Double-Dose Versus Standard-Dose Clopidogrel According to Smoking Status Among Patients With Acute Coronary Syndromes Undergoing Percutaneous Coronary Intervention

Background: Prior Studies have suggested better outcomes in smokers compared with nonsmokers receiving clopidogrel (“smoker's paradox”). The impact of a more intensive clopidogrel regimen on ischemic and bleeding risks in smokers with acute coronary syndromes requiring percutaneous coronary interventions remains unclear. Methods and Results: We analyzed 17 263 acute coronary syndrome patients undergoing percutaneous coronary intervention from the CURRENT‐OASIS 7 (Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events—Seventh Organization to Assess Strategies in Ischemic Symptoms) trial, which compared double‐dose (600 mg day 1;150 mg days 2–7; then 75 mg daily) versus standard‐dose (300 mg day 1; then 75 mg daily) clopidogrel in acute coronary syndrome patients. The primary outcome was cardiovascular death, myocardial infarction, or stroke at 30 days. Interactions between treatment allocation and smoking status (current smokers versus nonsmokers) were evaluated. Overall, 6394 patients (37.0%) were current smokers. For the comparison of double‐ versus standard‐dose clopidogrel, there were significant interactions in smokers and nonsmokers for the primary outcome (P=0.031) and major bleeding (P=0.002). Double‐ versus standard‐dose clopidogrel reduced the primary outcome among smokers by 34% (hazard ratio [HR] 0.66, 95% confidence interval [CI], 0.50–0.87, P=0.003), whereas in nonsmokers, there was no apparent benefit (HR 0.96, 95% CI, 0.80–1.14, P=0.61). For major bleeding, there was no difference between the groups in smokers (HR 0.77, 95% CI, 0.48–1.24, P=0.28), whereas in nonsmokers, the double‐dose clopidogrel regimen increased bleeding (HR 1.89, 95% CI, 1.37–2.60, P<0.0001). Double‐dose clopidogrel reduced the incidence of definite stent thrombosis in smokers (HR 0.41, 95% CI, 0.24–0.71) and nonsmokers (HR 0.63, 95% CI, 0.42–0.93; P for interaction=0.19). Conclusions: In smokers, a double‐dose clopidogrel regimen reduced major cardiovascular events and stent thrombosis after percutaneous coronary intervention, with no increase in major bleeding. This suggests that clopidogrel dosing in patients with acute coronary syndromes should be personalized, taking into consideration both ischemic and bleeding risk. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT00335452

Integrating plant physiology into simulation of fire behavior and effects

Wildfires are a global crisis, but current fire models fail to capture vegetation response to changing climate. With drought and elevated temperature increasing the importance of vegetation dynamics to fire behavior, and the advent of next generation models capable of capturing increasingly complex physical processes, we provide a renewed focus on representation of woody vegetation in fire models. Currently, the most advanced representations of fire behavior and biophysical fire effects are found in distinct classes of fine-scale models and do not capture variation in live fuel (i.e. living plant) properties. We demonstrate that plant water and carbon dynamics, which influence combustion and heat transfer into the plant and often dictate plant survival, provide the mechanistic linkage between fire behavior and effects. Our conceptual framework linking remotely sensed estimates of plant water and carbon to fine-scale models of fire behavior and effects could be a critical first step toward improving the fidelity of the coarse scale models that are now relied upon for global fire forecasting. This process-based approach will be essential to capturing the influence of physiological responses to drought and warming on live fuel conditions, strengthening the science needed to guide fire managers in an uncertain future

The Athena X-ray Integral Field Unit (X-IFU)

