Statistical aspects of the TNK-S2B trial of tenecteplase versus alteplase in acute ischemic stroke: an efficient, dose-adaptive, seamless phase II/III design

Background TNK-S2B, an innovative, randomized, seamless phase II/III trial of tenecteplase versus rt-PA for acute ischemic stroke, terminated for slow enrollment before regulatory approval of use of phase II patients in phase III

Increased consumption of fruit and vegetables for the primary prevention of cardiovascular diseases

There is increasing evidence that high consumption of fruit and vegetables is beneficial for cardiovascular disease (CVD) prevention

Diabetes mellitus in patients with heart failure and reduced ejection fraction: a post hoc analysis from the WARCEF trial.

Patients with heart failure with reduced ejection fraction (HFrEF) and diabetes mellitus (DM) have an increased risk of adverse events, including thromboembolism. In this analysis, we aimed to explore the association between DM and HFrEF using data from the "Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction" (WARCEF) trial. We analyzed factors associated with DM using multiple logistic regression models and evaluated the effect of DM on long-term prognosis, through adjusted Cox regressions. The primary outcome was the composite of all-cause death, ischemic stroke, or intracerebral hemorrhage; we explored individual components as the secondary outcomes and the interaction between treatment (warfarin or aspirin) and DM on the risk of the primary outcome, stratified by relevant characteristics. Of 2294 patients (mean age 60.8 (SD 11.3) years, 19.9% females) included in this analysis, 722 (31.5%) had DM. On logistic regression, cardiovascular comorbidities, symptoms and ethnicity were associated with DM at baseline, while age and body mass index showed a nonlinear association. Patients with DM had a higher risk of the primary composite outcome (Hazard Ratio [HR] and 95% Confidence Intervals [CI]: 1.48 [1.24-1.77]), as well as all-cause death (HR [95%CI]: 1.52 [1.25-1.84]). As in prior analyses, no statistically significant interaction was observed between DM and effect of Warfarin on the risk of the primary outcome, in any of the subgroups explored. In conclusion, we found that DM is common in HFrEF patients, and is associated with other cardiovascular comorbidities and risk factors, and with a worse prognosis

Educational status affects prognosis of patients with heart failure with reduced ejection fraction: A post-hoc analysis from the WARCEF trial.

AimsThe influence of social determinants of health (SDOH) on the prognosis of Heart Failure and reduced Ejection Fraction (HFrEF) is increasingly reported. We aim to evaluate the contribution of educational status on outcomes in patients with HFrEF.MethodsWe used data from the WARCEF trial, which randomized HFrEF patients with sinus rhythm to receive Warfarin or Aspirin; educational status of patients enrolled was collected at baseline. We defined three levels of education: low, medium and high level, according to the highest qualification achieved or highest school grade attended. We analysed the impact of the educational status on the risk of the primary composite outcome of all-cause death, ischemic stroke (IS) and intracerebral haemorrhage (ICH); components of the primary outcome were also analysed as secondary outcomes.Results2295 patients were included in this analysis; of these, 992 (43.2%) had a low educational level, 947 (41.3%) had a medium education level and the remaining 356 (15.5%) showed a high educational level. Compared to patients with high educational level, those with low educational status showed a high risk of the primary composite outcome (adjusted hazard ratio [aHR]: 1.31, 95% confidence intervals [CI] 1.02-1.69); a non-statistically significant association was observed in those with medium educational level (aHR: 1.20, 95%CI: .93-1.55). Similar results were observed for all-cause death, while no statistically significant differences were observed for IS or ICH.ConclusionCompared to patients with high educational levels, those with low educational status had worse prognosis. SDOH should be considered in patients with HFrEF.Clinical trial registrationNCT00041938

Routine Antenatal Anti-D Prophylaxis in Women Who Are Rh(D) Negative: Meta-Analyses Adjusted for Differences in Study Design and Quality

Background: To estimate the effectiveness of routine antenatal anti-D prophylaxis for preventing sensitisation in pregnant Rhesus negative women, and to explore whether this depends on the treatment regimen adopted. Methods: Ten studies identified in a previous systematic literature search were included. Potential sources of bias were systematically identified using bias checklists, and their impact and uncertainty were quantified using expert opinion. Study results were adjusted for biases and combined, first in a random-effects meta-analysis and then in a random-effects metaregression analysis. Results: In a conventional meta-analysis, the pooled odds ratio for sensitisation was estimated as 0.25 (95 % CI 0.18, 0.36), comparing routine antenatal anti-D prophylaxis to control, with some heterogeneity (I 2 = 19%). However, this naïve analysis ignores substantial differences in study quality and design. After adjusting for these, the pooled odds ratio for sensitisation was estimated as 0.31 (95 % CI 0.17, 0.56), with no evidence of heterogeneity (I 2 = 0%). A meta-regression analysis wa

hnRNP A1 and hnRNP F Modulate the Alternative Splicing of Exon 11 of the Insulin Receptor Gene

