Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Expression of vitamin D receptors and matrix metalloproteinases in osteoarthritic cartilage and human articular chondrocytes in vitro

AbstractObjectives To examine the in situ distributions of vitamin D receptors (VDR) and matrix metalloproteinases (MMPs) in osteoarthritic cartilage for comparison with non-arthritic, normal cartilage; and to assess the in vitro effects of 1α,25 dihydroxyvitaminD3(1α,25(OH)2D3) on MMPs-1, -3 and -9 and prostaglandin E2(PGE2) production by cultures of human articular chondrocytes (HAC) shown to be VDR-positive.Methods Using immunohistochemistry VDR expression in different specimens of osteoarthritic cartilage (N=11) was compared to that in normal cartilage (N=6), along with the immunodetection of MMPs-1, -3 and -9. The effects of 1α25(OH)2D3on MMP and PGE2production by HAC in vitro, with and without stimulation by TNFα or phorbol myristate acetate (PMA), was evaluated using ELISA methodology.Results VDR was demonstrated in HAC of all specimens of osteoarthritic cartilage, especially the superficial zone, whereas only two of five normal cartilage specimens were VDR+for a minor proportion of HAC. Immunolocalization of MMPs-1, -3 and -9 was often seen in areas where chondrocytes were VDR+, and dual immunolocalization has demonstrated individual chondrocytes positive for both VDR and MMP-3 in situ. In vitro, 1α25(OH)2D3alone had no effect on MMP-1, -9 and PGE2production by HAC, but MMP-3 production was up-regulated by 1α25(OH)2D3either with or without stimulation with TNFα or PMA. By contrast the increased production of MMP-9 and PGE2induced by PMA was significantly suppressed by concomitant treatment with 1α25(OH)2D3.Conclusions The demonstration of VDR expression by HAC in osteoarthritic cartilage was often associated with sites where MMP expression was prevalent, observations in contrast to their virtual absence in normal age-matched cartilage. Together with HAC in vitro studies, the data suggests that 1α25(OH)2D3contributes to the regulation of MMP and PGE2production by HAC in osteoarthritic cartilage

HIV in practice: current approaches and challenges in the diagnosis, treatment and management of HIV infection in Australia

As treatment improves, people living with HIV (PLWHIV) can now expect to live longer, which means that the foci of HIV-related care for them and their medical practitioners continue to change. With an increasingly older cohort of patients with HIV infection, practitioners’ key considerations are shifting from issues of acute treatment and patient survival to multiple comorbidities, toxicities associated with chronic therapy, and ongoing health maintenance. Within this context, this paper explores the current standard of practice for the management of HIV infection in Australia. We surveyed 56 Australian practitioners currently involved in managing HIV infection: ‘HIV section 100’ (HIV therapy-prescribing) general practitioners (s100 GPs; n = 26), sexual health physicians (SHPs; n = 24) and hospital-based physicians (HBPs; n = 6). Survey results for practice approaches and challenges were broadly consistent across the three practitioner specialties, apart from a few key areas. s100 GPs reported less prophylaxis use among patients whom they deemed at risk of HIV infection in comparison with SHPs, which may reflect differences in patient populations. Further, a higher proportion of s100 GPs nominated older HIV treatment regimens as their preferred therapy choices compared with the other specialties. In contrast with SHPs, s100 GPs were less likely to switch HIV therapies to simplify the treatment protocol, and to immediately initiate treatment upon patient request in those newly diagnosed with HIV infection. Considerably lower levels of satisfaction with current HIV practice guidelines were also reported by s100 GPs. It appears that greater support for s100 GPs may be needed to address these identified challenges and enhance approaches to HIV practice. Across all specialties, increasing access to mental health services for patients with HIV infection was reported as a key management issue. A renewed focus on providing improved mental health and wellbeing supports is recommended, particularly in the face of an ageing HIV-infected population