Thyroid Function Within the Reference Range and the Risk of Stroke: An Individual Participant Data Analysis.

The currently applied reference ranges for thyroid function are under debate. Despite evidence that thyroid function within the reference range is related with several cardiovascular disorders, its association with the risk of stroke has not been evaluated previously. We identified studies through a systematic literature search and the Thyroid Studies Collaboration, a collaboration of prospective cohort studies. Studies measuring baseline TSH, free T4, and stroke outcomes were included, and we collected individual participant data from each study, including thyroid function measurements and incident all stroke (combined fatal and nonfatal) and fatal stroke. The applied reference range for TSH levels was between 0.45 and 4.49 mIU/L. We collected individual participant data on 43 598 adults with TSH within the reference range from 17 cohorts, with a median follow-up of 11.6 years (interquartile range 5.1-13.9), including 449 908 person-years. Age- and sex-adjusted pooled hazard ratio for TSH was 0.78 (95% confidence interval [CI] 0.65-0.95 across the reference range of TSH) for all stroke and 0.83 (95% CI 0.62-1.09) for fatal stroke. For the free T4 analyses, the hazard ratio was 1.08 (95% CI 0.99-1.15 per SD increase) for all stroke and 1.10 (95% CI 1.04-1.19) for fatal stroke. This was independent of cardiovascular risk factors including systolic blood pressure, total cholesterol, smoking, and prevalent diabetes. Higher levels of TSH within the reference range may decrease the risk of stroke, highlighting the need for further research focusing on the clinical consequences associated with differences within the reference range of thyroid function

Twenty-six years of HIV science: an overview of anti-HIV drugs metabolism

From the identification of HIV as the agent causing AIDS, to the development of effective antiretroviral drugs, the scientific achievements in HIV research over the past twenty-six years have been formidable. Currently, there are twenty-five anti-HIV compounds which have been formally approved for clinical use in the treatment of AIDS. These compounds fall into six categories: nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), cell entry inhibitors or fusion inhibitors (FIs), co-receptor inhibitors (CRIs), and integrase inhibitors (INIs). Metabolism by the host organism is one of the most important determinants of the pharmacokinetic profile of a drug. Formation of active or toxic metabolites will also have an impact on the pharmacological and toxicological outcomes. Therefore, it is widely recognized that metabolism studies of a new chemical entity need to be addressed early in the drug discovery process. This paper describes an overview of the metabolism of currently available anti-HIV drugs.Da identificação do HIV como o agente causador da AIDS, ao desenvolvimento de fármacos antirretrovirais eficazes, os avanços científicos na pesquisa sobre o HIV nos últimos vinte e seis anos foram marcantes. Atualmente, existem vinte e cinco fármacos anti-HIV formalmente aprovados pelo FDA para utilização clínica no tratamento da AIDS. Estes compostos são divididos em seis classes: inibidores nucleosídeos de transcriptase reversa (INTR), inibidores nucleotídeos de transcriptase reversa (INtTR), inibidores não-nucleosídeos de transcriptase reversa (INNTR), inibidores de protease (IP), inibidores da entrada celular ou inibidores de fusão (IF), inibidores de co-receptores (ICR) e inibidores de integrase (INI). O metabolismo consiste em um dos maiores determinantes do perfil farmacocinético de um fármaco. A formação de metabólitos ativos ou tóxicos terá impacto nas respostas farmacológicas ou toxicológicas do fármaco. Portanto, é amplamente reconhecido que estudos do metabolismo de uma nova entidade química devem ser realizados durante as fases iniciais do processo de desenvolvimento de fármacos. Este artigo descreve uma abordagem do metabolismo dos fármacos anti-HIV atualmente disponíveis na terapêutica

Serum magnesium and calcium levels in relation to ischemic stroke : Mendelian randomization study

