Daily Sepsis Research Analysis

The cholinergic anti-inflammatory pathway (CAP) plays a central role in neuroimmunomodulation, and its activation is a potential strategy for ameliorating sepsis-associated acute kidney injury (SA-AKI). However, further investigations are necessary to understand the molecular mechanisms of CAP activation and develop therapies for SA-AKI. Here, we tested whether the Notch signaling pathway, which regulates cell-cell interactions, mediates the anti-inflammatory effects of CAP. Using a mouse model of lipopolysaccharide (LPS)-induced AKI, we found that CAP activation by vagus nerve stimulation (VNS) enhanced Notch2 signaling in macrophages, mitigating inflammation in the spleen and tissue damage in the kidneys. Consistently, macrophage-specific knockout of Notch2 resulted in an attenuation of these anti-inflammatory effects of VNS. We also demonstrated that VNS and macrophage-specific Notch2 signaling might upregulate transferrin, which maintains iron homeostasis, thereby protecting the kidneys. Taken together, our findings suggest the involvement of Notch signaling in the mechanisms of VNS-mediated CAP activation during LPS-induced AKI.

BACKGROUND: Blood stream infections (BSIs) are associated with sepsis, high morbidity and mortality rates, and substantial financial costs. Blood cultures are the gold standard diagnostic test for BSI, with UK Standards for Microbiology Investigations (SMI) recommending routine incubation for 5 days. However, reducing the incubation time to 4 days has been reported to adequately detect true bacteraemia whilst reducing contaminant recovery. In January 2025, Newcastle upon Tyne Hospitals implemented the bioMérieux BACT/ALERT VIRTUO system. This study compared 5-day versus 4-day blood culture incubation, assessing whether a 4-day incubation period is likely to be sufficient for detecting clinically significant bloodstream infections in a UK tertiary centre. METHODS: All blood cultures processed between 22 January 2025 and 31 March 2025, inclusive, were analysed. A case series review assessed the clinical significance of all growth from blood cultures after 4 days' incubation (> 96 h). Two doctors independently appraised the medical records to evaluate the degree to which results influenced clinical management, with double coding undertaken without inter-coder conferral. A resource impact model estimated the local operational cost of extending incubation beyond 4 days. RESULTS: In total, 6994 blood culture sets, including 13,103 bottles, were processed from 3221 distinct patients. Only twenty-three (0.18%) bottles flagged positive beyond 4 days' incubation, of which sixteen (69.6%) led to the isolation of contaminants and seven (30.4%) led to the isolation of clinically significant organisms. Retrospective review revealed that growth from only a single bottle yielded information that influenced a change in patient management, translating to one additional clinically meaningful result from over 13,000 extended incubations (0.008%). On the basis of the resource impact model, routine incubation of blood culture for 5 days is estimated to consume an additional 337 h of staff time annually. CONCLUSIONS: Routine incubation of blood cultures beyond 4 days is resource intensive but offers negligible clinical benefits. Our results support review of recommendations outlined in the UK SMI on Sepsis and Systemic or Disseminated infections (S 12). For laboratories equipped with automated continuous monitoring blood culture systems, a routine 4-day incubation period is likely to suffice, with extended incubation reserved for specialist-driven clinical indications.

BACKGROUND: Sepsis-induced myocardial injury (SIMI) is a common and severe complication of sepsis associated with increased mortality, yet its underlying mechanisms are not fully elucidated. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation and oxidative stress, has been implicated in preclinical models of septic cardiomyopathy. However, clinical evidence in humans remains limited, and the specificity of related biomarkers requires careful interpretation. METHODS: This prospective observational study enrolled 180 ICU-admitted sepsis patients (91 with SIMI and 89 without) from January to June 2025. Serum ferroptosis-related biomarkers, including malondialdehyde (MDA), lipid peroxidation (LPO), glutathione (GSH), reactive oxygen species (ROS), and ferrous iron (Fe²⁺), were measured at 24 h post-admission. Diagnostic performance was evaluated using receiver operating characteristic (ROC) curves, and independent predictors were identified via multivariable logistic regression adjusting for clinical confounders. RESULTS: Compared with the non-SIMI group, SIMI patients showed significantly altered ferroptosis-related markers (all P < 0.001): higher MDA [6.08 (5.38-6.67) vs. 4.47 (3.92-5.30) nmol/mL], LPO, ROS, and Fe²⁺, and lower GSH. ROC analysis demonstrated moderate-to-good diagnostic discrimination for SIMI (AUC 0.746-0.825), with Fe²⁺ showing the highest AUC (0.825), followed by ROS (0.793) and MDA (0.787); these outperformed BNP but were inferior to cTnI. Multivariable logistic regression identified Fe²⁺ (OR = 11.883, P < 0.001) as the only independent ferroptosis-related predictor of SIMI, alongside cTnI and APACHE II score. The full model exhibited excellent discrimination (AUC = 0.989) and good calibration (Hosmer-Lemeshow P = 0.935). CONCLUSIONS: Elevated ferroptosis-related biomarkers reflecting systemic oxidative stress and iron dysregulation are significantly associated with SIMI, with Fe²⁺ emerging as an independent predictor. These biomarkers provide additive diagnostic value beyond traditional cardiac markers but are not specific for ferroptosis as a regulated cell death mechanism and likely represent broader redox imbalance in severe sepsis. These findings support further investigation into iron-targeted and oxidative stress-modulating strategies in septic cardiac dysfunction.