Association analyses of East Asian individuals and trans-ancestry analyses with European individuals reveal new loci associated with cholesterol and triglyceride levels

Large-scale meta-analyses of genome-wide association studies (GWAS) have identified >175 loci associated with fasting cholesterol levels, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). With differences in linkage disequilibrium (LD) structure and allele frequencies between ancestry groups, studies in additional large samples may detect new associations. We conducted staged GWAS meta-analyses in up to 69,414 East Asian individuals from 24 studies with participants from Japan, the Philippines, Korea, China, Singapore, and Taiwan. These meta-analyses identified (P < 5 × 10-8) three novel loci associated with HDL-C near CD163-APOBEC1 (P = 7.4 × 10-9), NCOA2 (P = 1.6 × 10-8), and NID2-PTGDR (P = 4.2 × 10-8), and one novel locus associated with TG near WDR11-FGFR2 (P = 2.7 × 10-10). Conditional analyses identified a second signal near CD163-APOBEC1. We then combined results from the East Asian meta-analysis with association results from up to 187,365 European individuals from the Global Lipids Genetics Consortium in a trans-ancestry meta-analysis. This analysis identified (log10Bayes Factor ≥6.1) eight additional novel lipid loci. Among the twelve total loci identified, the index variants at eight loci have demonstrated at least nominal significance with other metabolic traits in prior studies, and two loci exhibited coincident eQTLs (P < 1 × 10-5) in subcutaneous adipose tissue for BPTF and PDGFC. Taken together, these analyses identified multiple novel lipid loci, providing new potential therapeutic targets

25th annual computational neuroscience meeting: CNS-2016

The same neuron may play different functional roles in the neural circuits to which it belongs. For example, neurons in the Tritonia pedal ganglia may participate in variable phases of the swim motor rhythms [1]. While such neuronal functional variability is likely to play a major role the delivery of the functionality of neural systems, it is difficult to study it in most nervous systems. We work on the pyloric rhythm network of the crustacean stomatogastric ganglion (STG) [2]. Typically network models of the STG treat neurons of the same functional type as a single model neuron (e.g. PD neurons), assuming the same conductance parameters for these neurons and implying their synchronous firing [3, 4]. However, simultaneous recording of PD neurons shows differences between the timings of spikes of these neurons. This may indicate functional variability of these neurons. Here we modelled separately the two PD neurons of the STG in a multi-neuron model of the pyloric network. Our neuron models comply with known correlations between conductance parameters of ionic currents. Our results reproduce the experimental finding of increasing spike time distance between spikes originating from the two model PD neurons during their synchronised burst phase. The PD neuron with the larger calcium conductance generates its spikes before the other PD neuron. Larger potassium conductance values in the follower neuron imply longer delays between spikes, see Fig. 17.Neuromodulators change the conductance parameters of neurons and maintain the ratios of these parameters [5]. Our results show that such changes may shift the individual contribution of two PD neurons to the PD-phase of the pyloric rhythm altering their functionality within this rhythm. Our work paves the way towards an accessible experimental and computational framework for the analysis of the mechanisms and impact of functional variability of neurons within the neural circuits to which they belong

Challenges and opportunities in setting up a phase III vaccine clinical trial in resource limited settings: Experience from Nepal

Clinical trials are complicated, time-consuming and costly. From the initial screening, informed consent and recruitment of the participants’ to study completion, the sponsor must undertake a wide array of complex and closely monitored operations, complying with international standards for human subject research and local requirements. Conducting these studies in an underdeveloped country, with limited resources, infrastructure, and experience with regulated clinical trials adds to this complexity. The initial site selection, set up and preparatory activities for the clinical trial are crucial to minimizing the risks to both participants and to successful completion during the subsequent study execution. In this paper, we describe the experience and lessons learned of building clinical trial site capacity in terms of infrastructure and human resource development for a Phase III vaccine clinical trial. We believe that sharing the experience of setting up a clinical trial in a resource-limited country will enable other entities contemplating clinical research in these countries, to prepare and plan ahead, to minimize the impact of barriers, and to contribute to bringing more studies to the countries where people live with the burden of vaccine-preventable, poverty-associated diseases

Paclitaxel- Versus Sirolimus-Eluting Stents for Treatment of ST-Segment Elevation Myocardial Infarction With Analyses for Diabetic and Nondiabetic Subpopulation

