A controlled trial of rivaroxaban after transcatheter aortic-valve replacement

Background: whether the direct factor Xa inhibitor rivaroxaban can prevent thromboembolic events after transcatheter aortic-valve replacement (TAVR) is unclear. Methods: we randomly assigned 1644 patients without an established indication for oral anticoagulation after successful TAVR to receive rivaroxaban at a dose of 10 mg daily (with aspirin at a dose of 75 to 100 mg daily for the first 3 months) (rivaroxaban group) or aspirin at a dose of 75 to 100 mg daily (with clopidogrel at a dose of 75 mg daily for the first 3 months) (antiplatelet group). The primary efficacy outcome was the composite of death or thromboembolic events. The primary safety outcome was major, disabling, or life-threatening bleeding. The trial was terminated prematurely by the data and safety monitoring board because of safety concerns. Results: after a median of 17 months, death or a first thromboembolic event (intention-to-treat analysis) had occurred in 105 patients in the rivaroxaban group and in 78 patients in the antiplatelet group (incidence rates, 9.8 and 7.2 per 100 person-years, respectively; hazard ratio with rivaroxaban, 1.35; 95% confidence interval [CI], 1.01 to 1.81; P = 0.04). Major, disabling, or life-threatening bleeding (intention-to-treat analysis) had occurred in 46 and 31 patients, respectively (4.3 and 2.8 per 100 person-years; hazard ratio, 1.50; 95% CI, 0.95 to 2.37; P = 0.08). A total of 64 deaths occurred in the rivaroxaban group and 38 in the antiplatelet group (5.8 and 3.4 per 100 person-years, respectively; hazard ratio, 1.69; 95% CI, 1.13 to 2.53). Conclusions: in patients without an established indication for oral anticoagulation after successful TAVR, a treatment strategy including rivaroxaban at a dose of 10 mg daily was associated with a higher risk of death or thromboembolic complications and a higher risk of bleeding than an antiplatelet-based strategy. (Funded by Bayer and Janssen Pharmaceuticals; GALILEO ClinicalTrials.gov number, NCT02556203.)

Updated Three-Stage Model for the Peopling of the Americas

Background: We re-assess support for our three stage model for the peopling of the Americas in light of a recent report that identified nine non-Native American mitochondrial genome sequences that should not have been included in our initial analysis. Removal of these sequences results in the elimination of an early (i.e.,40,000 years ago) expansion signal we had proposed for the proto-Amerind population. Methodology/Findings: Bayesian skyline plot analysis of a new dataset of Native American mitochondrial coding genomes confirms the absence of an early expansion signal for the proto-Amerind population and allows us to reduce the variation around our estimate of the New World founder population size. In addition, genetic variants that define New World founder haplogroups are used to estimate the amount of time required between divergence of proto-Amerinds from the Asian gene pool and expansion into the New World. Conclusions/Significance: The period of population isolation required for the generation of New World mitochondrial founder haplogroup-defining genetic variants makes the existence of three stages of colonization a logical conclusion. Thus, our three stage model remains an important and useful working hypothesis for researchers interested in the peopling of th

Evolutionary history of saber-toothed cats based on ancient mitogenomics

Saber-toothed cats (Machairodontinae) are among the most widely recognized representatives of the now largely extinct Pleistocene megafauna. However, many aspects of their ecology, evolution, and extinction remain uncertain. Although ancient-DNA studies have led to huge advances in our knowledge of these aspects of many other megafauna species (e.g., mammoths and cave bears), relatively few ancient-DNA studies have focused on saber-toothed cats, and they have been restricted to short fragments of mitochondrial DNA. Here we investigate the evolutionary history of two lineages of saber-toothed cats (Smilodon and Homotherium) in relation to living carnivores and find that the Machairodontinae form a well-supported clade that is distinct from all living felids. We present partial mitochondrial genomes from one S. populator sample and three Homotherium sp. samples, including the only Late Pleistocene Homotherium sample from Eurasia. We confirm the identification of the unique Late Pleistocene European fossil through ancient-DNA analyses, thus strengthening the evidence that Homotherium occurred in Europe over 200,000 years later than previously believed. This in turn forces a re-evaluation of its demography and extinction dynamics. Within the Machairodontinae, we find a deep divergence between Smilodon and Homotherium ( 18 million years) but limited diversity between the American and European Homotherium specimens. The genetic data support the hypothesis that all Late Pleistocene (or post-Villafrancian) Homotherium should be considered a single species, H. latidens, which was previously proposed based on morphological data

Population dynamics and range shifts of moose (Alces alces) during the Late Quaternary

