A catalog of associations between rare coding variants and COVID-19 outcomes.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease-19 (COVID-19), a respiratory illness that can result in hospitalization or death. We investigated associations between rare genetic variants and seven COVID-19 outcomes in 543,213 individuals, including 8,248 with COVID-19. After accounting for multiple testing, we did not identify any clear associations with rare variants either exome-wide or when specifically focusing on (i) 14 interferon pathway genes in which rare deleterious variants have been reported in severe COVID-19 patients; (ii) 167 genes located in COVID-19 GWAS risk loci; or (iii) 32 additional genes of immunologic relevance and/or therapeutic potential. Our analyses indicate there are no significant associations with rare protein-coding variants with detectable effect sizes at our current sample sizes. Analyses will be updated as additional data become available, with results publicly browsable at https://rgc-covid19.regeneron.com.

Genome-wide analysis in 756,646 individuals provides first genetic evidence that ACE2 expression influences COVID-19 risk and yields genetic risk scores predictive of severe disease.

SARS-CoV-2 enters host cells by binding angiotensin-converting enzyme 2 (ACE2). Through a genome-wide association study, we show that a rare variant (MAF = 0.3%, odds ratio 0.60, P=4.5×10-13) that down-regulates ACE2 expression reduces risk of COVID-19 disease, providing human genetics support for the hypothesis that ACE2 levels influence COVID-19 risk. Further, we show that common genetic variants define a risk score that predicts severe disease among COVID-19 cases.

Online patient safety education programme for junior doctors: is it worthwhile?

BACKGROUND: Increasing demand exists for blended approaches to the development of professionalism. Trainees of the Royal College of Physicians of Ireland participated in an online patient safety programme. AIMS: Study aims were: (1) to determine whether the programme improved junior doctors' knowledge, attitudes and skills relating to error reporting, open communication and care for the second victim and (2) to establish whether the methodology facilitated participants' learning. METHODS: 208 junior doctors who completed the programme completed a pre-online questionnaire. Measures were "patient safety knowledge and attitudes", "medical safety climate" and "experience of learning". Sixty-two completed the post-questionnaire, representing a 30 % matched response rate. RESULTS: Participating in the programme resulted in immediate (p < 0.01) improvement in skills such as knowing when and how to complete incident forms and disclosing errors to patients, in self-rated knowledge (p < 0.01) and attitudes towards error reporting (p < 0.01). Sixty-three per cent disagreed that doctors routinely report medical errors and 42 % disagreed that doctors routinely share information about medical errors and what caused them. Participants rated interactive features as the most positive elements of the programme. CONCLUSIONS: An online training programme on medical error improved self-rated knowledge, attitudes and skills in junior doctors and was deemed an effective learning tool. Perceptions of work issues such as a poor culture of error reporting among doctors may prevent improved attitudes being realised in practice. Online patient safety education has a role in practice-based initiatives aimed at developing professionalism and improving safety.

De novo mutations in schizophrenia implicate chromatin remodeling and support a genetic overlap with autism and intellectual disability.

Schizophrenia is a serious psychiatric disorder with a broadly undiscovered genetic etiology. Recent studies of de novo mutations (DNMs) in schizophrenia and autism have reinforced the hypothesis that rare genetic variation contributes to risk. We carried out exome sequencing on 57 trios with sporadic or familial schizophrenia. In sporadic trios, we observed a ~3.5-fold increase in the proportion of nonsense DNMs (0.101 vs 0.031, empirical P=0.01, Benjamini-Hochberg-corrected P=0.044). These mutations were significantly more likely to occur in genes with highly ranked probabilities of haploinsufficiency (P=0.0029, corrected P=0.006). DNMs of potential functional consequence were also found to occur in genes predicted to be less tolerant to rare variation (P=2.01 × 10(-)(5), corrected P=2.1 × 10(-)(3)). Genes with DNMs overlapped with genes implicated in autism (for example, AUTS2, CHD8 and MECP2) and intellectual disability (for example, HUWE1 and TRAPPC9), supporting a shared genetic etiology between these disorders. Functionally CHD8, MECP2 and HUWE1 converge on epigenetic regulation of transcription suggesting that this may be an important risk mechanism. Our results were consistent in an analysis of additional exome-based sequencing studies of other neurodevelopmental disorders. These findings suggest that perturbations in genes, which function in the epigenetic regulation of brain development and cognition, could have a central role in the susceptibility to, pathogenesis and treatment of mental disorders.

Evaluation of MEDLINE service by user survey.

The use of MEDLINE at the Calder Memorial Library of the University of Miami School of Medicine has grown so substantially over the past one and one-half years that we felt an evaluation of the service was appropriate. A one-page questionnaire was sent to 350 patrons who had requested MEDLINE searches in 1973. The response validated many of our assumptions about the user group and their reasons for using MEDLINE. Most surprising were the degree of enthusiasm, the willingness to pay out of personal funds, the apparent lack of knowledge about SDILINE, and the small number of critical comments. We expect that the experience gained from this assessment will enable us to make improvements in some aspects of our service, as well as to undertake more subject-specific evaluations at shorter intervals in the future.