48 research outputs found
Measurement of the branching fraction and angular amplitudes
A search for the decay with is performed with 0.37 fb of collisions at
= 7 TeV collected by the LHCb experiment, finding a \Bs \to J\psi
K^-\pi^+ peak of signal events. The mass spectrum of
the candidates in the peak is dominated by the contribution.
Subtracting the non-resonant component, the branching fraction of
\BsJpsiKst is , where the first
uncertainty is statistical and the second systematic. A fit to the angular
distribution of the decay products yields the \Kst polarization fractions and
Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial
Background:
Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke.
Methods:
We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30â50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515.
Findings:
Patients were screened between July 1, 2015, and Nov 24, 2016. 10â793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68â0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group.
Interpretation:
In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes.
Funding:
GlaxoSmithKline
Finishing the euchromatic sequence of the human genome
The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers âŒ99% of the euchromatic genome and is accurate to an error rate of âŒ1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead
Common breast cancer susceptibility alleles are associated with tumor subtypes in BRCA1 and BRCA2 mutation carriers : results from the Consortium of Investigators of Modifiers of BRCA1/2.
Abstract
Introduction
Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour.
Methods
We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach.
Results
The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 × 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status.
Conclusions
The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers
Socializing One Health: an innovative strategy to investigate social and behavioral risks of emerging viral threats
In an effort to strengthen global capacity to prevent, detect, and control infectious diseases in animals and people, the United States Agency for International Developmentâs (USAID) Emerging Pandemic Threats (EPT) PREDICT project funded development of regional, national, and local One Health capacities for early disease detection, rapid response, disease control, and risk reduction. From the outset, the EPT approach was inclusive of social science research methods designed to understand the contexts and behaviors of communities living and working at human-animal-environment interfaces considered high-risk for virus emergence. Using qualitative and quantitative approaches, PREDICT behavioral research aimed to identify and assess a range of socio-cultural behaviors that could be influential in zoonotic disease emergence, amplification, and transmission. This broad approach to behavioral risk characterization enabled us to identify and characterize human activities that could be linked to the transmission dynamics of new and emerging viruses. This paper provides a discussion of implementation of a social science approach within a zoonotic surveillance framework. We conducted in-depth ethnographic interviews and focus groups to better understand the individual- and community-level knowledge, attitudes, and practices that potentially put participants at risk for zoonotic disease transmission from the animals they live and work with, across 6 interface domains. When we asked highly-exposed individuals (ie. bushmeat hunters, wildlife or guano farmers) about the risk they perceived in their occupational activities, most did not perceive it to be risky, whether because it was normalized by years (or generations) of doing such an activity, or due to lack of information about potential risks. Integrating the social sciences allows investigations of the specific human activities that are hypothesized to drive disease emergence, amplification, and transmission, in order to better substantiate behavioral disease drivers, along with the social dimensions of infection and transmission dynamics. Understanding these dynamics is critical to achieving health security--the protection from threats to health-- which requires investments in both collective and individual health security. Involving behavioral sciences into zoonotic disease surveillance allowed us to push toward fuller community integration and engagement and toward dialogue and implementation of recommendations for disease prevention and improved health security
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Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990â2021: a systematic analysis for the Global Burden of Disease Study 2021
BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56â604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100â000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100â000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100â000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100â000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100â000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation
Le sufentanil modifie lâactivitĂ© antibactĂ©rienne de la bupivacaĂŻne et de la ropivacaĂŻne
