Viral and Host Factors Are Associated With Mortality in Hospitalized Patients With COVID-19.

BACKGROUND: Persistent mortality in adults hospitalized due to acute COVID-19 justifies pursuit of disease mechanisms and potential therapies. The aim was to evaluate which virus and host response factors were associated with mortality risk among participants in Therapeutics for Inpatients with COVID-19 (TICO/ACTIV-3) trials. METHODS: A secondary analysis of 2625 adults hospitalized for acute SARS-CoV-2 infection randomized to 1 of 5 antiviral products or matched placebo in 114 centers on 4 continents. Uniform, site-level collection of participant baseline clinical variables was performed. Research laboratories assayed baseline upper respiratory swabs for SARS-CoV-2 viral RNA and plasma for anti-SARS-CoV-2 antibodies, SARS-CoV-2 nucleocapsid antigen (viral Ag), and interleukin-6 (IL-6). Associations between factors and time to mortality by 90 days were assessed using univariate and multivariable Cox proportional hazards models. RESULTS: Viral Ag ≥4500 ng/L (vs <200 ng/L; adjusted hazard ratio [aHR], 2.07; 1.29-3.34), viral RNA (<35 000 copies/mL [aHR, 2.42; 1.09-5.34], ≥35 000 copies/mL [aHR, 2.84; 1.29-6.28], vs below detection), respiratory support (<4 L O2 [aHR, 1.84; 1.06-3.22]; ≥4 L O2 [aHR, 4.41; 2.63-7.39], or noninvasive ventilation/high-flow nasal cannula [aHR, 11.30; 6.46-19.75] vs no oxygen), renal impairment (aHR, 1.77; 1.29-2.42), and IL-6 >5.8 ng/L (aHR, 2.54 [1.74-3.70] vs ≤5.8 ng/L) were significantly associated with mortality risk in final adjusted analyses. Viral Ag, viral RNA, and IL-6 were not measured in real-time. CONCLUSIONS: Baseline virus-specific, clinical, and biological variables are strongly associated with mortality risk within 90 days, revealing potential pathogen and host-response therapeutic targets for acute COVID-19 disease.

Nonmonotonic Pathway Gene Expression Analysis Reveals Oncogenic Role of p27/Kip1 at Intermediate Dose.

The mechanistic basis by which the level of p27Kip1 expression influences tumor aggressiveness and patient mortality remains unclear. To elucidate the competing tumor-suppressing and oncogenic effects of p27Kip1 on gene expression in tumors, we analyzed the transcriptomes of squamous cell papilloma derived from Cdkn1b nullizygous, heterozygous, and wild-type mice. We developed a novel functional pathway analysis method capable of testing directional and nonmonotonic dose response. This analysis can reveal potential causal relationships that might have been missed by other nondirectional pathway analysis methods. Applying this method to capture dose-response curves in papilloma gene expression data, we show that several known cancer pathways are dominated by low-high-low gene expression responses to increasing p27 gene doses. The oncogene cyclin D1, whose expression is elevated at an intermediate p27 dose, is the most responsive gene shared by these cancer pathways. Therefore, intermediate levels of p27 may promote cellular processes favoring tumorigenesis-strikingly consistent with the dominance of heterozygous mutations in CDKN1B seen in human cancers. Our findings shed new light on regulatory mechanisms for both pro- and anti-tumorigenic roles of p27Kip1. Functional pathway dose-response analysis provides a unique opportunity to uncover nonmonotonic patterns in biological systems.