Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).
one when she can legally terminate the entire pregnancy. There are, however, grounds for caution if there is a lasting effect on the surviving twin. Through the Lone Twin Network, the Multiple Births Foundation meets a large number of adults whose twin died at or before birth and who feel the loss profoundly. How far this self selected group is representative is not known. Research on the long term psychological sequelae, including their prevalence and relative seriousness, is therefore badly needed.
Despite evidence that intensive rehabilitation speeds recovery from acute illness, several studies on British rehabilitation units have shown that the time spent by patients in therapeutic activities is low and that levels of 'engagement' are poor. We carried out an observational study of patient activity on four rehabilitation wards for the elderly (51 patients observed at half-hourly intervals between 8 a.m. and 5 p.m. on five successive days). Patients were found to be engaged in therapeutically useful activities at only 17% of the observation points. When time spent in the therapy departments (where activities were not monitored) was excluded the proportion of useful activities fell to 11%. Similar patterns of activity were seen in all patient subgroups. An intervention scheme was therefore devised, whereby an hourly activities programme tailored to the needs of each patient was worked out by therapists and ward staff, to be supervised by nurses. One nurse also organized regular group activities. The intervention programme, which required no extra resources, was instituted on two of the four wards. A repeat survey conducted two months later showed a 55% increase in the proportion of time spent in useful activities on the two intervention wards but no change on the other two wards.
This is a fascinating study of religious culture in England from 1050 to 1250. Drawing on the wealth of material about religious belief and practice that survives in the chronicles, Carl Watkins explores the accounts of signs, prophecies, astrology, magic, beliefs about death, and the miraculous and demonic. He challenges some of the prevailing assumptions about religious belief, questioning in particular the attachment of many historians to terms such as 'clerical' and 'lay', 'popular' and 'elite', 'Christian' and 'pagan' as explanatory categories. The evidence of the chronicles is also set in its broader context through explorations of miracle collections, penitential manuals, exempla and sermons. The book traces shifts in the way the supernatural was conceptualized by learned writers and the ways in which broader patterns of belief evolved during this period. This original account sheds important light on belief during a period in which the religious landscape was transformed.
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