Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Oligodendrocyte development in the embryonic tuberal hypothalamus and the influence of Ascl1

Abstract Background Although the vast majority of cells in our brains are glia, we are only beginning to understand programs governing their development, especially within the embryonic hypothalamus. In mice, gliogenesis is a protracted process that begins during embryonic stages and continues into the early postnatal period, with glial progenitors first producing oligodendrocyte precursor cells, which then differentiate into pro-oligodendrocytes, pro-myelinating oligodendrocytes, and finally, mature myelinating oligodendrocytes. The exact timing of the transition from neurogenesis to gliogenesis and the subsequent differentiation of glial lineages remains unknown for most of the Central Nervous System (CNS), and is especially true for the hypothalamus. Methods Here we used mouse embryonic brain samples to determine the onset of gliogenesis and expansion of glial populations in the tuberal hypothalamus using glial markers Sox9, Sox10, Olig2, PdgfRα, Aldh1L1, and MBP. We further employed Ascl1 and Neurog2 mutant mice to probe the influence of these proneural genes on developing embryonic gliogenic populations. Results Using marker analyses for glial precursors, we found that gliogenesis commences just prior to E13.5 in the tuberal hypothalamus, beginning with the detection of glioblast and oligodendrocyte precursor cell markers in a restricted domain adjacent to the third ventricle. Sox9+ and Olig2+ glioblasts are also observed in the mantle region from E13.5 onwards, many of which are Ki67+ proliferating cells, and peaks at E17.5. Using Ascl1 and Neurog2 mutant mice to investigate the influence of these bHLH transcription factors on the progression of gliogenesis in the tuberal hypothalamus, we found that the elimination of Ascl1 resulted in an increase in oligodendrocyte cells throughout the expansive period of oligodendrogenesis. Conclusion Our results are the first to define the timing of gliogenesis in the tuberal hypothalamus and indicate that Ascl1 is required to repress oligodendrocyte differentiation within this brain region

The ACCELERATE Plus (assessment and communication excellence for safe patient outcomes) Trial Protocol: a stepped-wedge cluster randomised trial, cost-benefit analysis, and process evaluation

Abstract Background Nurses play an essential role in patient safety. Inadequate nursing physical assessment and communication in handover practices are associated with increased patient deterioration, falls and pressure injuries. Despite internationally implemented rapid response systems, falls and pressure injury reduction strategies, and recommendations to conduct clinical handovers at patients’ bedside, adverse events persist. This trial aims to evaluate the effectiveness, implementation, and cost–benefit of an externally facilitated, nurse-led intervention delivered at the ward level for core physical assessment, structured patient-centred bedside handover and improved multidisciplinary communication. We hypothesise the trial will reduce medical emergency team calls, unplanned intensive care unit admissions, falls and pressure injuries. Methods A stepped-wedge cluster randomised trial will be conducted over 52 weeks. The intervention consists of a nursing core physical assessment, structured patient-centred bedside handover and improved multidisciplinary communication and will be implemented in 24 wards across eight hospitals. The intervention will use theoretically informed implementation strategies for changing clinician behaviour, consisting of: nursing executive site engagement; a train-the-trainer model for cascading facilitation; embedded site leads; nursing unit manager leadership training; nursing and medical ward-level clinical champions; ward nurses’ education workshops; intervention tailoring; and reminders. The primary outcome will be a composite measure of medical emergency team calls (rapid response calls and ‘Code Blue’ calls), unplanned intensive care unit admissions, in-hospital falls and hospital-acquired pressure injuries; these measures individually will also form secondary outcomes. Other secondary outcomes are: i) patient-reported experience measures of receiving safe and patient-centred care, ii) nurses’ perceptions of barriers to physical assessment, readiness to change, and staff engagement, and iii) nurses’ and medical officers’ perceptions of safety culture and interprofessional collaboration. Primary outcome data will be collected for the trial duration, and secondary outcome surveys will be collected prior to each step and at trial conclusion. A cost–benefit analysis and post-trial process evaluation will also be undertaken. Discussion If effective, this intervention has the potential to improve nursing care, reduce patient harm and improve patient outcomes. The evidence-based implementation strategy has been designed to be embedded within existing hospital workforces; if cost-effective, it will be readily translatable to other hospitals nationally. Trial registration Australian New Zealand Clinical Trials Registry ID: ACTRN12622000155796. Date registered: 31/01/2022

Cognitive and psychiatric symptom trajectories 2–3 years after hospital admission for COVID-19: a longitudinal, prospective cohort study in the UK

