Key PointsQuestionWhat is the effect of convalescent plasma therapy added to standard treatment, compared with standard treatment alone, on clinical outcomes in patients with severe or life-threatening coronavirus disease 2019 (COVID-19)?FindingIn this randomized clinical trial that included 103 patients and was terminated early, the hazard ratio for time to clinical improvement within 28 days in the convalescent plasma group vs the standard treatment group was 1.40 and was not statistically significant.MeaningAmong patients with severe or life-threatening COVID-19, convalescent plasma therapy added to standard treatment did not significantly improve the time to clinical improvement within 28 days, although the trial was terminated early and may have been underpowered to detect a clinically important difference.

For catheter ablation of persistent AF, the '2C3L' strategy is a fixed approach associated with clinical efficacy similar to that of the 'stepwise' approach but with less RF delivery, fewer X-ray exposure, and shorter procedural time.

Understanding the factors that shape the evolution of gene expression is a central goal in biology, but the molecular mechanisms behind this remain controversial. A related major goal is ascertaining how such factors may affect the adaptive potential of a species or population. Here we demonstrate that temperature-driven gene expression changes in fish adapted to differing thermal environments are constrained by the level of gene pleiotropy estimated by either the number of protein interactions or gene biological processes. Genes with low pleiotropy levels were the main drivers of both plastic and evolutionary global expression profile changes, while highly pleiotropic genes had limited expression response to temperature treatment. Our study provides critical insights into the molecular mechanisms by which natural populations can adapt to changing environments. In addition to having important implications for climate change adaptation, these results suggest that gene pleiotropy should be considered more carefully when interpreting expression profiling data.

Five new compounds (1-5), including two secolignans, two tetrahydrofuran lignans, and one highly methoxylated dihydronaphthalenone, were isolated from the whole plant of Peperomia pellucida. These compounds were accompanied by the known peperomins A, B, C, and E, 7,8-trans-8,8'-trans-7',8'-cis-7,7'-bis(5-methoxy-3,4-methylenedioxyphenyl)-8-acetoxymethyl-8'-hydroxymethyltetrahydrofuran, 7,8-trans-8,8'-trans-7',8'-cis-7-(5-methoxy-3,4-methylenedioxyphenyl)-7'-(4-hydroxy-3,5-dimethoxyphenyl)-8,8'-diacetoxymethyltetrahydrofuran, sesamin, and isoswertisin. New structures were elucidated mainly by NMR and MS techniques, and anticancer activities evaluated in HL-60, MCF-7, and HeLa cell lines. Compound 1 and peperomin E show growth inhibitory effects on the three cancer cell lines with IC(50) values ranging between 1.4 and 9.1 and between 1.8 and 11.1 microM, respectively. Compound 2 has a weak suppressive activity on HL-60 cells (IC(50) = 10.8 microM), while 7,8-trans-8,8'-trans-7',8'-cis-7,7'-bis(5-methoxy-3,4-methylenedioxyphenyl)-8-acetoxymethyl-8'-hydroxymethyltetrahydrofuran exhibits estrogen-like properties (EC(50) = 3.1 microM) in CV-1 cells transfected with human estrogen receptor (ERalpha).

