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).

Hepatic stellate cells (HSC) play a key role in liver fibrogenesis. Activation of PPARγ and inhibition of fibrogenic molecules are potential strategies to block HSC activation and differentiation. A number of natural products have been suggested to have antifibrotic effects for the de-activation and de-differentiation of HSCs. The purpose of this study was to investigate the in vitro effects of capsaicin on HSC de-activation and de-differentiation. The results demonstrated that capsaicin induced quiescent phenotype in GRX via PPARγ activation. Significant decrease in COX-2 and type I collagen mRNA expression was observed in the first 24 h of treatment. These events preceded the reduction of TGF-β1 and total collagen secretion. Thus, capsaicin promoted down-regulation of HSC activation by its antifibrotic and anti-inflammatory actions. These findings demonstrate that capsaicin may have potential as a novel therapeutic agent for the treatment of liver fibrosis.

No abstract

BACKGROUND: Septic shock presents as a continuum of infectious events, generating tissue hypoxia and hypovolemia, and increased oxidative stress. Chest physiotherapy helps reduce secretion, improving dynamic and static compliance, as well as improving secretion clearance and preventing pulmonary complications. The purpose of this study was to evaluate the immediate effect of chest physiotherapy on hemodynamic, metabolic, inflammatory, and oxidative stress parameters in subjects in septic shock. METHODS: We conducted a quasi-experimental study in 30 subjects in septic shock, who underwent chest physiotherapy, without associated heart diseases and with vasopressors < 0.5 g/kg/min. Venous and arterial blood gases, clinical and hemodynamic data, inflammatory data, lactate, and oxidative stress were evaluated before and 15 min after physiotherapy. RESULTS: Thirty subjects with a mean age of 61.8 ؎ 15.9 y and Sequential Organ Failure Assessment of 8 (range 6 -10) were included. Chest physiotherapy caused a normalization of pH (P ‫؍‬ .046) and P aCO 2 (P ‫؍‬ .008); reduction of lactate (P ‫؍‬ .001); and an increase in P aO 2 (P ‫؍‬ .03), arterial oxygen saturation (P ‫؍‬ .02), and P aO 2 /F IO 2 (P ‫؍‬ .034), 15 min after it was applied. CONCLUSIONS: The results indicate that chest physiotherapy has immediate effects, improving oxygenation and reducing lactate and oxidative damage in subjects in septic shock. However, it does not cause alterations in the inflammatory and hemodynamic parameters.

Periodontal disease is an infectious inflammatory disease related to the destruction of supporting tissues of the teeth, leading to a functional loss of the teeth. Inflammatory molecules present in the exudate are catalyzed and form different metabolites that can be identified and quantified. Thus, we evaluated the inflammatory exudate present in crevicular fluid to identify metabolic biological markers for diagnosing chronic periodontal disease in older adults. Research participants were selected from long-term institutions in Brazil. Participants were individuals aged 65 years or older, healthy, or with chronic periodontal disease. Gas chromatography/mass spectrometry was used to evaluate potential biomarkers in 120 crevicular fluid samples. We identified 969 metabolites in the individuals. Of these, 15 metabolites showed a variable importance with projection   score > 1 and were associated with periodontal disease. Further analysis showed that among the 15 metabolites, two (5-aminovaleric acid and serine, 3TMS derivative) were found at higher concentrations in the crevicular fluid, indicating their potential diagnostic power for periodontal disease in older adults. Our findings indicated that some metabolites are present at high concentrations in the crevicular fluid in older adults with periodontal disease and can be used as biomarkers of periodontal disease.