Exon 11 of the insulin receptor gene (INSR) is alternatively spliced in a developmentally and tissue-specific manner. Linker scanning mutations in a 5′ GA-rich enhancer in intron 10 identified AGGGA sequences that are important for enhancer function. Using RNA-affinity purification and mass spectrometry, we identified hnRNP F and hnRNP A1 binding to these AGGGA sites and also to similar motifs at the 3′ end of the intron. The hnRNPs have opposite functional effects with hnRNP F promoting and hnRNP A1 inhibiting exon 11 inclusion, and deletion of the GA-rich elements eliminates both effects. We also observed specific binding of hnRNP A1 to the 5′ splice site of intron 11. The SR protein SRSF1 (SF2/ASF) co-purified on the GA-rich enhancer and, interestingly, also competes with hnRNP A1 for binding to the splice site. A point mutation -3U→C decreases hnRNP A1 binding, increases SRSF1 binding and renders the exon constitutive. Lastly, our data point to a functional interaction between hnRNP F and SRSF1 as a mutant that eliminates SRSF1 binding to exon 11, or a SRSF1 knockdown, which prevents the stimulatory effect of hnRNP F over expression

The genomes of two key bumblebee species with primitive eusocial organization

Background: The shift from solitary to social behavior is one of the major evolutionary transitions. Primitively eusocial bumblebees are uniquely placed to illuminate the evolution of highly eusocial insect societies. Bumblebees are also invaluable natural and agricultural pollinators, and there is widespread concern over recent population declines in some species. High-quality genomic data will inform key aspects of bumblebee biology, including susceptibility to implicated population viability threats. Results: We report the high quality draft genome sequences of Bombus terrestris and Bombus impatiens, two ecologically dominant bumblebees and widely utilized study species. Comparing these new genomes to those of the highly eusocial honeybee Apis mellifera and other Hymenoptera, we identify deeply conserved similarities, as well as novelties key to the biology of these organisms. Some honeybee genome features thought to underpin advanced eusociality are also present in bumblebees, indicating an earlier evolution in the bee lineage. Xenobiotic detoxification and immune genes are similarly depauperate in bumblebees and honeybees, and multiple categories of genes linked to social organization, including development and behavior, show high conservation. Key differences identified include a bias in bumblebee chemoreception towards gustation from olfaction, and striking differences in microRNAs, potentially responsible for gene regulation underlying social and other traits. Conclusions: These two bumblebee genomes provide a foundation for post-genomic research on these key pollinators and insect societies. Overall, gene repertoires suggest that the route to advanced eusociality in bees was mediated by many small changes in many genes and processes, and not by notable expansion or depauperation

Left atrial volume and cardiovascular outcomes in systolic heart failure: effect of antithrombotic treatment

AimsLeft atrium (LA) dilation is associated with adverse cardiovascular (CV) outcomes. Blood stasis, thrombus formation and atrial fibrillation may occur, especially in heart failure (HF) patients. It is not known whether preventive antithrombotic treatment may decrease the incidence of CV events in HF patients with LA enlargement. We investigated the relationship between LA enlargement and CV outcomes in HF patients and the effect of different antithrombotic treatments.Methods and resultsTwo-dimensional echocardiography with LA volume index (LAVi) measurement was performed in 1148 patients with systolic HF from the Warfarin versus Aspirin in Reduced Ejection Fraction (WARCEF) trial. Patients were randomized to warfarin or aspirin and followed for 3.4 ± 1.7 years. While the primary aim of the trial was a composite of ischaemic stroke, death, and intracerebral haemorrhage, the present report focuses on the individual CV events, whose incidence was compared across different LAVi and treatment subgroups. After adjustment for demographics and clinical covariates, moderate or severe LA enlargement was significantly associated with total death (hazard ratio 1.6 and 2.7, respectively), CV death (HR 1.7 and 3.3), and HF hospitalization (HR 2.3 and 2.6) but not myocardial infarction (HR 1.0 and 1.4) or ischaemic stroke (1.1 and 1.5). The increased risk was observed in both patients treated with warfarin or aspirin. In warfarin-treated patients, a time in therapeutic range >60% was associated with lower event rates, and an interaction between LAVi and time in therapeutic range was observed for death (P = 0.034).ConclusionsIn patients with systolic HF, moderate or severe LA enlargement is associated with death and HF hospitalization despite treatment with antithrombotic medications. The possibility that achieving a more consistent therapeutic level of anticoagulation may decrease the risk of death requires further investigation

Sequence Relationships among C. elegans, D. melanogaster and Human microRNAs Highlight the Extensive Conservation of microRNAs in Biology

microRNAs act in a prevalent and conserved post-transcriptional gene regulatory mechanism that impacts development, homeostasis and disease, yet biological functions for the vast majority of miRNAs remain unknown. Given the power of invertebrate genetics to promote rapid evaluation of miRNA function, recently expanded miRNA identifications (miRBase 10.1), and the importance of assessing potential functional redundancies within and between species, we evaluated miRNA sequence relationships by 5′ end match and overall homology criteria to compile a snapshot overview of miRNA families within the C. elegans and D. melanogaster genomes that includes their identified human counterparts. This compilation expands literature documentation of both the number of families and the number of family members, within and between nematode and fly models, and highlights sequences conserved between species pairs or among nematodes, flies and humans. Themes that emerge include the substantial potential for functional redundancy of miRNA sequences within species (84/139 C. elegans miRNAs and 70/152 D. melanogaster miRNAs share significant homology with other miRNAs encoded by their respective genomes), and the striking extent to which miRNAs are conserved across species—over half (73/139) C. elegans miRNAs share sequence homology with miRNAs encoded also in both fly and human genomes. This summary analysis of mature miRNA sequence relationships provides a quickly accessible resource that should facilitate functional and evolutionary analyses of miRNAs and miRNA families