Background: COVID-19 is known to be associated with increased risks of cognitive and psychiatric outcomes after the acute phase of disease. We aimed to assess whether these symptoms can emerge or persist more than 1 year after hospitalisation for COVID-19, to identify which early aspects of COVID-19 illness predict longer-term symptoms, and to establish how these symptoms relate to occupational functioning. Methods: The Post-hospitalisation COVID-19 study (PHOSP-COVID) is a prospective, longitudinal cohort study of adults (aged ≥18 years) who were hospitalised with a clinical diagnosis of COVID-19 at participating National Health Service hospitals across the UK. In the C-Fog study, a subset of PHOSP-COVID participants who consented to be recontacted for other research were invited to complete a computerised cognitive assessment and clinical scales between 2 years and 3 years after hospital admission. Participants completed eight cognitive tasks, covering eight cognitive domains, from the Cognitron battery, in addition to the 9-item Patient Health Questionnaire for depression, the Generalised Anxiety Disorder 7-item scale, the Functional Assessment of Chronic Illness Therapy Fatigue Scale, and the 20-item Cognitive Change Index (CCI-20) questionnaire to assess subjective cognitive decline. We evaluated how the absolute risks of symptoms evolved between follow-ups at 6 months, 12 months, and 2–3 years, and whether symptoms at 2–3 years were predicted by earlier aspects of COVID-19 illness. Participants completed an occupation change questionnaire to establish whether their occupation or working status had changed and, if so, why. We assessed which symptoms at 2–3 years were associated with occupation change. People with lived experience were involved in the study. Findings: 2469 PHOSP-COVID participants were invited to participate in the C-Fog study, and 475 participants (191 [40·2%] females and 284 [59·8%] males; mean age 58·26 [SD 11·13] years) who were discharged from one of 83 hospitals provided data at the 2–3-year follow-up. Participants had worse cognitive scores than would be expected on the basis of their sociodemographic characteristics across all cognitive domains tested (average score 0·71 SD below the mean [IQR 0·16–1·04]; p<0·0001). Most participants reported at least mild depression (263 [74·5%] of 353), anxiety (189 [53·5%] of 353), fatigue (220 [62·3%] of 353), or subjective cognitive decline (184 [52·1%] of 353), and more than a fifth reported severe depression (79 [22·4%] of 353), fatigue (87 [24·6%] of 353), or subjective cognitive decline (88 [24·9%] of 353). Depression, anxiety, and fatigue were worse at 2–3 years than at 6 months or 12 months, with evidence of both worsening of existing symptoms and emergence of new symptoms. Symptoms at 2–3 years were not predicted by the severity of acute COVID-19 illness, but were strongly predicted by the degree of recovery at 6 months (explaining 35·0–48·8% of the variance in anxiety, depression, fatigue, and subjective cognitive decline); by a biocognitive profile linking acutely raised D-dimer relative to C-reactive protein with subjective cognitive deficits at 6 months (explaining 7·0–17·2% of the variance in anxiety, depression, fatigue, and subjective cognitive decline); and by anxiety, depression, fatigue, and subjective cognitive deficit at 6 months. Objective cognitive deficits at 2–3 years were not predicted by any of the factors tested, except for cognitive deficits at 6 months, explaining 10·6% of their variance. 95 of 353 participants (26·9% [95% CI 22·6–31·8]) reported occupational change, with poor health being the most common reason for this change. Occupation change was strongly and specifically associated with objective cognitive deficits (odds ratio [OR] 1·51 [95% CI 1·04–2·22] for every SD decrease in overall cognitive score) and subjective cognitive decline (OR 1·54 [1·21–1·98] for every point increase in CCI-20). Interpretation: Psychiatric and cognitive symptoms appear to increase over the first 2–3 years post-hospitalisation due to both worsening of symptoms already present at 6 months and emergence of new symptoms. New symptoms occur mostly in people with other symptoms already present at 6 months. Early identification and management of symptoms might therefore be an effective strategy to prevent later onset of a complex syndrome. Occupation change is common and associated mainly with objective and subjective cognitive deficits. Interventions to promote cognitive recovery or to prevent cognitive decline are therefore needed to limit the functional and economic impacts of COVID-19. Funding: National Institute for Health and Care Research Oxford Health Biomedical Research Centre, Wolfson Foundation, MQ Mental Health Research, MRC-UK Research and Innovation, and National Institute for Health and Care Research.</p