Influence of Bulk Microphysics Schemes upon Weather Research and Forecasting (WRF) Version 3.6.1 Nor'easter Simulations

This study evaluated the impact of five single- or double-moment bulk microphysics schemes (BMPSs) on Weather Research and Forecasting model (WRF) simulations of seven intense wintertime cyclones impacting the mid-Atlantic United States; 5-day long WRF simulations were initialized roughly 24 hours prior to the onset of coastal cyclogenesis off the North Carolina coastline. In all, 35 model simulations (five BMPSs and seven cases) were run and their associated microphysics-related storm properties (hydrometer mixing ratios, precipitation, and radar reflectivity) were evaluated against model analysis and available gridded radar and ground-based precipitation products. Inter-BMPS comparisons of column-integrated mixing ratios and mixing ratio profiles reveal little variability in non-frozen hydrometeor species due to their shared programming heritage, yet their assumptions concerning snow and graupel intercepts, ice supersaturation, snow and graupel density maps, and terminal velocities led to considerable variability in both simulated frozen hydrometeor species and radar reflectivity. WRF-simulated precipitation fields exhibit minor spatiotemporal variability amongst BMPSs, yet their spatial extent is largely conserved. Compared to ground-based precipitation data, WRF simulations demonstrate low-to-moderate (0.217 to 0.414) threat scores and a rainfall distribution shifted toward higher values. Finally, an analysis of WRF and gridded radar reflectivity data via contoured frequency with altitude (CFAD) diagrams reveals notable variability amongst BMPSs, where better performing schemes favored lower graupel mixing ratios and better underlying aggregation assumptions

Effects of dalcetrapib in patients with a recent acute coronary syndrome

In observational analyses, higher levels of high-density lipoprotein (HDL) cholesterol have been associated with a lower risk of coronary heart disease events. However, whether raising HDL cholesterol levels therapeutically reduces cardiovascular risk remains uncertain. Inhibition of cholesteryl ester transfer protein (CETP) raises HDL cholesterol levels and might therefore improve cardiovascular outcomes

Evolving targets for lipid-modifying therapy

Published online: August 29, 2014The pathogenesis and progression of atherosclerosis are integrally connected to the concentration and function of lipoproteins in various classes. This review examines existing and emerging approaches to modify low-density lipoprotein and lipoprotein (a), triglyceride-rich lipoproteins, and high-density lipoproteins, emphasizing approaches that have progressed to clinical evaluation. Targeting of nuclear receptors and phospholipases is also discussed.Rose Q Do, Stephen J Nicholls and Gregory G Schwart

Constraints on the Progenitor of SN 2016gkg From Its Shock-Cooling Light Curve

SN 2016gkg is a nearby Type IIb supernova discovered shortly after explosion. Like several other Type IIb events with early-time data, SN 2016gkg displays a double-peaked light curve, with the first peak associated with the cooling of a low-mass extended progenitor envelope. We present unprecedented intranight-cadence multi-band photometric coverage of the first light-curve peak of SN 2016gkg obtained from the Las Cumbres Observatory Global Telescope network, the Asteroid Terrestrial-impact Last Alert System, the Swift satellite and various amateur-operated telescopes. Fitting these data to analytical shock-cooling models gives a progenitor radius of ~25-140 solar radii with ~2-30 x 10^-2 solar masses of material in the extended envelope (depending on the model and the assumed host-galaxy extinction). Our radius estimates are broadly consistent with values derived independently (in other works) from HST imaging of the progenitor star. However, the shock-cooling model radii are on the lower end of the values indicated by pre-explosion imaging. Hydrodynamical simulations could refine the progenitor parameters deduced from the shock-cooling emission and test the analytical models.Comment: Accepted by ApJ

Exposure and response analysis of aleglitazar on cardiovascular risk markers and safety outcomes:An analysis of the AleCardio trial

Aims The AleCardio trial aimed to characterize the efficacy and safety of peroxisome proliferator-activated receptor-alpha gamma agonist aleglitazar in patients with type 2 diabetes mellitus and acute coronary syndrome. The trial terminated early because of futility and safety signals. We evaluated whether the safety signals could be attributed to increased exposure to aleglitazar. Materials and Methods The AleCardio trial enrolled 7226 patients to receive aleglitazar 150 mu g or matching placebo on top of standard care. A population pharmacokinetic analysis was conducted in a pharmacokinetic substudy to identify covariates that explained interindividual variability in exposure. Subsequently, the effect of these covariates on surrogate and clinical outcomes was assessed in the full patient population. Results Concomitant administration of clopidogrel was identified as a covariate that influenced the apparent clearance of aleglitazar. Patients using clopidogrel had a mean predicted area under the plasma-concentration-time curve (AUC(0-24)) of 174.7 ng h/mL (SD: +/- 112.9 ng h/mL) versus 142.2 ng h/mL (SD: +/- 92.6 ng h/mL) in patients without clopidogrel. The effect of aleglitazar compared with placebo on HbA1c, haemoglobin, serum creatinine and adiponectin was modified by concomitant clopidogrel use (P for interaction 0.007, 0.002

Randomised nano-/micro- impact testing – A novel experimental test method to simulate erosive damage caused by solid particle impacts

A novel randomised nano-/micro-scale impact test method has been developed to experimentally simulate particulate erosion where statistically distributed impacts with defined energy occur sequentially within the test area. Tests have been performed on two brittle glasses (fused silica and BK7) to easily highlight the interaction between impacts, as well as on two ceramic thermal barrier coating systems (TBCs, yttria stabilised zirconia, 7YSZ, and gadolinium zirconate, GZO) that experience erosion in service. Differences in erosion resistance were reproduced in the randomised impact tests, with GZO less impact resistant than 7YSZ, and BK7 significantly worse than fused silica. The impact data show that erosion resistance is influenced by different factors for the glasses (crack morphology, longer-length interaction of radial-lateral cracks in BK7 vs cone-cracking in fused silica) and TBCs (fracture toughness).Support from Innovate UK under Smart Award project #10020751, High temperature tools for designing sustainable erosion resistant coatings, is gratefully acknowledged

