Detrital U-Pb geochronology provenance analyses: case studies in the Greater Green River Basin, Wyoming, and the Book Cliffs, Utah

Heavy mineral modal abundances and U-Pb geochronology are used to determine sediment provenance, provenance changes through time, and timing of crustal exhumation. Optimal preparation of datable detrital minerals (zircon, rutile, monazite, etc.) for provenance research using U-Pb geochronology has been a subject of debate and concern. Potential biases that are a concern consist of preferentially including or excluding datable detrital grains during mineral separation and data processing techniques. Exclusion of grains can lead to under- representation of source areas for a given sedimentary unit and alter the U-Pb age signature. The purpose of this study is to provide insight into this potential biasing by performing Laser Ablation-Inductively Coupled Plasma-Mass Spectrometer (LA-ICP-MS) U-Pb analyses of rutile and zircon with an optimized mineral separation and grain selection procedure. The Quantitative Evaluation of Minerals by SCANning electron microscopy (QEMSCAN®) was thus used to provide insight into potential biasing by automated quantification of modal abundances of minerals. A reliable technique for sample preparation was developed based on the LA-ICP-MS U-Pb analyses and QEMSCAN® mineralogical data. This technique includes minimal separation steps without preferential loss of mineral grains, representative sample splitting, and random and representative selection of grains to be dated. The result is a more comprehensive dataset for provenance analysis. The Late Cretaceous sedimentary rocks of the Pine Ridge Sandstone and Almond Formation of the Mesaverde Group, Lewis Shale and Fox Hills Sandstone in the Greater Green River Basin, Rawlins, Wyoming, were investigated to test and develop mineral separation techniques. The methods developed here were also used to test whether there are variations in U- Pb provenance signal and modal mineralogy due to changes in depositional facies using samples from the Upper Cretaceous Blackhawk Formation and Castlegate Sandstone from the Book Cliffs, Utah. These stratal units were selected because while the age of the potential source areas are well known and the sequence stratigraphy, and sedimentology of the strata is well characterized, provenance has not been determined. The results from LA-ICP-MS and QEMCAN analyses of Greater Green River Basin sedimentary rocks show that standard mineral separation procedures are not ideal for detrital provenance investigations. The standard mineral separation procedures introduce bias, resulting in a misrepresentation of the modal mineralogy and provenance age signal. LA-ICP-MS and QEMSCAN analyses of sedimentary samples from the Book Cliffs, Utah show that there are variations in the U-Pb provenance signal and modal mineralogy between samples from different depositional facies

Increased 5-year risk of stroke, atrial fibrillation, acute coronary syndrome, and heart failure in out-of-hospital cardiac arrest survivors compared with population controls:A nationwide registry-based study

AimLong-term risks of stroke, atrial fibrillation, or flutter (AF), acute coronary syndrome (ACS), and heart failure (HF) among survivors of out-of-hospital cardiac arrest (OHCA) are unknown. We aimed to examine 5-year risks of these outcomes among 30-day survivors of OHCA.MethodsThirty-day survivors of OHCA without a prior (or within 30 days after cardiac arrest) history of stroke, AF, ACS, or HF and population controls without a prior history of these conditions were identified using Danish nationwide registries. Five-year risks of stroke, AF, ACS, and HF standardized to the distributions of age, sex, and comorbidities among OHCA survivors and controls were obtained using multivariable regression.ResultsOf 4,362 30-day OHCA-survivors, 1,051 were stroke-, AF-, ACS-, and HF-naïve and matched with controls using age, sex, and time of OHCA event. Absolute five-year risks for OHCA survivors vs. controls were for stroke: 6.3% [95% confidence interval (CI) 4.1-8.5] vs. 2.0% [1.6-2.5], AF: 7.9% [5.7-10.2] vs. 2.6% [2.1-3.1], ACS: 5.0% [3.2-6.8] vs. 1.5% [1.1-1.9], and HF: 12.7% [10.1-15.4] vs. 1.2% [0.9-1.6], respectively. Corresponding relative risks were 3.18 [95% CI 1.76-4.61] for stroke, 3.03 [1.93-4.14] for AF, 3.23 [1.69-4.77] for ACS, and 10.40 [6.57-14.13] for HF.ConclusionWhen compared with population controls, OHCA survivors had significantly increased five-year risks of incident stroke, AF, ACS, and HF

Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden

On impact and volcanism across the Cretaceous-Paleogene boundary.

The cause of the end-Cretaceous mass extinction is vigorously debated, owing to the occurrence of a very large bolide impact and flood basalt volcanism near the boundary. Disentangling their relative importance is complicated by uncertainty regarding kill mechanisms and the relative timing of volcanogenic outgassing, impact, and extinction. We used carbon cycle modeling and paleotemperature records to constrain the timing of volcanogenic outgassing. We found support for major outgassing beginning and ending distinctly before the impact, with only the impact coinciding with mass extinction and biologically amplified carbon cycle change. Our models show that these extinction-related carbon cycle changes would have allowed the ocean to absorb massive amounts of carbon dioxide, thus limiting the global warming otherwise expected from postextinction volcanism

Mapping the human genetic architecture of COVID-19

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3–7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease

Genetic Architecture of Atherosclerosis in Mice: A Systems Genetics Analysis of Common Inbred Strains

Common forms of atherosclerosis involve multiple genetic and environmental factors. While human genome-wide association studies have identified numerous loci contributing to coronary artery disease and its risk factors, these studies are unable to control environmental factors or examine detailed molecular traits in relevant tissues. We now report a study of natural variations contributing to atherosclerosis and related traits in over 100 inbred strains of mice from the Hybrid Mouse Diversity Panel (HMDP). The mice were made hyperlipidemic by transgenic expression of human apolipoprotein E-Leiden (APOE-Leiden) and human cholesteryl ester transfer protein (CETP). The mice were examined for lesion size and morphology as well as plasma lipid, insulin and glucose levels, and blood cell profiles. A subset of mice was studied for plasma levels of metabolites and cytokines. We also measured global transcript levels in aorta and liver. Finally, the uptake of acetylated LDL by macrophages from HMDP mice was quantitatively examined. Loci contributing to the traits were mapped using association analysis, and relationships among traits were examined using correlation and statistical modeling. A number of conclusions emerged. First, relationships among atherosclerosis and the risk factors in mice resemble those found in humans. Second, a number of trait-loci were identified, including some overlapping with previous human and mouse studies. Third, gene expression data enabled enrichment analysis of pathways contributing to atherosclerosis and prioritization of candidate genes at associated loci in both mice and humans. Fourth, the data provided a number of mechanistic inferences; for example, we detected no association between macrophage uptake of acetylated LDL and atherosclerosis. Fifth, broad sense heritability for atherosclerosis was much larger than narrow sense heritability, indicating an important role for gene-by-gene interactions. Sixth, stepwise linear regression showed that the combined variations in plasma metabolites, including LDL/VLDL-cholesterol, trimethylamine N-oxide (TMAO), arginine, glucose and insulin, account for approximately 30 to 40% of the variation in atherosclerotic lesion area. Overall, our data provide a rich resource for studies of complex interactions underlying atherosclerosis