Aims/hypothesis Two recent genome-wide association studies have identified several novel type 2 diabetes susceptibility variants in intron 15 of the KCNQ1 gene. We aimed to evaluate the effects of the variants in KCNQ1 on type 2 diabetes and metabolic traits in the population of mainland China. Methods Three candidate single nucleotide polymorphisms were genotyped in 1,912 individuals with type 2 diabetes and 2,041 normal controls using the ligase detection reaction method.Results We confirmed the association of KCNQ1 with type 2 diabetes in the population of mainland China. Allele frequency ORs of the three single nucleotide polymorphisms (SNPs) were: rs2237892 (OR 1.19, 95% CI 1.08-1.31, p = 3.0 × 10 −4 ); rs2237895 (OR 1.20, 95% CI 1.09-1.32, p=1.9×10 −4 ); and rs2237897 (OR 1.24, 95% CI 1.13-1.36, p= 3.9×10 −5 ). We also found a significant difference in the distribution of the global haplotypes between the type 2 diabetes group and the normal control group (p= 2.6×10 −5 ). In addition, in the control group SNP rs2237892 was marginally associated with increasing fasting plasma glucose and SNPs rs2237892 and rs2237897 were associated with HbA 1c . Furthermore, for all three variants, homozygous carriers of the diabetes-associated allele had significantly decreased BMI and waist circumferences. Conclusions/interpretation Our investigation confirmed the effects of KCNQ1 variants on type 2 diabetes risk in the Chinese population.

4-Phenoxynicotinamide and 4-phenoxypyrimidine-5-carboxamide derivatives as potent and orally efficacious TGR5 agonists are reported. Several 4-phenoxynicotinamide derivatives were found to activate human and mouse TGR5 (hTGR5 and mTGR5) with EC50 values in the low nanomolar range. Compound 23g, with an EC50 value of 0.72 nM on hTGR5 and an EC50 value of 6.2 nM on mTGR5, was selected for further in vivo efficacy studies. This compound exhibited a significant dose-dependent glucagon-like peptide-1 (GLP-1) secretion effect. A single oral dose of 23g (50 mg/kg) significantly reduced blood glucose levels in db/db mice and caused a 49% reduction in the area under the blood glucose curve (AUC)0-120 min following an oral glucose tolerance test (OGTT) in imprinting control region (ICR) mice. However, 23g stimulated gallbladder filling, which might result in side effects to the gallbladder.

Activation of TGR5 stimulates intestinal glucagon-like peptide-1 (GLP-1) release, but activation of the receptors in gallbladder and heart has been shown to cause severe on-target side effects. A series of low-absorbed TGR5 agonists was prepared by modifying compound 2 with polar functional groups to limit systemic exposure and specifically activate TGR5 in the intestine. Compound 15c, with a molecular weight of 1401, a PSA value of 223 Å(2), and low permeability on Caco-2 cells, exhibited satisfactory potency both in vitro and in vivo. Low levels of 15c were detected in blood, bile, and gallbladder tissue, and gallbladder-related side effects were substantially decreased compared to the absorbed small-molecule TGR5 agonist 2.

BackgroundRobust data on the contemporary management of atrial fibrillation (AF) patients in China are limited. Importantly current practice in AF management has changing dramatically in recent years. Data from a large registry study will enable us to evaluate the uptake and outcomes with different therapies in a large Chinese AF population.Methods/DesignThe Chinese Atrial Fibrillation Registry study (CAFR) aims to enroll 20,000 consecutive atrial fibrillation (AF) patients from 32 tertiary and non-tertiary hospitals in Beijing, China, and follow up these patients every 6 months until 2020. Key data collected includes basic sociodemographic information, symptoms and signs, medical history, results of physical examination and laboratory test, details of treatments and personal insurance status. For patients who consent, 5 ml of blood sample will be stored at −80 °C for future analyses of biomarkers. At each 6 month follow up visit, data relating to clinical outcomes will be collected. Data from a randomly selected 10 % of patients will be internally validated with their raw source data. Ischemic stroke events will be adjudicated by an independent endpoint committee.DiscussionCAFR will be one of the largest registries of Asian AF patients (and the largest in Chinese AF patients), as well as providing the longest follow up. This study would provide a valuable opportunity for ‘real world’ clinical epidemiology with insights into the uptake (and outcomes) of contemporary AF management.Trial registrationChinese Clinical Trial Registry ChiCTR-OCH-13003729. Registered 22 October 2013.Electronic supplementary materialThe online version of this article (doi:10.1186/s12872-016-0308-1) contains supplementary material, which is available to authorized users.