Analysis of Protein Biomarkers From Hospitalized COVID-19 Patients Reveals Severity-Specific Signatures and Two Distinct Latent Profiles With Differential Responses to Corticosteroids.

OBJECTIVES: To identify and validate novel COVID-19 subphenotypes with potential heterogenous treatment effects (HTEs) using electronic health record (EHR) data and 33 unique biomarkers. DESIGN: Retrospective cohort study of adults presenting for acute care, with analysis of biomarkers from residual blood collected during routine clinical care. Latent profile analysis (LPA) of biomarker and EHR data identified subphenotypes of COVID-19 inpatients, which were validated using a separate cohort of patients. HTE for glucocorticoid use among subphenotypes was evaluated using both an adjusted logistic regression model and propensity matching analysis for in-hospital mortality. SETTING: Emergency departments from four medical centers. PATIENTS: Patients diagnosed with COVID-19 based on International Classification of Diseases , 10th Revision codes and laboratory test results. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Biomarker levels generally paralleled illness severity, with higher levels among more severely ill patients. LPA of 522 COVID-19 inpatients from three sites identified two profiles: profile 1 ( n = 332), with higher levels of albumin and bicarbonate, and profile 2 ( n = 190), with higher inflammatory markers. Profile 2 patients had higher median length of stay (7.4 vs 4.1 d; p < 0.001) and in-hospital mortality compared with profile 1 patients (25.8% vs 4.8%; p < 0.001). These were validated in a separate, single-site cohort ( n = 192), which demonstrated similar outcome differences. HTE was observed ( p = 0.03), with glucocorticoid treatment associated with increased mortality for profile 1 patients (odds ratio = 4.54). CONCLUSIONS: In this multicenter study combining EHR data with research biomarker analysis of patients with COVID-19, we identified novel profiles with divergent clinical outcomes and differential treatment responses.

Zinc-induced envelope stress diminishes type III secretion in enteropathogenic Escherichia coli.

BACKGROUND: Dietary supplementation with zinc has been shown to reduce the duration and severity of diarrhoeal disease caused by Enteropathogenic Escherichia coli, common in infants in developing countries. Initially this therapeutic benefit was attributed to the correction of zinc deficiency in malnourished individuals, but recently evidence has emerged that zinc significantly impacts the pathogens themselves: zinc concentrations achievable by oral supplementation can reduce the expression of key virulence-related genes in EPEC and related organisms. RESULTS: Here, we investigate three possible mechanisms for such zinc-induced changes in expression of EPEC virulence: direct interaction of zinc with regulators of LEE operons; genetic interaction of LEE operons with known regulators of zinc homeostasis; and finally, downregulation of LEE transcription associated with activation of the σ(E) envelope stress response by zinc. We find evidence only for the latter mechanism, including zinc-induced down-regulation of type III secretion in EPEC similar to that caused by ammonium metavanadate, another known inducer of the σ(E) stress response. CONCLUSIONS: We conclude therefore that envelope stress is a major mechanism by which zinc attenuates the virulence of EPEC and related pathogens.

Familial Adenomatous Polyposis Syndrome: An Update and Review of Extraintestinal Manifestations.

CONTEXT.­: Familial adenomatous polyposis (FAP) is a rare genetic disorder with autosomal dominant inheritance, defined by numerous adenomatous polyps, which inevitably progress to colorectal carcinoma unless detected and managed early. Greater than 70% of patients with this syndrome also develop extraintestinal manifestations, such as multiple osteomas, dental abnormalities, and a variety of other lesions located throughout the body. These manifestations have historically been subcategorized as Gardner syndrome, Turcot syndrome, or gastric adenocarcinoma and proximal polyposis of the stomach. Recent studies, however, correlate the severity of gastrointestinal disease and the prominence of extraintestinal findings to specific mutations within the adenomatous polyposis coli gene (APC), supporting a spectrum of disease as opposed to subcategorization. Advances in immunohistochemical and molecular techniques shed new light on the origin, classification, and progression risk of different entities associated with FAP. OBJECTIVE.­: To provide a comprehensive clinicopathologic review of neoplastic and nonneoplastic entities associated with FAP syndrome, with emphasis on recent developments in immunohistochemical and molecular profiles of extraintestinal manifestations in the thyroid, skin, soft tissue, bone, central nervous system, liver, and pancreas, and the subsequent changes in classification schemes and risk stratification. DATA SOURCES.­: This review will be based on peer-reviewed literature and the authors' experiences. CONCLUSIONS.­: In this review we will provide an update on the clinicopathologic manifestations, immunohistochemical profiles, molecular features, and prognosis of entities seen in FAP, with a focus on routine recognition and appropriate workup of extraintestinal manifestations.