Cause of Death and Predictors of All-Cause Mortality in Anticoagulated Patients With Nonvalvular Atrial Fibrillation : Data From ROCKET AF

M. Kaste on työryhmän ROCKET AF Steering Comm jäsen.Background-Atrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all-cause mortality may guide interventions. Methods and Results-In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all-cause mortality in the 14 171 participants in the intention-to-treat population. The median age was 73 years, and the mean CHADS(2) score was 3.5. Over 1.9 years of median follow-up, 1214 (8.6%) patients died. Kaplan-Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all-cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33-1.70, P= 75 years (hazard ratio 1.69, 95% CI 1.51-1.90, P Conclusions-In a large population of patients anticoagulated for nonvalvular atrial fibrillation, approximate to 7 in 10 deaths were cardiovascular, whereasPeer reviewe

Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management. © 2021, The Author(s)

Evidence for deliberate burial of the dead by Homo naledi

In this study, we describe new results of excavations in the Dinaledi Subsystem of the Rising Star cave system, South Africa. In two areas within the Hill Antechamber and the Dinaledi Chamber, this work uncovered concentrations of abundant Homo naledi fossils including articulated, matrix-supported skeletal regions consistent with rapid covering by sediment prior to the decomposition of soft tissue. We additionally re-examine the spatial positioning of skeletal material and associated sediments within the Puzzle Box area, from which abundant H. naledi remains representing a minimum of six individuals were recovered in 2013 and 2014. Multiple lines of evidence exclude the hypothesis that skeletal remains from these three areas come from bodies that decomposed on the floor of the chamber or within a shallow depression prior to burial by sediments. The spatial positioning of skeletal material, the topography of the subsystem, and observations on sediments within and surrounding features exclude the hypothesis that rapid burial by sediment was a result of gravity-driven slumping or spontaneous movement of sediments. We present a minimal hypothesis of hominin cultural burial and test the evidence from all three areas, finding that this hypothesis is most compatible with the pattern of evidence. These results suggest that mortuary behavior, including cultural burial, was part of the repertoire of Homo naledi

Identification of regulatory variants associated with genetic susceptibility to meningococcal disease.

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes

'OLDER' WORKERS: THE NEGOTIATION OF AGE DISCRIMINATION AND IDENTITY IN THE JOB SEARCH PROCESS

Given the aging of the Canadian workforce and the trend for unemployed older workers (aged 45 to 65) to take considerably longer than younger ones to become re-employed, the purpose of this dissertation is to examine the importance of age in the job search process, how age influences identity when searching for work, and the management techniques used by older workers to obtain employment. There is little qualitative research generated in a Canadian context that examines the views of older workers themselves. Thus, this research uses qualitative methodologies (i.e. 30 semi-structured interviews supplemented by 35 hours of participant observation) and an interactionist framework, to contribute new insights into older workers' job search process. Findings indicate that study participants feel employers discriminate against them in the hiring process through both subtle and overt mechanisms related to employers' ageist stereotypes concerning skills, training, adaptability or flexibility, and financial costs. Respondents believe that employers use specific wording in job advertisements, choose candidates to interview by assessing age in applicants' resumes, further assess age in the interview setting, and use an ageist discourse. With respect to the impact of age on identity in the job search process, the ata suggest that once participants perceive they have been labelled "old" by others (i.e. potential employers and personnel at older worker programs) they begin to define themselves as "old" and become susceptible to identity degradation. These findings highlight the paradoxical nature of the job search process-Individuals go to older worker programs for assistance, yet some of the experiences encountered during attendance at these programs mirrored many experiences encountered with discriminatory employers. Despite this occurrence, most who experience identity degradation are able to successfully negotiate their identities by drawing on social support, attending older worker programs, changing their identities, maintaining their key roles, and altering their overall mental outlook. Finally, in an attempt to avoid being considered "old" when searching for work, respondents develop "counteractions" and "concealments". These age-related management techniques are believed to counteract employers' ageist stereotypes by maintaining skills and changing work-related expectations, and conceal age by altering resumes, physical appearance, and language. Overall, this dissertation advances the knowledge within the sociology of aging and work by using the richness of study participants' accounts to conceptualize the meaning and import of age in the job search process. Conclusions are drawn in relation to improving policies and practices that govern employers' behaviours in order to remove the structural barriers from older workers' route to re-employment.Doctor of Philosophy (PhD