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).
Subarachnoid cisterns and their contents are described briefly in the light of observations made during microsurgical explorations. The concept of intracranial surgery in terms of moving from one cistern to another is presented here with particular emphasis on the cisterns in surgical approaches to intracranial vessels and nerves for the treatment of aneurysms, arteriovenous malformations, and for surgery of basal tumors.
Studies in adults show that pretreatment with an optimal emollient may improve transmission of ultraviolet-B. In our study, we evaluated whether the preirradiation use of mineral oil enhanced the efficacy of narrow-band ultraviolet-B phototherapy in childhood psoriasis. Twenty children, aged 5 to 14 years with widespread, symmetrical psoriasis involving >20% body surface area were enrolled in a prospective, single-blind, controlled study. Mineral oil was applied prior to irradiation over one half of the body and the other half was emollient-free control. Narrow-band ultraviolet-B phototherapy was administered to whole body twice a week on nonconsecutive days with initial dose of 50 mJ/cm(2) and increment of 10% at each session. Clinical response was evaluated as grades of erythema, scaling and induration, area of involvement and modified psoriasis area severity index score on each side at baseline, 3, 6, 9, and 12 weeks. Two patients dropped out, 18 patients completed the study. Significantly greater improvement (p< 0.05) in scaling, induration, area of involvement, and modified psoriasis area severity index score was seen on the mineral oil pretreated side as early as 3 weeks and was maintained throughout the study. Difference in erythema was noticed later at 6 weeks. The cumulative dose for clearance was significantly lower on the emollient pretreated side. No adverse effects were observed with mineral oil or narrow-band ultraviolet-B phototherapy. We conclude that preirradiation use of mineral oil enhances the therapeutic efficacy of narrow-band ultraviolet-B phototherapy in children with widespread psoriasis.
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