Intracranial Aneurysm Classifier Using Phenotypic Factors: An International Pooled Analysis

Intracranial aneurysms (IAs) are usually asymptomatic with a low risk of rupture, but consequences of aneurysmal subarachnoid hemorrhage (aSAH) are severe. Identifying IAs at risk of rupture has important clinical and socio-economic consequences. The goal of this study was to assess the effect of patient and IA characteristics on the likelihood of IA being diagnosed incidentally versus ruptured. Patients were recruited at 21 international centers. Seven phenotypic patient characteristics and three IA characteristics were recorded. The analyzed cohort included 7992 patients. Multivariate analysis demonstrated that: (1) IA location is the strongest factor associated with IA rupture status at diagnosis; (2) Risk factor awareness (hypertension, smoking) increases the likelihood of being diagnosed with unruptured IA; (3) Patients with ruptured IAs in high-risk locations tend to be older, and their IAs are smaller; (4) Smokers with ruptured IAs tend to be younger, and their IAs are larger; (5) Female patients with ruptured IAs tend to be older, and their IAs are smaller; (6) IA size and age at rupture correlate. The assessment of associations regarding patient and IA characteristics with IA rupture allows us to refine IA disease models and provide data to develop risk instruments for clinicians to support personalized decision-making

Understanding the genetic complexity of puberty timing across the allele frequency spectrum

Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease

IMPACT OF NICORANDIL IN ANGINA: SUBGROUP ANALYSES

Aims: IONA (impact of nicorandil in angina) is a randomised, double blind, placebo controlled trial of nicorandil, with a target dose of 20 mg twice daily. The consistency of benefits seen in subgroups is reported. Methods: The primary composite end point of the study was coronary heart disease death, non-fatal myocardial infarction, or unplanned hospitalisation for cardiac chest pain. Subgroups were defined using baseline characteristics including, age, sex, histories of smoking, diabetes, hypertension, myocardial infarction, revascularisation, anginal status, anti-anginal treatment, other cardiovascular drugs, and an overall assessment of risk. Results: A total of 5126 patients were randomised to receive nicorandil or identical placebo in addition to standard anti-anginal treatment. Overall, nicorandil reduced the incidence of the primary end point from 15.5% to 13.1% (hazard ratio (HR) 0.83, 95% confidence interval (CI) 0.72 to 0.97; p = 0.014). There was no evidence of significant heterogeneity of benefit across all subgroups studied. The absolute risk reduction was greatest and the numbers needed to treat to prevent one event was lowest in subjects at greatest risk. Conclusions: The IONA study demonstrates a significant improvement in outcome by nicorandil treatment across a broad range of patients with stable angina

Pyrazinamide Resistance In Multidrug-Resistant Strains of Mycobacterium tuberculosis Isolated in Abkhazia

The emergence of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) strains, i.e. strains resistant at least to isoniazid (INH) and rifampin (RMP), the two most powerful first-line drugs for the treatment of tuberculosis (TB), represents a worldwide health care problem. Patients with MDR strains should receive therapy based on individual drug susceptibility testing (DST), including residual first-line (streptomycin, SM; ethambutol, EMB; and pyrazinamide, PZA) and second-line (ofloxacin, kanamycin, capreomycin, ethionamide, p-aminosalicylic acid, cycloserine) anti-tuberculosis (TB) drugs. MDR TB has been reported as a major problem in former Soviet Union countries . Many TB programs have been described, based on DST for INH, RMP, SM, and EMB and, in some cases, for second- line drugs, but not for PZA. PZA is currently considered the third most important drug in the treatment of TB but it is not routinely tested for DST in most countries due to the requirement for an acid pH of the medium to demonstrate drug activity. PZA testing, when available, has mainly been done with the Wayne method; in later studies, BACTEC testing became more common