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Background COVID‐19 has become a pandemic, but its reported characteristics and outcomes vary greatly amongst studies. Objectives We determined pooled estimates for clinical characteristics and outcomes in COVID‐19 patients including subgroups by disease severity (based on WHO Interim Guidance Report or IDSA/ATS criteria) and by country/region. Methods We searched Pubmed, Embase, Scopus, Cochrane, Chinese Medical Journal, and preprint databases from January 1, 2020 to April 6, 2020. Studies of laboratory confirmed COVID‐19 patients with relevant data were included. Two reviewers independently performed study selection and data extraction. Results From 6,007 articles, 212 studies from 11 countries/regions involving 281,461 individuals were analyzed. Overall, mean age was 46 . 7 years, 51.8% were male, 22.9% had severe disease, and mortality was 5.6%. Underlying immunosuppression, diabetes, and malignancy were most strongly associated with severe COVID‐19 (coefficient=53.9, 23.4, 23.4, respectively, all p<0.0007), while older age, male gender, diabetes, and hypertension were also associated with higher mortality (coefficient=0.05 per year, 5.1, 8.2, 6.99, respectively, p=0.006 to 0.0002). Gastrointestinal (nausea, vomiting, abdominal pain) and respiratory symptoms (shortness of breath, chest pain) were associated with severe COVID‐19, while pneumonia and end organ failure were associated with mortality. Conclusion COVID‐19 is associated with a severe disease course in about 23% and mortality in about 6% of infected persons. Individuals with comorbidities and clinical features associated with severity should be monitored closely, and preventive efforts should especially target those with diabetes, malignancy and immunosuppression. This article is protected by copyright. All rights reserved.

In acute graft-versus-host disease (GVHD), naive donor CD4

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Major barriers to cancer therapy include the lack of selective inhibitors of regulatory T cells (T) and the lack of broadly applicable ways to directly target tumors through frequently expressed surface oncogenes. Tumor necrosis factor receptor 2 (TNFR2) is an attractive target protein because of its restricted abundance to highly immunosuppressive T and oncogenic presence on human tumors. We characterized the effect of TNFR2 inhibition using antagonistic antibodies. In culture-based assays, we found that two TNFR2 antagonists inhibited T proliferation, reduced soluble TNFR2 secretion from normal cells, and enabled T effector cell expansion. The antagonistic activity occurred in the presence of added TNF, a natural TNFR2 agonist. These TNFR2 antibodies killed T isolated from ovarian cancer ascites more potently than it killed T from healthy donor samples, suggesting that these antibodies may have specificity for the tumor microenvironment. The TNFR2 antagonists also killed OVCAR3 ovarian cancer cells, which have abundant surface TNFR2. The antibodies stabilized antiparallel dimers in cell surface TNFR2 that rendered the receptor unable to activate the nuclear factor κB pathway and trigger cell proliferation. Our data suggest that, by targeting tumor cells and immunosuppressive tumor-associated T, antagonistic TNFR2 antibodies may be an effective treatment for cancers positive for TNFR2.

Mycobacterium are among the oldest co-evolutionary partners of humans. The attenuated Mycobacterium bovis Bacillus Calmette Guérin (BCG) strain has been administered globally for 100 years as a vaccine against tuberculosis. BCG also shows promise as treatment for numerous inflammatory and autoimmune diseases. Here, we report on a randomized 8-year long prospective examination of type 1 diabetic subjects with long-term disease who received two doses of the BCG vaccine. After year 3, BCG lowered hemoglobin A1c to near normal levels for the next 5 years. The BCG impact on blood sugars appeared to be driven by a novel systemic and blood sugar lowering mechanism in diabetes. We observe a systemic shift in glucose metabolism from oxidative phosphorylation to aerobic glycolysis, a state of high glucose utilization. Confirmation is gained by metabolomics, mRNAseq, and functional assays of cellular glucose uptake after BCG vaccinations. To prove BCG could induce a systemic change to promote accelerated glucose utilization and impact blood sugars, murine data demonstrated reduced blood sugars and aerobic induction in non-autoimmune mice made chemically diabetic. BCG via epigenetics also resets six central T-regulatory genes for genetic re-programming of tolerance. These findings set the stage for further testing of a known safe vaccine therapy for improved blood sugar control through changes in metabolism and durability with epigenetic changes even in advanced Type 1 diabetes.

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