Objectives The aim of this study was to determine which drug-eluting stent (DES) is preferable for the treatment of ST-segment elevation myocardial infarction (STEMI) and to elucidate the impact of diabetes mellitus on the outcome of each DES. Background Recent studies have shown the benefit of DES in patients with STEMI. Diabetes mellitus might differentially affect outcomes of each DES. Methods We analyzed the large-scale, prospective, observational KAMIR (Korea Acute Myocardial Infarction Registry) study, which enrolled 4,416 STEMI patients (26% with diabetes) treated with paclitaxel-eluting stent (PES) or sirolimus-eluting stent (SES). Primary outcome was major adverse cardiac event (MACE), defined as a composite of mortality, nonfatal myocardial infarction, and target lesion revascularization (TLR). Results In the overall population, the MACE rate at 1 year was significantly higher in the PES than the SES group (11.6% vs. 8.6%, p = 0.014), which was mainly due to increased TLR (3.7% vs. 1.8%, p < 0.001). In the diabetic subgroup, however, the MACE rate was not significantly different between PES and SES (14.5% vs. 12.3%, p = 0.217), in contrast to the nondiabetic subgroup, where PES was inferior to SES as in the overall population. Matching by propensity-score did not significantly alter these results. For TLR, there was interaction between the type of stents and diabetes mellitus (unadjusted: p = 0.052; after propensity-score matching: p = 0.035). Conclusions The PES was inferior to the SES in the overall population, with regard to the occurrence of MACE and TLR. However, subgroup analysis for diabetic subjects showed no differences in clinical outcomes between PES and SES. These results suggest that diabetes differentially affects the outcome of first-generation DES. (J Am Coll Cardiol Intv 2010;3:498-506) (C) 2010 by the American College of Cardiology FoundationPark KW, 2010, AM HEART J, V159, P446, DOI 10.1016/j.ahj.2010.01.001RABER L, 2009, TRANSC CARD THER M SLee KH, 2008, INT J CARDIOL, V130, P227, DOI 10.1016/j.ijcard.2007.08.044Mauri L, 2008, NEW ENGL J MED, V359, P1330Mahmud E, 2008, J AM COLL CARDIOL, V51, P2385, DOI 10.1016/j.jacc.2008.03.028Buch AN, 2008, AM J CARDIOL, V101, P1253, DOI 10.1016/j.amjcard.2007.12.021Stone GW, 2008, JAMA-J AM MED ASSOC, V299, P1903Simonton CA, 2007, J AM COLL CARDIOL, V50, P1214, DOI 10.1016/j.jacc.2007.06.019Stettler C, 2007, LANCET, V370, P937Menichelli M, 2007, J AM COLL CARDIOL, V49, P1924, DOI 10.1016/j.jacc.2007.01.081Daemen J, 2007, AM J CARDIOL, V99, P1027, DOI 10.1016/j.amjcard.2006.11.070Suh JW, 2007, INT J CARDIOL, V117, P31, DOI 10.1016/j.ijcard.2006.03.009Daemen J, 2007, EUR HEART J, V28, P26, DOI 10.1093/eurheartj/ehl412Pfisterer M, 2006, J AM COLL CARDIOL, V48, P2584, DOI 10.1016/j.jacc.2006.10.026Kim YH, 2006, CIRCULATION, V114, P2148, DOI 10.1161/CIRCULATIONAHA.106.666396Spaulding C, 2006, NEW ENGL J MED, V355, P1093Laarman GJ, 2006, NEW ENGL J MED, V355, P1105Patterson C, 2006, ARTERIOSCL THROM VAS, V26, P1473, DOI 10.1161/01.ATV.0000223866.42883.3bKastrati A, 2006, CIRCULATION, V113, P2293, DOI 10.1161/CIRCULATIONAHA.105.601823Sabate M, 2005, CIRCULATION, V112, P2175, DOI 10.1061/CIRCULATIONHA.105.562421Windecker S, 2005, NEW ENGL J MED, V353, P653Dibra A, 2005, NEW ENGL J MED, V353, P663Hermiller JB, 2005, J AM COLL CARDIOL, V45, P1172, DOI 10.1016/j.jacc.2004.10.075Virmani R, 2004, CIRCULATION, V109, P701, DOI 10.1161/01.CIR.0000116202.41966.D4D`Agostino RB, 1998, STAT MED, V17, P2265Krook A, 1997, DIABETES, V46, P2110Axel DI, 1997, CIRCULATION, V96, P636MARX SO, 1995, CIRC RES, V76, P412ROSENBAUM PR, 1985, AM STAT, V39, P33

Analysis of Outcomes in Ischemic vs Nonischemic Cardiomyopathy in Patients With Atrial Fibrillation A Report From the GARFIELD-AF Registry

IMPORTANCE Congestive heart failure (CHF) is commonly associated with nonvalvular atrial fibrillation (AF), and their combination may affect treatment strategies and outcomes

Erratum to: Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) (Autophagy, 12, 1, 1-222, 10.1080/15548627.2015.1100356

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