PubChem3D: Diversity of shape

<p>Abstract</p> <p>Background</p> <p>The shape diversity of 16.4 million biologically relevant molecules from the PubChem Compound database and their 1.46 billion diverse conformers was explored as a function of molecular volume.</p> <p>Results</p> <p>The diversity of shape space was investigated by determining the shape similarity threshold to achieve a maximum on the count of reference shapes per unit of conformer volume. The rate of growth in shape space, as represented by a decreasing shape similarity threshold, was found to be remarkably smooth as a function of volume. There was no apparent correlation between the count of conformers per unit volume and their diversity, meaning that a single reference shape can describe the shape space of many chemical structures. The ability of a volume to describe the shape space of lesser volumes was also examined. It was shown that a given volume was able to describe 40-70% of the shape diversity of lesser volumes, for the majority of the volume range considered in this study.</p> <p>Conclusion</p> <p>The relative growth of shape diversity as a function of volume and shape similarity is surprisingly uniform. Given the distribution of chemicals in PubChem versus what is theoretically synthetically possible, the results from this analysis should be considered a conservative estimate to the true diversity of shape space.</p

Effect of Apabetalone on Cardiovascular Events in Diabetes, CKD, and Recent Acute Coronary Syndrome: Results from the BETonMACE Randomized Controlled Trial

CKD and type 2 diabetes mellitus interact to increase the risk of major adverse cardiovascular events (i.e., cardiovascular death, nonfatal myocardial infarction, or stroke) and congestive heart failure. A maladaptive epigenetic response may be a cardiovascular risk driver and amenable to modification with apabetalone, a selective modulator of the bromodomain and extraterminal domain transcription system. We examined this question in a prespecified analysis of BETonMACE, a phase 3 trial.BETonMACE was an event-driven, randomized, double-blind, placebo-controlled trial comparing effects of apabetalone versus placebo on major adverse cardiovascular events and heart failure hospitalizations in 2425 participants with type 2 diabetes and a recent acute coronary syndrome, including 288 participants with CKD with eGFR <60 ml/min per 1.73 m2 at baseline. The primary end point in BETonMACE was the time to the first major adverse cardiovascular event, with a secondary end point of time to hospitalization for heart failure.Median follow-up was 27 months (interquartile range, 20-32 months). In participants with CKD, apabetalone compared with placebo was associated with fewer major adverse cardiovascular events (13 events in 124 patients [11%] versus 35 events in 164 patients [21%]; hazard ratio, 0.50; 95% confidence interval, 0.26 to 0.96) and fewer heart failure-related hospitalizations (three hospitalizations in 124 patients [3%] versus 14 hospitalizations in 164 patients [9%]; hazard ratio, 0.48; 95% confidence interval, 0.26 to 0.86). In the non-CKD group, the corresponding hazard ratio values were 0.96 (95% confidence interval, 0.74 to 1.24) for major adverse cardiovascular events, and 0.76 (95% confidence interval, 0.46 to 1.27) for heart failure-related hospitalization. Interaction of CKD on treatment effect was P=0.03 for major adverse cardiovascular events, and P=0.12 for heart failure-related hospitalization. Participants with CKD showed similar numbers of adverse events, regardless of randomization to apabetalone or placebo (119 [73%] versus 88 [71%] patients), and there were fewer serious adverse events (29% versus 43%; P=0.02) in the apabetalone group.Apabetalone may reduce the incidence of major adverse cardiovascular events in patients with CKD and type 2 diabetes who have a high burden of cardiovascular disease

Apabetalone and hospitalization for heart failure in patients following an acute coronary syndrome: a prespecified analysis of the BETonMACE study

Background Patients with diabetes and acute coronary syndrome (ACS) are at high risk for subsequent heart failure. Apabetalone is a selective inhibitor of bromodomain and extra-terminal (BET) proteins, epigenetic regulators of gene expression. Preclinical data suggest that apabetalone exerts favorable effects on pathways related to myocardial structure and function and therefore could impact subsequent heart failure events. The effect of apabetalone on heart failure events after an ACS is not currently known. Methods The phase 3 BETonMACE trial was a double-blind, randomized comparison of apabetalone versus placebo on the incidence of major adverse cardiovascular events (MACE) in 2425 patients with a recent ACS and diabetes. This prespecified secondary analysis investigated the impact of apabetalone on hospitalization for congestive heart failure, not previously studied. Results Patients (age 62 years, 74.4% males, 90% high-intensity statin use, LDL-C 70.3 mg/dL, HDL-C 33.3 mg/dL and HbA1c 7.3%) were followed for an average 26 months. Apabetalone treated patients experienced the nominal finding of a lower rate of first hospitalization for heart failure (2.4% vs. 4.0%, HR 0.59 [95%CI 0.38–0.94], P = 0.03), total number of hospitalizations for heart failure (35 vs. 70, HR 0.47 [95%CI 0.27–0.83], P = 0.01) and the combination of cardiovascular death or hospitalization for heart failure (5.7% vs. 7.8%, HR 0.72 [95%CI 0.53–0.98], P = 0.04). Conclusion Apabetalone treatment was associated with fewer hospitalizations for heart failure in patients with type 2 diabetes and recent ACS. Future studies are warranted to define the potential for BET inhibition with apabetalone to prevent heart failure in patients with diabetes and ACS