The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Ligand binding study revealing a human olfactory receptor involved in waxy-floral odor perception

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Odorant molecules and human olfactory receptor

International audienceWhen a molécule interacts with the olfactory sensorial system, it carries out the encoding of the characteristics. The treatment and processing of this data gives rise to a cérébral construction:The "odor". THE PERCEPTION on thousands of odorant molecules by a few hundred human olfactory receptors (ORs) results in a combined coding.one OR can recognize several odorant molécules and one odorant molecule can be deterred by different ORs. Moreover, the odorants can be agonist (activators) or antagonist (mhibitors) as a function of the ORs This makes the coding of the odors even more complex and can be the cause of interactions between odors (examples: masking, synergy, Ishii et al. 2008) observed when the odorants are in a mix, which constitutes the most frequent case in "daily life" ln this way, it is often difficult to predict the perceived odor of an odorant molecule from its structure alone. However, the detection of the odorants by the ORs constitutes the starting point of the cerebral construction that results in the conscious perception of what wc call "odor". Because of this, it is possible to make the hypothesis of a link between the structure of the odorant molecules, their level of interaction with the ORs and the quality of the odor that they generate. The purpose of our study was to test this hypothesisLorsqu'une molécule interagit avec le système sensoriel olfactif, celui-ci procède à l'encodage des caractéristiques. Le traitement de cette information donne naissance à une construction cérébrale : « l'odeur ». LA PERCEPTION de milliers de molécules odorantes par quelques centaines de récepteurs olfactifs (ROs) humains résulte d un codage combinatoire un RO peut reconnaître plusieurs molécules odorantes et une molécule odorante peut être détectée par différents ROs En outre, les odorants peuvent être des agonistes (activateurs) ou des antagonistes (inhibiteurs) en fonction es ROs Ceci complexifie encore le codage des odeurs et peut être a l'origine des interactions entre odeurs (ex masquage, synergie, Ishii et al 2008) observées lorsque les odorants sont en mélange, ce qui constitue le cas le plus fréquent dans la « vie quotidienne » Ainsi, il est souvent difficile de prédire l'odeur perçue d'une molécule odorante a partir de sa seule structure. Cependant la détection des odorants par les ROs constitue le point de départ de la construction cérébrale qui aboutit a la perception consciente de ce que l'on nomme « odeur » De ce fait, il est possible de poser l'hypothèse d'un lien entre la structure des molécules odorantes, leur niveau d'interaction avec les ROs et la qualité de l'odeur qu'elles génèrent. Notre étude avait pour but de tester cette hypothès

Perturbation of astroglial Slc38 glutamine transporters by NH4 + contributes to neurophysiologic manifestations in acute liver failure

Ammonia is considered the main pathogenic toxin in hepatic encephalopathy (HE). However, the molecular mechanisms involved have been disputed. As altered glutamatergic and GABAergic neurotransmission has been reported in HE, we investigated whether four members of the solute carrier 38 (Slc38) family of amino acid transporters—involved in the replenishment of glutamate and GABA—contribute to ammonia neurotoxicity in HE. We show that ammonium ion exerts multiple actions on the Slc38 transporters: It competes with glutamine for the binding to the system N transporters Slc38a3 and Slc38a5, consequently inhibiting bidirectional astroglial glutamine transport. It also competes with H+, Na+, and K+ for uncoupled permeation through the same transporters, which may perturb astroglial intracellular pH, membrane potential, and K+-buffering. Knockdown of Slc38a3 in mice results in cerebral cortical edema and disrupted neurotransmitter synthesis mimicking events contributing to HE development. Finally, in a mouse model of acute liver failure (ALF), we demonstrate the downregulation of Slc38a3 protein, impeded astroglial glutamine release, and cytotoxic edema. Altogether, we demonstrate contribution of Slc38 transporters to the ammonia-induced impairment of glutamine recycling between astrocytes and neurons, a phenomenon underlying acute ammonia neurotoxicity in the setting of ALF

Perturbation of astroglial Slc38 glutamine transporters by NH4 + contributes to neurophysiologic manifestations in acute liver failure

Ammonia is considered the main pathogenic toxin in hepatic encephalopathy (HE). However, the molecular mechanisms involved have been disputed. As altered glutamatergic and GABAergic neurotransmission has been reported in HE, we investigated whether four members of the solute carrier 38 (Slc38) family of amino acid transporters—involved in the replenishment of glutamate and GABA—contribute to ammonia neurotoxicity in HE. We show that ammonium ion exerts multiple actions on the Slc38 transporters: It competes with glutamine for the binding to the system N transporters Slc38a3 and Slc38a5, consequently inhibiting bidirectional astroglial glutamine transport. It also competes with H+, Na+, and K+ for uncoupled permeation through the same transporters, which may perturb astroglial intracellular pH, membrane potential, and K+-buffering. Knockdown of Slc38a3 in mice results in cerebral cortical edema and disrupted neurotransmitter synthesis mimicking events contributing to HE development. Finally, in a mouse model of acute liver failure (ALF), we demonstrate the downregulation of Slc38a3 protein, impeded astroglial glutamine release, and cytotoxic edema. Altogether, we demonstrate contribution of Slc38 transporters to the ammonia-induced impairment of glutamine recycling between astrocytes and neurons, a phenomenon underlying acute ammonia neurotoxicity in the setting of ALF

An olfactory receptor detects waxy, fatty and rose odors

An olfactory receptor detects waxy, fatty and rose odors. Salon Européen de la Recherche et de l’Innovatio

A human olfactory receptor for waxy, fatty and rose odors

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