Aim: Late Quaternary climate oscillations had major impacts on species distributions and abundances across the northern Holarctic. While many large mammals in this region went extinct towards the end of the Quaternary, some species survived and flourished. Here, we examine population dynamics and range shifts of one of the most widely distributed of these, the moose (Alces alces). Location: Northern Holarctic. Taxon: Moose (A. alces). Methods: We collected samples of modern and ancient moose from across their present and former range. We assessed their phylogeographical relations using part of the mitochondrial DNA in conjunction with radiocarbon dating to investigate the history of A. alces during the last glacial. Results: This species has a relatively shallow history, with the most recent common ancestor estimated at ca. 150–50 kyr. Ancient samples corroborate that its region of greatest diversity is in east Asia, supporting proposals that this is the region of origin of all extant moose. Both eastern and western haplogroups occur in the Ural Mountains during the last glacial period, implying a broader contact zone than previously proposed. It seems that this species went extinct over much of its northern range during the last glacial maximum (LGM) and recolonized the region with climate warming beginning around 15,000 yr bp. The post-LGM expansion included a movement from northeast Siberia to North America via Beringia, although the northeast Siberian source population is not the one currently occupying that area. Main conclusions: Moose are a relatively recently evolved species but have had a dynamic history. As a large-bodied subarctic browsing species, they were seemingly confined to refugia during full-glacial periods and expanded their range northwards when the boreal forest returned after the LGM. The main modern phylogeographical division is ancient, though its boundary has not remained constant. Moose population expansion into America was roughly synchronous with human and red deer expansion. © 2020 The Authors. Journal of Biogeography published by John Wiley & Sons LtdWe warmly thank the following museums, curators and people for access to samples: the late Andrei Sher, Severtsov Institute, Moscow; Andy Currant, Natural History Museum, London; Alfred Gardner, Smithsonian, Washington DC; R. Dale Guthrie, University of Alaska, Fairbanks; John de Vos, National Museum of Natural History (Naturalis), Leiden; Eileen Westwig, American Museum of Natural History, NY; Fyodor Shidlovsky, Ice-Age Museum, Moscow; Tong Haowen, Institute of Vertebrate Palaeontology and Paleoanthropology, Beijing; Mammoth Museum, Yakutsk; Geological Museum, Yakutsk; Paleontological Institute, Moscow; Royal Alberta Museum, Edmonton; Zoological Institute, Saint Petersburg; Museum of the Institute of Plant and Animal Ecology, Ekaterinburg. We thank our Yukon First Nation research partners for their continued support for our work on the ice age fossils of Yukon Territory. We are grateful to the placer gold mining community and the Tr'ond?k Hw?ch'in First Nation for their continued support and partnership with our research in the Klondike goldfields region; and the Vuntut Gwitchin First Nation for their collaboration with research in the Old Crow region. We would also like to thank Shai Meiri for help in drawing the map and useful discussion, Tony Stuart for access to radiocarbon dates, and Iris van Pijlen for laboratory assistance. This research was funded by NERC grant NE/G00269X/1 through the European Union FP7 ERA-NET program BiodivERsA. Funding for AMS dating was provided through NERC/AHRC/ORAU Grant NF/2008/2/15

Nitrogen and Carbon Isotopic Dynamics of Subarctic Soils and Plants in Southern Yukon Territory and its Implications for Paleoecological and Paleodietary Studies

We examine here the carbon and nitrogen isotopic compositions of bulk soils (8 topsoil and 7 subsoils, including two soil profiles) and five different plant parts of 79 C3 plants from two main functional groups: herbs and shrubs/subshrubs, from 18 different locations in grasslands of southern Yukon Territory, Canada (eastern shoreline of Kluane Lake and Whitehorse area). The Kluane Lake region in particular has been identified previously as an analogue for Late Pleistocene eastern Beringia. All topsoils have higher average total nitrogen δ15N and organic carbon δ13C than plants from the same sites with a positive shift occurring with depth in two soil profiles analyzed. All plants analyzed have an average whole plant δ13C of −27.5 ± 1.2 ‰ and foliar δ13C of ±28.0 ± 1.3 ‰, and average whole plant δ15N of −0.3 ± 2.2 ‰ and foliar δ15N of ±0.6 ± 2.7 ‰. Plants analyzed here showed relatively smaller variability in δ13C than δ15N. Their average δ13C after suitable corrections for the Suess effect should be suitable as baseline for interpreting diets of Late Pleistocene herbivores that lived in eastern Beringia. Water availability, nitrogen availability, spacial differences and intra-plant variability are important controls on δ15N of herbaceous plants in the study area. The wider range of δ15N, the more numerous factors that affect nitrogen isotopic composition and their likely differences in the past, however, limit use of the modern N isotopic baseline for vegetation in paleodietary models for such ecosystems. That said, the positive correlation between foliar δ15N and N content shown for the modern plants could support use of plant δ15N as an index for plant N content and therefore forage quality. The modern N isotopic baseline cannot be applied directly to the past, but it is prerequisite to future efforts to detect shifts in N cycling and forage quality since the Late Pleistocene through comparison with fossil plants from the same region