ObjectiveTo determine whether serum magnesium and calcium concentrations are causally associated with ischemic stroke or any of its subtypes using the mendelian randomization approach.MethodsAnalyses were conducted using summary statistics data for 13 single-nucleotide polymorphisms robustly associated with serum magnesium (n = 6) or serum calcium (n = 7) concentrations. The corresponding data for ischemic stroke were obtained from the MEGASTROKE consortium (34,217 cases and 404,630 noncases).ResultsIn standard mendelian randomization analysis, the odds ratios for each 0.1 mmol/L (about 1 SD) increase in genetically predicted serum magnesium concentrations were 0.78 (95% confidence interval [CI] 0.69-0.89; p = 1.3 7 10-4) for all ischemic stroke, 0.63 (95% CI 0.50-0.80; p = 1.6 7 10-4) for cardioembolic stroke, and 0.60 (95% CI 0.44-0.82; p = 0.001) for large artery stroke; there was no association with small vessel stroke (odds ratio 0.90, 95% CI 0.67-1.20; p = 0.46). Only the association with cardioembolic stroke was robust in sensitivity analyses. There was no association of genetically predicted serum calcium concentrations with all ischemic stroke (per 0.5 mg/dL [about 1 SD] increase in serum calcium: odds ratio 1.03, 95% CI 0.88-1.21) or with any subtype.ConclusionsThis study found that genetically higher serum magnesium concentrations are associated with a reduced risk of cardioembolic stroke but found no significant association of genetically higher serum calcium concentrations with any ischemic stroke subtype

Performance of a neutron transport code with full phase space decomposition on the Cray Research T3D

We present performance results obtained on a 128-node Cray Research T3D computer by a neutron transport code implementing a standard mtiltigroup, discrete ordinates algorithm on a three-dimensional Cartesian grid. After summarizing the implementation strategy used to obtain a full decomposition of phase space (i.e., simultaneous parallelization of the neutron energy, directional and spatial variables), we investigate the scalability of the fundamental source iteration step with respect to each phase space variable. We also describe enhancements that have enabled performance rates approaching 10 gigaflops on the full 128-node machine

Identification of Functional Genetic Determinants of Cardiac Troponin T and I in a Multiethnic Population and Causal Associations With Atrial Fibrillation

Background: Elevated cardiac troponin levels in blood are associated with increased risk of cardiovascular diseases and mortality. Cardiac troponin levels are heritable, but their genetic architecture remains elusive. Methods: We conducted a transethnic genome-wide association analysis on high-sensitivity cTnT (cardiac troponin T; hs-cTnT) and high-sensitivity cTnI (cardiac troponin I; hs-cTnI) levels in 24 617 and 14 336 participants free of coronary heart disease and heart failure from 6 population-based cohorts, followed by a series of bioinformatic analyses to decipher the genetic architecture of hs-cTnT and hs-cTnI. Results: We identified 4 genome-wide significant loci for hs-cTnT including a novel locus rs3737882 in PPFIA4 and 3 previously reported loci at NCOA2, TRAM1, and BCL2. One known locus at VCL was replicated for hs-cTnI. One copy of C allele for rs3737882 was associated with a 6% increase in hs-cTnT levels (minor allele frequency, 0.18; P=2.80x10(-9)). We observed pleiotropic loci located at BAG3 and ANO5. The proportions of variances explained by single-nucleotide polymorphisms were 10.15% and 7.74% for hs-cTnT and hs-cTnI, respectively. Single-nucleotide polymorphisms were colocalized with BCL2 expression in heart tissues and hs-cTnT and with ANO5 expression in artery, heart tissues, and whole blood and both troponins. Mendelian randomization analyses showed that genetically increased hs-cTnT and hs-cTnI levels were associated with higher odds of atrial fibrillation (odds ratio, 1.38 [95% CI, 1.25-1.54] for hs-cTnT and 1.21 [95% CI, 1.06-1.37] for hs-cTnI). Conclusions: We identified a novel genetic locus associated with hs-cTnT in a multiethnic population and found that genetically regulated troponin levels were associated with atrial fibrillation.Cardiolog