The X-ray Integral Field Unit (X-IFU) is the high resolution X-ray spectrometer of the ESA Athena X-ray observatory. Over a field of view of 5' equivalent diameter, it will deliver X-ray spectra from 0.2 to 12 keV with a spectral resolution of 2.5 eV up to 7 keV on similar to 5 '' pixels. The X-IFU is based on a large format array of super-conducting molybdenum-gold Transition Edge Sensors cooled at similar to 90 mK, each coupled with an absorber made of gold and bismuth with a pitch of 249 mu m. A cryogenic anti-coincidence detector located underneath the prime TES array enables the non X-ray background to be reduced. A bath temperature of similar to 50 mK is obtained by a series of mechanical coolers combining 15K Pulse Tubes, 4K and 2K Joule-Thomson coolers which pre-cool a sub Kelvin cooler made of a He-3 sorption cooler coupled with an Adiabatic Demagnetization Refrigerator. Frequency domain multiplexing enables to read out 40 pixels in one single channel. A photon interacting with an absorber leads to a current pulse, amplified by the readout electronics and whose shape is reconstructed on board to recover its energy with high accuracy. The defocusing capability offered by the Athena movable mirror assembly enables the X-IFU to observe the brightest X-ray sources of the sky (up to Crab-like intensities) by spreading the telescope point spread function over hundreds of pixels. Thus the X-IFU delivers low pile-up, high throughput (> 50%), and typically 10 eV spectral resolution at 1 Crab intensities, i.e. a factor of 10 or more better than Silicon based X-ray detectors. In this paper, the current X-IFU baseline is presented, together with an assessment of its anticipated performance in terms of spectral resolution, background, and count rate capability. The X-IFU baseline configuration will be subject to a preliminary requirement review that is scheduled at the end of 2018. The X-IFU will be provided by an international consortium led by France, the Netherlands and Italy, with further ESA member state contributions from Belgium, Czech Republic, Finland, Germany, Ireland, Poland, Spain, Switzerland and contributions from Japan and the United States.Peer reviewe

Identification of constrained sequence elements across 239 primate genomes

Noncoding DNA is central to our understanding of human gene regulation and complex diseases1,2, and measuring the evolutionary sequence constraint can establish the functional relevance of putative regulatory elements in the human genome3–9. Identifying the genomic elements that have become constrained specifically in primates has been hampered by the faster evolution of noncoding DNA compared to protein-coding DNA10, the relatively short timescales separating primate species11, and the previously limited availability of whole-genome sequences12. Here we construct a whole-genome alignment of 239 species, representing nearly half of all extant species in the primate order. Using this resource, we identified human regulatory elements that are under selective constraint across primates and other mammals at a 5% false discovery rate. We detected 111,318 DNase I hypersensitivity sites and 267,410 transcription factor binding sites that are constrained specifically in primates but not across other placental mammals and validate their cis-regulatory effects on gene expression. These regulatory elements are enriched for human genetic variants that affect gene expression and complex traits and diseases. Our results highlight the important role of recent evolution in regulatory sequence elements differentiating primates, including humans, from other placental mammals

The landscape of tolerated genetic variation in humans and primates.

Personalized genome sequencing has revealed millions of genetic differences between individuals, but our understanding of their clinical relevance remains largely incomplete. To systematically decipher the effects of human genetic variants, we obtained whole-genome sequencing data for 809 individuals from 233 primate species and identified 4.3 million common protein-altering variants with orthologs in humans. We show that these variants can be inferred to have nondeleterious effects in humans based on their presence at high allele frequencies in other primate populations. We use this resource to classify 6% of all possible human protein-altering variants as likely benign and impute the pathogenicity of the remaining 94% of variants with deep learning, achieving state-of-the-art accuracy for diagnosing pathogenic variants in patients with genetic diseases

Caractéristiques et modalités de la territorialisation de l’action publique en Colombie

En el marco de sus reflexiones sobre lo que suele llamarse “la territorialización de la acción pública”, el autor se interesa sucesivamente por las características y las modalidades de la misma a partir de un análisis de los debates respectivos sobre la descentralización y el ordenamiento territorial durante la Asamblea Constituyente de 1991. Después de detallar los argumentos de los que piensan que la Constitución sólo ha confirmado la descentralización y de aquellos que piensan que ha marcado la afirmación de nuevos principios y avances, y constatado que analistas y ex constituyentes son de acuerdo para indicar que no se ha relacionado funcionalmente descentralización y el ordenamiento territorial, el articulo analiza los referenciales y modos de actuar de los partidarios respectivos de la provincia, el departamento y la región. Se puede interpretar las razones de las polémicas y la ambivalencia de las discusiones y decisiones tomadas a propósito del estatuto de la región como una “neutralización”’ de las fuerzas en presencia que deja sin respuesta real el reto, siempre presente pero nunca evocado, que plantea la territorialización de la acción pública “desde abajo”