Prevalence of anginal symptoms and myocardial ischemia and their effect on clinical outcomes in outpatients with stable coronary artery disease: data from the international observational CLARIFY registry

Importance: In the era of widespread revascularization and effective antianginals, the prevalence and prognostic effect of anginal symptoms and myocardial ischemia among patients with stable coronary artery disease (CAD) are unknown.<p></p> Objective: To describe the current clinical patterns among patients with stable CAD and the association of anginal symptoms or myocardial ischemia with clinical outcomes.<p></p> Design, Setting, and Participants: The Prospective Observational Longitudinal Registry of Patients With Stable Coronary Artery Disease (CLARIFY) registry enrolled outpatients in 45 countries with stable CAD in 2009 to 2010 with 2-year follow-up (median, 24.1 months; range, 1 day to 3 years). Enrollees included 32 105 outpatients with prior myocardial infarction, chest pain, and evidence of myocardial ischemia, evidence of CAD on angiography, or prior revascularization. Of these, 20 291 (63.2%) had undergone a noninvasive test for myocardial ischemia within 12 months of enrollment and were categorized into one of the following 4 groups: no angina or ischemia (n = 13 207 [65.1%]); evidence of myocardial ischemia without angina (silent ischemia) (n = 3028 [14.9%]); anginal symptoms alone (n = 1842 [9.1%]); and angina and ischemia (n = 2214 [10.9%]).<p></p> Exposures: Stable CAD.<p></p> Main Outcome and Measure: The composite of cardiovascular (CV)–related death or nonfatal myocardial infarction.<p></p> Results: Overall, 4056 patients (20.0%) had anginal symptoms and 5242 (25.8%) had evidence of myocardial ischemia on results of noninvasive testing. Of 469 CV-related deaths or myocardial infarctions, 58.2% occurred in patients without angina or ischemia, 12.4% in patients with ischemia alone, 12.2% in patients with angina alone, and 17.3% in patients with both. The hazard ratios for the primary outcome relative to patients without angina or ischemia and adjusted for age, sex, geographic region, smoking status, hypertension, diabetes mellitus, and dyslipidemia were 0.90 (95% CI, 0.68-1.20; P = .47) for ischemia alone, 1.45 (95% CI, 1.08-1.95; P = .01) for angina alone, and 1.75 (95% CI, 1.34-2.29; P <.001) for both. Similar findings were observed for CV-related death and for fatal or nonfatal myocardial infarction.<p></p> Conclusions and Relevance: In outpatients with stable CAD, anginal symptoms (with or without ischemia on noninvasive testing) but not silent ischemia appear to be associated with an increased risk for adverse CV outcomes. Most CV events occurred in patients without angina or ischemia

Meta-analysis of genome-wide association studies for cattle stature identifies common genes that regulate body size in mammals

Stature is affected by many polymorphisms of small effect in humans1. In contrast, variation in dogs, even within breeds, has been suggested to be largely due to variants in a small number of genes2,3. Here we use data from cattle to compare the genetic architecture of stature to those in humans and dogs. We conducted a meta-analysis for stature using 58,265 cattle from 17 populations with 25.4 million imputed whole-genome sequence variants. Results showed that the genetic architecture of stature in cattle is similar to that in humans, as the lead variants in 163 significantly associated genomic regions (P \u3c 5 × 10−8) explained at most 13.8% of the phenotypic variance. Most of these variants were noncoding, including variants that were also expression quantitative trait loci (eQTLs) and in ChIP–seq peaks. There was significant overlap in loci for stature with humans and dogs, suggesting that a set of common genes regulates body size in mammals