Avis de l'Anses relatif Ă des nouveaux cas dâintoxications Ă la vitamine D chez des nourrissonspar mĂ©susage de complĂ©ments alimentaires
Citation suggĂ©rĂ©e : Anses. 2023. Avis de lâAnses relatif à « des intoxications Ă la vitamine D chez des nourrissons par mĂ©susage de complĂ©ments alimentaires » (saisine 2022-VIG-0166). Maisons-Alfort: Anses, 13 pDans le cadre de son dispositif de nutrivigilance crĂ©Ă© en 2009 et depuis la publication de sonavis du 28 juillet 2021 relatif Ă trois cas de signalements dâeffets indĂ©sirables sĂ©vĂšresa chezdes nourrissons Ă la suite du mĂ©susage de complĂ©ments alimentaires contenant de lavitamine Db (Anses 2021b), lâAnses a reçu trois nouveaux signalements dâeffets indĂ©sirablessĂ©vĂšres (sĂ©vĂ©ritĂ© de niveau 3, dont deux cas avec menace du pronostic vital) chez desnourrissons susceptibles dâĂȘtre liĂ©s au mĂ©susage de complĂ©ments alimentaires achetĂ©s surinternet contenant 5 000 UI et 10 000 UI par goutte de vitamine D. Ces trois cas, enregistrĂ©sdans la base de donnĂ©es de nutrivigilance sous les numĂ©ros 2022-140, 2022-335 et 2022-380ont Ă©tĂ© jugĂ©s dâimputabilitĂ© trĂšs vraisemblable.En raison de la sĂ©vĂ©ritĂ© des effets indĂ©sirables rapportĂ©s (hypercalcĂ©mies sĂ©vĂšres associĂ©esĂ une nĂ©phrocalcinose, anorexie, hypokaliĂ©mie, trouble de la repolarisation cardiaque),lâAnses sâest Ă nouveau autosaisie le 21 septembre 2022, estimant nĂ©cessaire de porter cescas de mĂ©susage Ă la connaissance du public, des metteurs en marchĂ© et des professionnelsde santĂ©, dans un but dâamĂ©lioration de la sĂ©curitĂ© sanitaire du consommateur
Avis de l'Anses relatif Ă des nouveaux cas dâintoxications Ă la vitamine D chez des nourrissonspar mĂ©susage de complĂ©ments alimentaires
Citation suggĂ©rĂ©e : Anses. 2023. Avis de lâAnses relatif à « des intoxications Ă la vitamine D chez des nourrissons par mĂ©susage de complĂ©ments alimentaires » (saisine 2022-VIG-0166). Maisons-Alfort: Anses, 13 pDans le cadre de son dispositif de nutrivigilance crĂ©Ă© en 2009 et depuis la publication de sonavis du 28 juillet 2021 relatif Ă trois cas de signalements dâeffets indĂ©sirables sĂ©vĂšresa chezdes nourrissons Ă la suite du mĂ©susage de complĂ©ments alimentaires contenant de lavitamine Db (Anses 2021b), lâAnses a reçu trois nouveaux signalements dâeffets indĂ©sirablessĂ©vĂšres (sĂ©vĂ©ritĂ© de niveau 3, dont deux cas avec menace du pronostic vital) chez desnourrissons susceptibles dâĂȘtre liĂ©s au mĂ©susage de complĂ©ments alimentaires achetĂ©s surinternet contenant 5 000 UI et 10 000 UI par goutte de vitamine D. Ces trois cas, enregistrĂ©sdans la base de donnĂ©es de nutrivigilance sous les numĂ©ros 2022-140, 2022-335 et 2022-380ont Ă©tĂ© jugĂ©s dâimputabilitĂ© trĂšs vraisemblable.En raison de la sĂ©vĂ©ritĂ© des effets indĂ©sirables rapportĂ©s (hypercalcĂ©mies sĂ©vĂšres associĂ©esĂ une nĂ©phrocalcinose, anorexie, hypokaliĂ©mie, trouble de la repolarisation cardiaque),lâAnses sâest Ă nouveau autosaisie le 21 septembre 2022, estimant nĂ©cessaire de porter cescas de mĂ©susage Ă la connaissance du public, des metteurs en marchĂ© et des professionnelsde santĂ©, dans un but dâamĂ©lioration de la sĂ©curitĂ© sanitaire du consommateur
Avis de l'Anses relatif à l'actualisation de la méthode d'imputabilité des signalements d'effets indésirables de nutrivigilance
A lâinstar des autres systĂšmes de vigilance français et compte tenu de lâimportance des consĂ©quences en matiĂšre de santĂ© et des dĂ©cisions industrielles qui en dĂ©coulent, lâanalyse de la relation de causalitĂ© entre un produit visĂ© par le dispositif national de nutrivigilance et lâeffetindĂ©sirable dĂ©clarĂ© doit ĂȘtre rĂ©alisĂ©e avec une mĂ©thode dâanalyse appropriĂ©e et objective. Cette mĂ©thode dite « mĂ©thode dâimputabilitĂ© de nutrivigilance » estime le degrĂ© de causalitĂ©, dâun ou de plusieurs produits dans la survenue de lâeffet indĂ©sirable dĂ©clarĂ©, de maniĂšre standardisĂ©e, permettant dâĂ©liminer les divergences dâopinion pouvant exister entre plusieurs observateurs. De telles mĂ©thodes sont couramment mises en oeuvre en France pour les mĂ©dicaments (Arimone et al. 2011, BĂ©gaud et al. 1985, Montastruc et al. 2005), les produits cosmĂ©tiques (Afssaps 2009) ou les xĂ©nobiotiques en cas dâintoxication (CCTv 2015). En raison de diffĂ©rences notables avec les mĂ©dicaments (absence de bĂ©nĂ©fice dĂ©montrĂ© et dâĂ©tude dâinnocuitĂ©), lâAnses sâĂ©tait auto-saisie le 25 aoĂ»t 2010 pour construire une mĂ©thode dâimputabilitĂ© spĂ©cifique aux signalements dâeffets indĂ©sirables susceptibles dâĂȘtre liĂ©s Ă la consommation de produits concernĂ©s par le dispositif national de nutrivigilance. Cette mĂ©thode dâimputabilitĂ© a Ă©tĂ© publiĂ©e le 11 mai 2011 (Anses 2011).Depuis 2011, cette mĂ©thode a Ă©tĂ© complĂ©tĂ©e et prĂ©cisĂ©e au fur et Ă mesure de son application par le groupe de travail « Nutrivigilance ». Ces prĂ©cisions ont Ă©tĂ© enregistrĂ©es dans un « manuel de dĂ©cisions » non publiĂ©. Dans ce contexte, lâAnses sâest auto-saisie le 12 fĂ©vrier 2018 afin dâactualiser la mĂ©thode dâimputabilitĂ© des signalements dâeffets indĂ©sirables de nutrivigilance en prenant en compte les Ă©volutions proposĂ©es par le groupe de travail depuis 2011