Daily Sepsis Research Analysis

BACKGROUND: Sepsis remains a leading cause of mortality among critically ill patients worldwide. Although an increasing number of prediction models have been published in recent years, their predictive performance, methodological quality, and major predictors have not been comprehensively evaluated in a systematic and quantitative manner. This study aims to evaluate the performance of these models and to identify common predictors associated with sepsis mortality. METHODS: We systematically searched PubMed, Embase, Cochrane Library, and Web of Science for studies on sepsis mortality prediction models published up to July 1, 2025. Data were extracted and appraised using the Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modeling Studies (CHARMS), and risk of bias was assessed with the Prediction Model Risk of Bias Assessment Tool for Artificial Intelligence (PROBAST+AI). Meta-analyses were performed to pool area under the curve of the receiver operating characteristic (AUC) metric of externally validated models and the odds ratio (OR) of common predictors. The study was registered in PROSPERO (CRD42024604119). RESULTS: A total of 84 eligible studies were included, reporting 235 prediction models for sepsis mortality and involving approximately 2.7 million patient records reported across studies, with 461,387 deaths. Only 11(13.10%) studies encompassed model development, internal validation, and external validation. The included studies comprised 78(92.86%) retrospective cohort studies, 57(67.86%) studies developed in intensive care unit (ICU) settings, with MIMIC databases being among the most commonly used data sources. The most prevalent mortality endpoints were in-hospital (

Acute brain dysfunction (delirium) is common in sepsis, and many survivors develop persistent cognitive impairment. Cerebral hypoperfusion and edema are implicated, yet it is unknown whether intracranial hypertension contributes to the neurological sequelae of sepsis, and no therapies specifically target cerebral hemodynamic dysfunction. Intravenous megadose sodium ascorbate has been reported to reverse cerebral tissue ischemia and hypoxia and reduce vasopressor requirements in preclinical and clinical studies. Here, we test for the first time the effects of sepsis and megadose sodium ascorbate on intracranial pressure (ICP), cerebral perfusion pressure (CPP) and pressor responsiveness to norepinephrine in a clinically relevant ovine model of Gram-negative sepsis. Adult Merino ewes were surgically instrumented with lateral cerebral ventricular catheters and carotid arterial and jugular venous catheters. Non-anesthetized sheep were infused with intravenous live Escherichia coli for 31-h. After 23-h of sepsis animals received bolus fluid resuscitation (30 mL/kg from 23-23.5-h; sodium lactate) and were randomized to receive intravenous 3 g/kg of sodium ascorbate (n = 7) or fluid-matched placebo (n = 6), as a bolus followed by a 7-h infusion. ICP and mean arterial pressure (MAP) were measured continuously. Changes in MAP to escalating norepinephrine doses were recorded at baseline and 23-h of sepsis, and after treatment at 27.5 and 31-h of sepsis. Sepsis reduced MAP and CPP and increased heart rate and ICP (all P < 0.01). By 31-h of sepsis, sodium ascorbate improved MAP compared with placebo (75 ± 5 to 87 ± 11 vs. 69 ± 11 to 66 ± 7 mmHg; P = 0.020). In addition, sodium ascorbate normalised ICP, whereas it remained elevated with placebo (17.0 ± 3.4 to 9.3 ± 1.9 vs. 20.6 ± 3.7 to 19.3 ± 5.0 mmHg; P = 0.024). Sodium ascorbate improved CPP versus no effect with placebo (61 ± 11 to 75 ± 5 mmHg vs. 48 ± 16 to 49 ± 12 mmHg; P = 0.046). MAP responsiveness to norepinephrine was impaired at 23-h of sepsis in both groups and was fully restored at 27.5- and 31-h of sepsis by sodium ascorbate but not by placebo. Norepinephrine did not increase ICP in either group.

BACKGROUND: Neutrophils play an important role in the immune system by sensing environmental perturbations, including pathogens. Upon activation, neutrophils extrude their chromatin to form neutrophil extracellular traps (NETs), which trap and remove pathogens. Chromatin decondensation during NET formation is a regulated process that reflects both the inducing pathways and the cellular environment. However, most studies rely on non-physiological stimuli like phorbol 12-myristate 13-acetate (PMA), which bypass key regulatory mechanisms. As a result, how physiologically relevant inflammatory signals change neutrophil chromatin accessibility and relate to disease associated transcriptional states remains poorly understood. METHODS: We used the Assay for Transposase-Accessible Chromatin with sequencing (ATAC-Seq) to profile chromatin accessibility in neutrophils stimulated in whole blood with PMA and physiologically relevant inflammatory natural factors (NFs), including TNF-α, GM-CSF, fMLP, C5a, and IL-1β, alone and in combination. Chromatin responses were compared across conditions and integrated with publicly available transcriptomic sepsis cohorts. RESULTS: NF stimulation induced stimulus specific chromatin accessibility programs distinct from PMA. Individual NFs enriched specific transcription factor (TF) motif enrichments in a stimulus dependent manner, with GM-CSF associated with STAT motifs, TNF-α with NF-κB, and C5a/fMLP with AP-1, while the combined condition showed a cooperative response including CEBP. Integration with sepsis transcriptomic datasets revealed that promoter accessibility changes under NF stimulation corresponded to transcriptional states associated with disease severity, highlighting the upstream regulatory programs linked to clinical outcomes. CONCLUSIONS: These findings demonstrate that NF stimulation in whole blood reveals chromatin accessibility programs in neutrophils that correlate with disease severity in sepsis. This approach provides a framework for linking cytokine driven neutrophil regulation to heterogenous inflammatory states in sepsis and other NET-associated diseases.