Multi-Step Level-Set Ice Accretion Simulation with the NSMB solver

Icing effects can reduce the flight safety under certain weather conditions. According to the US National Transport Safety Board, icing is one of the major causes of flight accidents. Supercooled water droplets present in clouds impinge on the surface of aircraft structures. They either solidify totally on impact or partially then creating a thin liquid film runback depending on the flow temperature and speed hence, creating dry rime ice or glaze wet ice respectively. Designing an adequate de-icing mechanisms requires full knowledge of the icing phenomenon itself. Icing experimental study cannot exceed the scope of a handful of simple cases due to complexity and cost. Consequently the use of computational fluid dynamics is justified. The icing process is assumed broken up into four steps: 1) single phase air flows around the wing 2) transporting water suspended droplets; droplets impinge into the surface 3) generating a liquid or dry film exchanging energy with the surface 4) accreated to shape the final form during a certain exposure time. This process is usually assumed to occur on a single step considering that the time scale of the icing process is very long compared with that of the air flow. Current Icing simulation codes used by industries are based on over-simplified models. 1) A 2D inviscid panel methods with an empirical boundary layer method is used for the air flow. Which is usually followed by 2) a Lagrangian transport of droplets. And finally 3,4) an iterative thermodynamic model for the liquid film to compute the ice thickness. To generate the final geometry however, a Lagrangian node displacement is needed. A multi-step icing approach repeats this process for portions of the required exposure time but still with decoupled time scales. Maintaining a good grid quality requires a tedious amount of work, since strange irregularities in iced shapes are difficult to be fully accounted for. The Level-Set method introduced by Osher and Fedkiw could alleviate such a task. A passive scalar function is introduced and is put equal to zero at the interface, positively defined outside and negatively inside; the zero level represents the time evolution of the air/ice interface. To complete the model, a PDE type thermodynamic model is used for the film, coupled with an external flow solver. In the present study a new method of icing simulation is developed. To get the most out of such model, it is developed in the three-dimensional structured multiblock Navier-Stokes solver NSMB. For a multi-step icing procedure, the geometry is defined by a passive scalar called the level-set. This level-set function is set equal to the distance, negative on the inside and positive outside. A penalized Navier-Stokes equation is solved on the external flow using a simple non-body fitted mesh, wherein the solid is represented by the negative level-set valued cells. The droplets are transported using an Eulerian approach using a TVD and a local time stepping schemes. The impingement rate or what's called the collection efficiency is then fed to a Shallow-Water Icing Model that evaluates the ice accretion, its height and velocity. The convective heat transfer coefficient is obtained from the Navier-Stokes solver. Following that the Level-set function is advected with the icing velocity to predict the new deformed geometry. The process is then repeated for as many portions of the exposure time as needed

Domestication history and geographical adaptation inferred from a SNP map of African rice

African rice (Oryza glaberrima Steud.) is a cereal crop species closely related to Asian rice (Oryza sativa L.) but was independently domesticated in West Africa-3,000 years ago. African rice is rarely grown outside sub-Saharan Africa but is of global interest because of its tolerance to abiotic stresses. Here we describe a map of 2.32 million SNPs of African rice from whole-genome resequencing of 93 landraces. Population genomic analysis shows a population bottleneck in this species that began-13,000-15,000 years ago with effective population size reaching its minimum value-3,500 years ago, suggesting a protracted period of population size reduction likely commencing with predomestication management and/or cultivation. Genome-wide association studies (GWAS) for six salt tolerance traits identify 11 significant loci, 4 of which are within-300 kb of genomic regions that possess signatures of positive selection, suggesting adaptive geographical divergence for salt tolerance in this species

Multicenter, Phase 2, Randomized Controlled Study of the Efficacy and Safety of Etripamil Nasal Spray for the Acute Reduction of Rapid Ventricular Rate in Patients With Symptomatic Atrial Fibrillation (ReVeRA-201).

