Sex-Specific Clinical Outcomes of the PACT-HF Randomized Trial

BACKGROUND: Transitional care may have different effects in males and females hospitalized for heart failure. We assessed the sex-specific effects of a transitional care model on clinical outcomes following hospitalization for heart failure. METHODS: In this stepped-wedge cluster randomized trial of adults hospitalized for heart failure in Ontario, Canada, 10 hospitals were randomized to a group of transitional care services or usual care. Outcomes in this exploratory analysis were composite all-cause readmission, emergency department visit, or death at 6 months; and composite all-cause readmission or emergency department visit at 6 months. Models were adjusted for stepped-wedge design and patient age. RESULTS: Among 2494 adults, mean (SD) age was 77.7 (12.1) years, and 1258 (50.4%) were female. The first composite outcome occurred in 371 (66.3%) versus 433 (64.1%) males (hazard ratio [HR], 1.04 [95% CI, 0.86-1.26]; P=0.67) and in 326 (59.9%) versus 463 (64.8%) females (HR, 0.83 [95% CI, 0.69-1.01]; P=0.06) in the intervention and usual care groups, respectively (P=0.012 for sex interaction). The second composite outcome occurred in 357 (63.8%) versus 417 (61.7%) males (HR, 1.03 [95% CI, 0.85-1.24]; P=0.76) and 314 (57.7%) versus 450 (63.0%) females (HR, 0.81 [95% CI, 0.67-0.99]; P=0.037) in the intervention and usual care groups, respectively (P=0.024 for sex interaction). The sex differences were driven by a reduction in all-cause emergency department visits among females (HR, 0.66 [95% CI, 0.51-0.87]; P=0.003), but not males (HR, 1.10 [95% CI, 0.85-1.43]; P=0.46), receiving the intervention (P<0.001 for sex interaction). CONCLUSIONS: A transitional care model offered a reduction in all-cause emergency department visits among females but not males following hospitalization for heart failure. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02112227

Dynamics of earthquake nucleation process represented by the Burridge-Knopoff model

Dynamics of earthquake nucleation process is studied on the basis of the one-dimensional Burridge-Knopoff (BK) model obeying the rate- and state-dependent friction (RSF) law. We investigate the properties of the model at each stage of the nucleation process, including the quasi-static initial phase, the unstable acceleration phase and the high-speed rupture phase or a mainshock. Two kinds of nucleation lengths L_sc and L_c are identified and investigated. The nucleation length L_sc and the initial phase exist only for a weak frictional instability regime, while the nucleation length L_c and the acceleration phase exist for both weak and strong instability regimes. Both L_sc and L_c are found to be determined by the model parameters, the frictional weakening parameter and the elastic stiffness parameter, hardly dependent on the size of an ensuing mainshock. The sliding velocity is extremely slow in the initial phase up to L_sc, of order the pulling speed of the plate, while it reaches a detectable level at a certain stage of the acceleration phase. The continuum limits of the results are discussed. The continuum limit of the BK model lies in the weak frictional instability regime so that a mature homogeneous fault under the RSF law always accompanies the quasi-static nucleation process. Duration times of each stage of the nucleation process are examined. The relation to the elastic continuum model and implications to real seismicity are discussed.Comment: Title changed. Changes mainly in abstract and in section 1. To appear in European Physical Journal

Sex differences in the clinical presentation and natural history of dilated cardiomyopathy

