Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Effects of locally rare taxa on the precision and sensitivity of RIVPACS bioassessment of freshwaters

1. An overall aim in freshwater bioassessment is to use biological methods, metrics and forms of indices which are precise, in that they give repeatable results between replicate samples, but which are also sensitive to changes in environmental impacts and stresses. Here we studied the effects of excluding taxa with site-specific River Invertebrate Prediction and Classification System (RIVPACS)-type model expected probabilities less than (or equal to) a threshold Pt (0.0, 0.1, 0.2,…,0.9) on the value, precision and power to detect biological effects of environmental stress using the observed to expected ratios (O/E) of biotic indices used to assess the ecological status of U.K. river sites. 2. Amongst the 614 high quality GB RIVPACS reference sites, excluding taxa with low expected probabilities of occurrence gave less total variation (i.e. lower SD) in the estimates O/E for number of taxa (O/ETAXA) and the average score per taxon (O/EASPT). 3. A separate analysis of a replicated sampling study of sites from a wide range of physical types and qualities revealed that sampling variances in O/E for reference condition sites decreased as more locally rare taxa were excluded (but only up to Pt = 0.5 for O/EASPT). However, for moderately impacted and poor quality sites, estimates of both O/ETAXA and O/EASPT based on all (Pt = 0.0) or most taxa (i.e. Pt ≤ 0.3) had lower sampling variances and were more precise. 4. Within a very large independent set of test sites with a wide range of perceived levels of environmental stress, increasing the threshold Pt led to systematic compression of the realised O/E scale towards unity. Specifically, with increasing threshold, O/E values >1 are on average reduced, while O/E values <1 have a tendency to be higher and closer to unity (with the exception of O/EASPT for the most severely stressed sites). 5. Accuracy and statistical power to detect environmental stress (measured by the percentage of stressed sites with O/E below the lower 10-percentile value for reference sites) was very similar using O/ETAXA for Pt up to 0.7. Using O/EASPT, power to detect overall general stress decreased slowly as Pt was increased; the rate of fall in power was slightly faster when restricted to sites subject to moderate or severe stress from organic inputs. 6. Taxa which are more sensitive to (organic) stresses [i.e. have high Biological Monitoring Working Party (BMWP) scores] tend to be naturally less widespread (i.e. amongst reference sites) and thus were found to have considerably lower average site-specific expected probabilities; this may explain why the use of higher thresholds Pt can exclude more such sensitive taxa and lead to underestimation of the extent of impacts. 7. The standard U.K. RIVPACS sampling and sample processing procedures aim to identify all taxa within a sample. This may lead to a longer distribution tail of rarer (low probability) taxa than sampling methods based on a fixed count subsample and influence the practical effects of excluding rare taxa with low expected probabilities from bioassessments

A cold model study of raceway hysteresis

The effect of a gas flow field on the size of raceway has been studied experimentally using a two-dimensional (2-D) cold model. It is observed that as the blast velocity from the tuyere increases, raceway size increases, and when the blast velocity is decreased from its highest value, raceway size does not change much until the velocity reaches a critical velocity. Below the critical velocity, raceway size decreases with decreasing velocity but is always larger than that for the same velocity when the velocity increased. This phenomenon is called raceway hysteresis. Raceway hysteresis has been studied in the presence of different gas flow rates and different particle densities. Raceway hysteresis has been observed in all the experiments. The effect of liquid flow, with various superficial velocities, on raceway hysteresis has also been studied. A study of raceway size hysteresis shows that interparticle and particle-wall friction have a very large effect on raceway size. A hypothesis has been proposed to describe the hysteresis phenomenon in the packed beds. The relevance of hysteresis to blast furnace raceways has been discussed. Existing literature correlations for raceway size ignore the frictional effects. Therefore, their applicability to the ironmaking blast furnace is questionable

Erratum: Pharmacological Characterization of the αvβ6 Integrin Binding and Internalization Kinetics of the Foot-and-Mouth Disease Virus Derived Peptide A20FMDV2

A20FMDV2 is a peptide derived from the foot-and-mouth disease virus with a high affinity and selectivity for the alpha-v beta-6 (αvβ6) arginyl-glycinyl-aspartic acid (RGD)-binding integrin. It has been shown to be an informative tool ligand in pre-clinical imaging studies for selective labelling of the αvβ6 integrin in a number of disease models. In a radioligand binding assay using a radiolabelled form of the peptide ([³H]A20FMDV2), its high affinity (K_D: 0.22 nmol/l) and selectivity (at least 85-fold) for αvβ6 over the other members of the RGD integrin family was confirmed. [³H]A20FMDV2 αvβ6 binding could be fully reversed only in the presence of EDTA, whereas a partial reversal was observed in the presence of excess concentrations of an RGD-mimetic small molecule (SC-68448) or unlabelled A20FMDV2. Using flow cytometry on bronchial epithelial cells, the ligand-induced internalization of αvβ6 by A20FMDV2 and latency-associated peptide-1 was shown to be fast (t_1/2: 1.5 and 3.1 min, respectively), concentration-dependent (EC₅₀: values 1.1 and 3.6 nmol/l, respectively) and was followed by a moderately slow return of integrin to the surface. The results of the radioligand binding studies suggest that the binding of A20FMDV2 to the RGD-binding site on αvβ6 is required to maintain its engagement with the hypothesised A20FMDV2 synergy site on the integrin. In addition, there is evidence from flow cytometric studies that the RGD-ligand engagement of αvβ6 post-internalization plays a role in delaying recycling of the integrin to the cell surface. This mechanism may act as a homeostatic control of membrane αvβ6 following RGD ligand engagement