BACKGROUND: Despite chronic therapies, atrial fibrillation (AF) leads to rapid ventricular rates (RVR) often requiring intravenous treatments. Etripamil is a fast-acting, calcium-channel blocker administered intranasally affecting the atrioventricular node within minutes. METHODS: Reduction of Ventricular Rate in Patients with Atrial Fibrillation evaluated the efficacy and safety of etripamil for the reduction of ventricular rate (VR) in patients presenting urgently with AF-RVR (VR ≥110 beats per minute [bpm]), was randomized, double-blind, placebo-controlled, and conducted in Canada and the Netherlands. Patients presenting urgently with AF-RVR were randomized (1:1, etripamil nasal spray 70 mg: placebo nasal spray). The primary objective was to demonstrate the effectiveness of etripamil in reducing VR in AF-RVR within 60 minutes of treatment. Secondary objectives assessed achievement of VR <100 bpm, reduction by ≥10% and ≥20%, relief of symptoms and treatment effectiveness; adverse events; and additional measures to 360 minutes. RESULTS: Sixty-nine patients were randomized, 56 dosed with etripamil (n=27) or placebo (n=29). The median age was 65 years; 39% were female patients; proportions of AF types were similar between groups. The difference of mean maximum reductions in VR over 60 minutes, etripamil versus placebo, adjusting for baseline VR, was -29.91 bpm (95% CI, -40.31 to -19.52; P<0.0001). VR reductions persisted up to 150 minutes. Significantly greater proportions of patients receiving etripamil achieved VR reductions <100 bpm (with longer median duration <100 bpm), or VR reduction by ≥10% or ≥20%, versus placebo. VR reduction ≥20% occurred in 66.7% of patients in the etripamil arm and no patients in placebo. Using the Treatment Satisfaction Questionnaire for Medication-9, there was significant improvement in satisfaction on symptom relief and treatment effectiveness with etripamil versus placebo. Serious adverse events were rare; 1 patient in the etripamil arm experienced transient severe bradycardia and syncope, assessed as due to hypervagotonia. CONCLUSIONS: Intranasal etripamil 70 mg reduced VR and improved symptom relief and treatment satisfaction. These data support further development of self-administered etripamil for the treatment of AF-RVR. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT04467905

A Glycemia Risk Index (GRI) of Hypoglycemia and Hyperglycemia for Continuous Glucose Monitoring Validated by Clinician Ratings

BackgroundA composite metric for the quality of glycemia from continuous glucose monitor (CGM) tracings could be useful for assisting with basic clinical interpretation of CGM data.MethodsWe assembled a data set of 14-day CGM tracings from 225 insulin-treated adults with diabetes. Using a balanced incomplete block design, 330 clinicians who were highly experienced with CGM analysis and interpretation ranked the CGM tracings from best to worst quality of glycemia. We used principal component analysis and multiple regressions to develop a model to predict the clinician ranking based on seven standard metrics in an Ambulatory Glucose Profile: very low-glucose and low-glucose hypoglycemia; very high-glucose and high-glucose hyperglycemia; time in range; mean glucose; and coefficient of variation.ResultsThe analysis showed that clinician rankings depend on two components, one related to hypoglycemia that gives more weight to very low-glucose than to low-glucose and the other related to hyperglycemia that likewise gives greater weight to very high-glucose than to high-glucose. These two components should be calculated and displayed separately, but they can also be combined into a single Glycemia Risk Index (GRI) that corresponds closely to the clinician rankings of the overall quality of glycemia (r = 0.95). The GRI can be displayed graphically on a GRI Grid with the hypoglycemia component on the horizontal axis and the hyperglycemia component on the vertical axis. Diagonal lines divide the graph into five zones (quintiles) corresponding to the best (0th to 20th percentile) to worst (81st to 100th percentile) overall quality of glycemia. The GRI Grid enables users to track sequential changes within an individual over time and compare groups of individuals.ConclusionThe GRI is a single-number summary of the quality of glycemia. Its hypoglycemia and hyperglycemia components provide actionable scores and a graphical display (the GRI Grid) that can be used by clinicians and researchers to determine the glycemic effects of prescribed and investigational treatments