Background Biological sex has a diverse impact on the cardiovascular system. Its influence on dilated cardiomyopathy (DCM) remains unresolved. Objectives This study aims to investigate sex-specific differences in DCM presentation, natural history, and prognostic factors. Methods We conducted a prospective observational cohort study of DCM patients assessing baseline characteristics, cardiac magnetic resonance imaging, biomarkers, and genotype. The composite outcome was cardiovascular mortality or major heart failure (HF) events. Results Overall, 206 females and 398 males with DCM were followed for a median of 3.9 years. At baseline, female patients had higher left ventricular ejection fraction, smaller left ventricular volumes, less prevalent mid-wall myocardial fibrosis (23% vs 42%), and lower high-sensitivity cardiac troponin I than males (all P &lt; 0.05) with no difference in time from diagnosis, age at enrollment, N-terminal pro-B-type natriuretic peptide levels, pathogenic DCM genetic variants, myocardial fibrosis extent, or medications used for HF. Despite a more favorable profile, the risk of the primary outcome at 2 years was higher in females than males (8.6% vs 4.4%, adjusted HR: 3.14; 95% CI: 1.55-6.35; P = 0.001). Between 2 and 5 years, the effect of sex as a prognostic modifier attenuated. Age, mid-wall myocardial fibrosis, left ventricular ejection fraction, left atrial volume, N-terminal pro-B-type natriuretic peptide, high-sensitivity cardiac troponin I, left bundle branch block, and NYHA functional class were not sex-specific prognostic factors. Conclusions We identify a novel paradox in prognosis for females with DCM. Female DCM patients have a paradoxical early increase in major HF events despite less prevalent myocardial fibrosis and a milder phenotype at presentation. Future studies should interrogate the mechanistic basis for these sex differences

Combined point of care nucleic acid and antibody testing for SARS-CoV-2 following emergence of D614G Spike Variant

Rapid COVID-19 diagnosis in hospital is essential, though complicated by 30-50% of nose/throat swabs being negative by SARS-CoV-2 nucleic acid amplification testing (NAAT). Furthermore, the D614G spike mutant now dominates the pandemic and it is unclear how serological tests designed to detect anti-Spike antibodies perform against this variant. We assess the diagnostic accuracy of combined rapid antibody point of care (POC) and nucleic acid assays for suspected COVID-19 disease due to either wild type or the D614G spike mutant SARS-CoV-2. The overall detection rate for COVID-19 is 79.2% (95CI 57.8-92.9%) by rapid NAAT alone. Combined point of care antibody test and rapid NAAT is not impacted by D614G and results in very high sensitivity for COVID-19 diagnosis with very high specificity

Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes.

Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ2 = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals.JW is supported by a Cancer Research UK Cambridge Cancer Centre Clinical Research Training Fellowship. Funding for the NIHR BioResource – Rare diseases project was provided by the National Institute for Health Research (NIHR, grant number RG65966). ERM acknowledges support from the European Research Council (Advanced Researcher Award), NIHR (Senior Investigator Award and Cambridge NIHR Biomedical Research Centre), Cancer Research UK Cambridge Cancer Centre and Medical Research Council Infrastructure Award. The University of Cambridge has received salary support in respect of EM from the NHS in the East of England through the Clinical Academic Reserve. The views expressed are those of the authors and not necessarily those of the NHS or Department of Health. DGE is an NIHR Senior Investigator and is supported by the all Manchester NIHR Biomedical Research Centre

Genetic Sharing with Cardiovascular Disease Risk Factors and Diabetes Reveals Novel Bone Mineral Density Loci.

Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR < 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity

Rare variants in BNC2 are implicated in autosomal-dominant congenital lower urinary-tract obstruction

Congenital lower urinary-tract obstruction (LUTO) is caused by anatomical blockage of the bladder outflow tract or by functional impairment of urinary voiding. About three out of 10,000 pregnancies are affected. Although several monogenic causes of functional obstruction have been defined, it is unknown whether congenital LUTO caused by anatomical blockage has a monogenic cause. Exome sequencing in a family with four affected individuals with anatomical blockage of the urethra identified a rare nonsense variant (c.2557C>T [p.Arg853(∗)]) in BNC2, encoding basonuclin 2, tracking with LUTO over three generations. Re-sequencing BNC2 in 697 individuals with LUTO revealed three further independent missense variants in three unrelated families. In human and mouse embryogenesis, basonuclin 2 was detected in lower urinary-tract rudiments. In zebrafish embryos, bnc2 was expressed in the pronephric duct and cloaca, analogs of the mammalian lower urinary tract. Experimental knockdown of Bnc2 in zebrafish caused pronephric-outlet obstruction and cloacal dilatation, phenocopying human congenital LUTO. Collectively, these results support the conclusion that variants in BNC2 are strongly implicated in LUTO etiology as a result of anatomical blockage