Daily Sepsis Research Analysis

BACKGROUND: Sepsis is a life-threatening condition characterized by an excessive inflammatory response and immune dysregulation. Effective treatments remain limited, necessitating the exploration of novel therapeutic agents. Although berbamine (BBM) exhibits notable anti-inflammatory properties, its specific mechanisms and therapeutic potential in sepsis have yet to be elucidated. PURPOSE: This study aims to investigate the protective effects of BBM in sepsis models and elucidate its underlying mechanisms, with a focus on immune modulation and the Notch1 signaling pathway. METHODS: We employed two murine sepsis models-lipopolysaccharide (LPS)-induced endotoxemia and cecal ligation and puncture (CLP)-induced sepsis-to assess BBM's therapeutic potential. Histopathological and cytokine analyses were performed to evaluate inflammation and lung injury. Flow cytometry was used to examine immune cell development. Additionally, in vitro assays with bone marrow-derived macrophages (BMDMs) were conducted to assess cytokine production. Network pharmacology and cellular thermal shift assays (CETSA) were utilized to identify potential molecular targets, focusing on Notch1 signaling. We also evaluated the effects of BBM on myeloid-specific Notch1 knockout (Notch1 RESULTS: BBM significantly improved survival rates and reduced lung inflammation in septic mice. In vitro, BBM inhibited LPS-induced secretion of proinflammatory cytokines (TNF-α, IL-6, and IL-1β) in BMDMs without impairing macrophage differentiation or viability. Network pharmacology analyses identified Notch1 as a potential BBM target, which was validated by CETSA. Mechanistically, BBM accelerated Notch1 degradation via the ubiquitin-proteasome pathway, leading to decreased Notch1 protein levels. Notably, notch1-deficient macrophages exhibited blunted inflammatory responses to LPS, and BBM treatment failed to confer additional suppression, indicating that BBM's anti-septic effects are mediated predominantly through Notch1 inhibition. CONCLUSION: BBM exerts a protective effect in sepsis by suppressing inflammation and promoting Notch1 degradation. These findings suggest that BBM may serve as a promising therapeutic agent for sepsis.

INTRODUCTION: Microvascular injury is central to the pathophysiology of sepsis, but its interaction with the immune system in early infection is unclear. This study aimed to phenotype peripheral blood mononuclear cells (PBMC) from emergency department (ED) patients with suspected bacterial infection and correlate the results with microvascular changes. METHODS: This prospective observational study included 49 adult ED patients with suspected infection and 17 healthy controls. Capillary density and glycocalyx dimensions were measured by sublingual microscopy, while peripheral blood immune cell subsets were analyzed by deep flow cytometry. RESULTS: Network visualization of 72 diIerentially regulated parameters revealed specific changes in diIerent immune cell subsets. Innate immune changes included a functional diversion of monocytes towards pathogen defense and tissue repair, whereas adaptive immune changes included the development of CD4+ T cells with Th2-profile and cytotoxic CD8+ T cells. Unsupervised clustering revealed two distinct immune endotypes: E1 with a suppressed immune response and higher disease severity, and E2 with an enhanced immune response and lower disease severity. Patients showed significant reductions in capillary density and glycocalyx dimensions, which were neither correlated in magnitude nor associated with endotypes. There was a strong association between damaged glycocalyx and several monocyte and T-cell subsets. This association was not observed for capillary density. DISCUSSION: We demonstrate that glycocalyx damage is associated with a unique immunological signature, distinct from functional capillary density. These findings provide a strong basis for future studies of immune dysregulation and microvascular dysfunction in infection.

BACKGROUND: Carbapenem-resistant Acinetobacter baumannii (CRAB) infections carry high case-fatality rates. Although the incidence of these infections is increasing and therapeutic options are limited, effective interventions to prevent the cross-transmission of CRAB have rarely been tested. AIM: To assess the impact of cohorting CRAB patients combined with intensified environmental cleaning on CRAB bloodstream infections (BSIs). METHODS: A quasi-experimental study at a tertiary hospital during January 2022 to June 2024. All patients with CRAB (either colonization or infection) hospitalized in the internal medicine departments were cohorted. Simultaneously, a twice-daily routine and a double terminal cleaning of all hospital rooms occupied by CRAB patients were performed. The monthly acquired CRAB BSI rates were calculated and the incidence rate ratio (IRR) estimated using Poisson regression discontinuity analysis with robust standard errors controlled for the influx of CRAB patients into the hospital. FINDINGS: During January 2022 to June 2024, 610 hospitalized patients with CRAB were identified, 350 (57%) of whom acquired the bacterium in hospital and 138 (39%) developed BSI. The average overall 30-day mortality rate was 61% and remained relatively similar throughout the study period. Cumulative BSI incidence decreased by 55%, from 1.43 per 10,000 hospitalization-days before the intervention to 0.65 afterwards. The slope of the BSI incidence rate decreased by 9% per month (adjusted IRR: 0.909; 95% CI: 0.834-0.990; P = 0.029). CONCLUSION: Cohorting CRAB patients in the internal medicine departments, combined with intensified cleaning throughout the hospital, significantly reduced the incidence of CRAB BSI across the entire institution.