounts of weight loss, prevent weight gain, and have potential for widespread dissemination as a population health approach. TRIAL REGISTRATION: NCT00417599.