Canadian COVID-19 host genetics cohort replicates known severity associations.

The HostSeq initiative recruited 10,059 Canadians infected with SARS-CoV-2 between March 2020 and March 2023, obtained clinical information on their disease experience and whole genome sequenced (WGS) their DNA. We analyzed the WGS data for genetic contributors to severe COVID-19 (considering 3,499 hospitalized cases and 4,975 non-hospitalized after quality control). We investigated the evidence for replication of loci reported by the International Host Genetics Initiative (HGI); analyzed the X chromosome; conducted rare variant gene-based analysis and polygenic risk score testing. Population stratification was adjusted for using meta-analysis across ancestry groups. We replicated two loci identified by the HGI for COVID-19 severity: the LZTFL1/SLC6A20 locus on chromosome 3 and the FOXP4 locus on chromosome 6 (the latter with a variant significant at P < 5E-8). We found novel significant associations with MRAS and WDR89 in gene-based analyses, and constructed a polygenic risk score that explained 1.01% of the variance in severe COVID-19. This study provides independent evidence confirming the robustness of previously identified COVID-19 severity loci by the HGI and identifies novel genes for further investigation.

The association between functional social support and memory in middle-aged and older adults: A Prospective Analysis of the Canadian Longitudinal Study on Aging's Comprehensive Cohort.

BACKGROUND: Functional social support (FSS) impacts memory function through biological and psychological pathways. In a national sample of middle-aged and older adults in Canada, we explored the association between FSS and changes in memory over three years and investigated effect modification by age group and sex. METHODS: We analyzed data from the Comprehensive Cohort of the Canadian Longitudinal Study on Aging (CLSA). FSS was measured with the Medical Outcomes Study - Social Support Survey; memory was measured with combined z-scores from immediate and delayed recall administrations of a modified version of the Rey Auditory Verbal Learning Test. We regressed memory change scores over three years on baseline overall FSS and four FSS subtypes in separate multiple linear regression models, controlling for sociodemographic, health, and lifestyle covariates. We also stratified our models by age group and sex. RESULT: We found positive associations between higher FSS and improvement in memory score, although only the tangible FSS subtype (availability of practical assistance) was significantly associated with changes in memory (ß^ = 0.07; 95% confidence interval = 0.01, 0.14). After stratification by age group and sex, this association remained significant for males, although we found no evidence of effect modification. CONCLUSION: In a cognitively healthy sample of middle-aged and older adults, we found a statistically significant and positive association between tangible FSS and memory change over three years of follow-up. We did not find adults with low FSS to be at increased risk of memory decline compared to adults with higher FSS.

Pre- and Post-Operative Rehabilitation Interventions in Patients at Risk of Poor Outcomes Following Knee or Hip Arthroplasty: Protocol for Two Systematic Reviews.

Objective: Total knee (TKA) and hip arthroplasty (THA) are successful procedures in treating end-stage osteoarthritis when nonoperative treatments fail. However, a growing body of literature has been reporting suboptimal outcomes following TKA and THA. While pre- and post-operative rehabilitation is imperative to recovery, little is known about their effectiveness for patients at risk of poor outcomes. In the 2 systematic reviews with identical methodology, we aim to evaluate the effectiveness of (a) pre-operative and (b) post-operative rehabilitation interventions for patients at risk of poor outcomes following TKA and THA. Methods: The 2 systematic reviews will follow the principles and recommendations outlined in the Cochrane Handbook. Only randomized controlled trials (RCTs) and pilot RCTs will be searched in 6 databases: CINAHL, MEDLINE, Embase, Web of Science, Pedro, and OTseeker. Eligible studies including patients at risk of poor outcomes and evaluating rehabilitation interventions following and preceding arthroplasty will be considered for inclusion. Primary outcomes will include performance-based tests and functional patient-reported outcome measures, and secondary outcomes will include health-related quality of life and pain. The quality of eligible RCTs will be evaluated using the Cochrane's risk of bias tool, and the strength of evidence will be assessed using the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE). Discussion: These reviews will synthesize the evidence regarding the effectiveness of pre-and post-operative rehabilitation interventions for patients at risk of poor outcomes, which in turn may inform practitioners and patients in planning and implementing the most optimal rehabilitation programs to achieve the best outcomes after arthroplasty. Systematic Review Registration: PROSPERO CRD42022355574.

Expression of IL-20 Receptor Subunit ß Is Linked to EAE Neuropathology and CNS Neuroinflammation.

Considerable clinical evidence supports that increased blood-brain barrier (BBB) permeability is linked to immune extravasation of CNS parenchyma during neuroinflammation. Although BBB permeability and immune extravasation are known to be provoked by vascular endothelial growth factor-A (i.e., VEGF-A) and C-X-C motif chemokine ligand 12 (CXCL12), respectively, the mechanisms that link both processes are still elusive. The interleukin-20 (i.e., IL-20) cytokine signaling pathway was previously implicated in VEGF-mediated angiogenesis and is known to induce cellular response by way of signaling through IL-20 receptor subunit ß (i.e., IL-20RB). Dysregulated IL-20 signaling is implicated in many inflammatory pathologies, but it's contribution to neuroinflammation has yet to be reported. We hypothesize that the IL-20 cytokine, and the IL cytokine subfamily more broadly, play a key role in CNS neuroinflammation by signaling through IL-20RB, induce VEGF activity, and enhance both BBB-permeability and CXCL12-mediated immune extravasation. To address this hypothesis, we actively immunized IL-20RB-/- mice and wild-type mice to induce experimental autoimmune encephalomyelitis (EAE) and found that IL-20RB-/- mice showed amelioration of disease progression compared to wild-type mice. Similarly, we passively immunized IL-20RB-/- mice and wild-type mice with myelin-reactive Th1 cells from either IL-20RB-/- and wild-type genotype. Host IL-20RB-/- mice showed lesser disease progression than wild-type mice, regardless of the myelin-reactive Th1 cells genotype. Using multianalyte bead-based immunoassay and ELISA, we found distinctive changes in levels of pro-inflammatory cytokines between IL-20RB-/- mice and wild-type mice at peak of EAE. We also found detectable levels of all cytokines of the IL-20 subfamily within CNS tissues and specific alteration to IL-20 subfamily cytokines IL-19, IL-20, and IL-24, expression levels. Immunolabeling of CNS region-specific microvessels confirmed IL-20RB protein at the spinal cord microvasculature and upregulation during EAE. Microvessels isolated from macaques CNS tissues also expressed IL-20RB. Moreover, we identified the expression of all IL-20 receptor subunits: IL-22 receptor subunit α-1 (IL-22RA1), IL-20RB, and IL-20 receptor subunit α (IL-20RA) in human CNS microvessels. Notably, human cerebral microvasculature endothelial cells (HCMEC/D3) treated with IL-1ß showed augmented expression of the IL-20 receptor. Lastly, IL-20-treated HCMEC/D3 showed alterations on CXCL12 apicobasal polarity consistent with a neuroinflammatory status. This evidence suggests that IL-20 subfamily cytokines may signal at the BBB via IL-20RB, triggering neuroinflammation.