Grey wolf genomic history reveals a dual ancestry of dogs

The grey wolf (Canis lupus) was the first species to give rise to a domestic population, and they remained widespread throughout the last Ice Age when many other large mammal species went extinct. Little is known, however, about the history and possible extinction of past wolf populations or when and where the wolf progenitors of the present-day dog lineage (Canisfamiliaris) lived(1-8). Here we analysed 72 ancient wolf genomes spanning the last 100,000 years from Europe, Siberia and North America. We found that wolf populations were highly connected throughout the Late Pleistocene, with levels of differentiation an order of magnitude lower than they are today. This population connectivity allowed us to detect natural selection across the time series, including rapid fixation of mutations in the gene IFT8840,000-30,000 years ago. We show that dogs are overall more closely related to ancient wolves from eastern Eurasia than to those from western Eurasia, suggesting a domestication process in the east. However, we also found that dogs in the Near East and Africa derive up to half of their ancestry from a distinct population related to modern southwest Eurasian wolves, reflecting either an independent domestication process or admixture from local wolves. None of the analysed ancient wolf genomes is a direct match for either of these dog ancestries, meaning that the exact progenitor populations remain to be located.Peer reviewe

Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes.

Abstract BACKGROUND: The cardiovascular effects of adding once-weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown. METHODS: We randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy. RESULTS: In all, 14,752 patients (of whom 10,782 [73.1%] had previous cardiovascular disease) were followed for a median of 3.2 years (interquartile range, 2.2 to 4.4). A primary composite outcome event occurred in 839 of 7356 patients (11.4%; 3.7 events per 100 person-years) in the exenatide group and in 905 of 7396 patients (12.2%; 4.0 events per 100 person-years) in the placebo group (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00), with the intention-to-treat analysis indicating that exenatide, administered once weekly, was noninferior to placebo with respect to safety (P<0.001 for noninferiority) but was not superior to placebo with respect to efficacy (P=0.06 for superiority). The rates of death from cardiovascular causes, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, hospitalization for heart failure, and hospitalization for acute coronary syndrome, and the incidence of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events did not differ significantly between the two groups. CONCLUSIONS: Among patients with type 2 diabetes with or without previous cardiovascular disease, the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo. (Funded by Amylin Pharmaceuticals; EXSCEL ClinicalTrials.gov number, NCT01144338 .)

Grey wolf genomic history reveals a dual ancestry of dogs

The grey wolf (Canis lupus) was the first species to give rise to a domestic population, and they remained widespread throughout the last Ice Age when many other large mammal species went extinct. Little is known, however, about the history and possible extinction of past wolf populations or when and where the wolf progenitors of the present-day dog lineage (Canis familiaris) lived1,2,3,4,5,6,7,8. Here we analysed 72 ancient wolf genomes spanning the last 100,000 years from Europe, Siberia and North America. We found that wolf populations were highly connected throughout the Late Pleistocene, with levels of differentiation an order of magnitude lower than they are today. This population connectivity allowed us to detect natural selection across the time series, including rapid fixation of mutations in the gene IFT88 40,000–30,000 years ago. We show that dogs are overall more closely related to ancient wolves from eastern Eurasia than to those from western Eurasia, suggesting a domestication process in the east. However, we also found that dogs in the Near East and Africa derive up to half of their ancestry from a distinct population related to modern southwest Eurasian wolves, reflecting either an independent domestication process or admixture from local wolves. None of the analysed ancient wolf genomes is a direct match for either of these dog ancestries, meaning that the exact progenitor populations remain to be located

A New Concept In The Design Of The Lhc Beam Dump

Recent Monte Carlo cascade simulations have shown that a reduction in the maximum of deposited energy density can be obtained by applying a uniform magnetic field over a front part of the graphite core of the LHC dump. This paper shows the effect of field strength on spatial distributions of absorbed energy and temperatures, and discusses problems to be solved when designing a suitable magnet. I. INTRODUCTION TheLHC energy of nominally 333 MJ per ring (2.97#10 14 protons at 7.0 TeV), extremely concentrated in a small region around the beam axis, gives rise to severe thermal and mechanical constraints on the construction of the beam dump, which will be installed at a distance of about 750 m from the ejection point. Several beam diluting procedures exist and have already been discussed [1]. Each of them applied alone is either not sufficient to keep the maximum temperature rise in the graphite below a tolerable level---or kicker magnet performance or the tunnel length are forced to e..