Daily Sepsis Research Analysis

Immunosuppression in sepsis often leads to treatment failure due to impaired host defense, underscoring an urgent need for novel therapeutic strategies to restore immune function. To address this challenge, we designed functional selenium nanoparticles (SeNPs) and conducted a pilot randomized clinical trial to evaluate the efficacy and safety of SeNPs in sepsis patients with immune dysfunction. The trial was registered with the Chinese Clinical Trial Registry (ChiCTR2300072222). Eligible patients were randomly assigned in 1:1 ratio to receive either standard care alone or standard care supplemented with SeNPs (400 μg selenium daily). The primary endpoint was immune function, assessed by lymphocyte counts and subsets on days 1, 4, 7, and 10 after randomization. Seventy patients were enrolled, and 68 completed the trial (34 per group). Compared with the control group, SeNPs supplementation was associated with improved immune function, reflected by higher total lymphocyte counts and increased absolute counts of CD3

The liver is a central immunometabolic organ during endotoxemia and a major target of sepsis-related injury. Intriguingly, the liver exhibits a notable resilience to endotoxemia or septic insults, suggesting the activation of endogenous protective mechanisms. The bile acid taurodeoxycholic acid (TDCA) demonstrates hepatoprotective properties; nonetheless, its role and mechanism in lipopolysaccharide (LPS)-driven inflammatory liver injury remain elusive. This study reveals that LPS challenge induces significant reprogramming of hepatic bile acid metabolism, with TDCA being markedly elevated in LPS-challenged mice. In vitro, TDCA dose-dependently attenuated pyroptosis in bone marrow-derived macrophages, as evidenced by reduced lactate dehydrogenase (LDH) release, decreased interleukin-1 beta (IL-1β) and interleukin-18 (IL-18) secretion, and suppressed dye Oxazole yellow uptake. Consistent with reduced non-canonical inflammasome signaling, TDCA treatment was associated with decreased activation of caspase-11 and its downstream targets Gasdermin D (GSDMD) and IL-1β. In a lethal D-Galactosamine (D-GalN)/LPS-induced toxin-sensitized inflammatory liver injury model, therapeutic administration of TDCA (3, 6 mg/kg) profoundly improved survival rates (40% and 80%, respectively), attenuated liver injury, reduced alanine aminotransferase (ALT) and aspartate aminotransferase (AST), suppressed systemic inflammation (IL-1β and IL-18), and ameliorated histopathological damage. Crucially, TDCA treatment reduced the activation of the caspase-11/GSDMD pathway in the septic liver. Our findings demonstrate that TDCA is an endogenously mobilized bile acid that confers protection against LPS-driven inflammatory liver injury, with effects supporting a role for modulation of the Caspase-11/GSDMD pyroptotic pathway. These observations provide hypothesis-generating implications for sepsis-associated liver injury that warrant further validation in clinically relevant sepsis models and pathway-necessity studies.

OBJECTIVES: To search for colistin heteroresistance (CHR) prevalence in Acinetobacter baumannii bloodstream isolates, and to investigate potential molecular contributors to CHR using WGS. METHODS: A total of 267 A. baumannii isolates were recovered from bloodstream infections between January 2014 and July 2018 at a tertiary care hospital in Türkiye. Antimicrobial susceptibility to colistin was assessed using the broth microdilution method. CHR was evaluated by population analysis profiling (PAP). WGS was performed on a representative heteroresistant strain (A325) to investigate putative CHR-associated mechanisms. RESULTS: Thirty-five isolates (13.9%) were classified as colistin-resistant. CHR was identified in 86 of 267 isolates (32.2%) using PAP. Comparative genomic analysis of the colistin-susceptible main population and the colistin-resistant subpopulation of isolate A325 revealed identical mutational profiles in known resistance-associated genes, with the exception of a partial deletion in the lpxD gene between codons 2 and 75, identified exclusively in the resistant subpopulation. Notably, tetracyclines, macrolides and aminoglycosides were fully inactive in the colistin-susceptible main population, whereas an inhibition zone around these antibiotic discs was observed with the colistin-resistant subpopulation. CONCLUSIONS: This study demonstrates a high prevalence of both colistin resistance and CHR among A. baumannii bloodstream isolates. The identification of a partial lpxD deletion in the resistant subpopulation of the colistin-heteroresistant isolate suggests a potential contributory role of LPS-related alterations in CHR. Inverse antimicrobial activity profiles between populations highlight distinct resistance mechanisms potentially shaped by evolutionary trade-offs and collateral sensitivity.