Daily Sepsis Research Analysis

BACKGROUND: Sepsis, a life-threatening inflammatory syndrome with incompletely understood genetic mechanisms, necessitates identification of pathogenic proteins to advance precision medicine. This study integrated Mendelian randomization (MR) and multi-omics analyses to systematically investigate causal proteins and their regulatory mechanisms in sepsis. METHODS: We employed a multi-step framework combining two-sample MR, expression validation, immune infiltration analysis, single-cell RNA sequencing and mediation analysis. Exposure variables included cis-protein quantitative trait loci (cis-pQTLs) from two plasma proteome datasets (4,907 proteins from Decode and 2,640 proteins from UKB-PPP), with sepsis (ieu-b-4980) and 28-day sepsis (ieu-b-5086) serving as the outcome. Intersection analysis revealed the candidate proteins common between the two cis-pQTL datasets, followed by multi-omics validation using microarray expression profiling, receiver operating characteristic (ROC) analysis, and methylation quantitative trait loci (mQTLs). We also performed mediation analyses to assess whether immune cells potentially mediate causal pathways linking proteins to sepsis. Drug prediction was performed using DGIdb and molecular docking was subsequently used to identify the candidate drugs. RESULTS: MR analysis identified 97 (Decode) and 130 (UKB-PPP) sepsis-associated proteins, with 15 overlapping candidates. Among these, SFRP1, IL1RL1, and INHBB were validated as risk factors, while GSTP1 exhibited protective effects. They exhibited directionally concordant expression differences across an independent microarray dataset GSE95233. Furthermore, the associations of IL1RL1, INHBB, and GSTP1 with sepsis were replicated in the 28-day mortality dataset. ROC analysis demonstrated the superior diagnostic performance of GSTP1 for sepsis. MR further revealed that methylation at the GSTP1 locus cg25135322 increased the risk of sepsis (OR = 1.0844, 95% CI = 1.0339-1.1374). Immune infiltration analysis showed that GSTP1 expression was positively correlated with resting NK cells and CD8 + T cells, but negatively correlated with neutrophils. Single-cell RNA sequencing revealed the elevated GSTP1 expression in T cells and B cells, but reduced expression in monocytes of patients with sepsis. Mediation analysis suggested that CD39 + CD8br Treg cells might partially mediate the protective effects of GSTP1, accounting for 9.8% (Decode) and 11.47% (UKB-PPP) of the total effect, respectively. Four candidate drugs were identified, with Exatecan mesylate and Misonidazole showing optimal binding with GSTP1. CONCLUSIONS: This study identified three proteins with putative causal associations with sepsis risk, providing valuable clues for the development of biomarkers and therapeutic targets for sepsis.

IMPORTANCE: Early and accurate identification of clinical warning signs in young infants may help avert sepsis morbidity and mortality in resource-limited settings. OBJECTIVE: To systematically review evidence on the association and accuracy of clinical signs to diagnose sepsis or predict mortality in young infants aged 0 to 59 days to inform management in settings with limited laboratory diagnostics. DATA SOURCES: MEDLINE, Embase, CINAHL, Global Index Medicus, and Cochrane CENTRAL Register were searched from inception through May 2023, with updated searches on September 5, 2024. An umbrella search of systematic reviews was conducted in January 2024. STUDY SELECTION: Included studies reported data on 24 infant clinical signs informed by current World Health Organization (WHO) Integrated Management of Childhood Illness (IMCI) and hospital-based algorithms for the care of sick young infants reporting odds ratios (OR), risk ratios, or sensitivity and specificity. DATA EXTRACTION AND SYNTHESIS: Data were extracted independently by 2 reviewers. Quality assessment used the Newcastle-Ottawa, Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2), and Quality Assessment of Prognostic Accuracy Studies (QUAPAS) scales. OR data were pooled using random-effects models. Data analysis was performed from July to September 2025. MAIN OUTCOMES AND MEASURES: OR of all-cause mortality, culture-confirmed sepsis, or clinical sepsis (with access to laboratory investigations). RESULTS: Of 7641 studies, 52 studies with 140 885 participants were included. A total of 16 clinical signs were significantly associated with mortality, 11 with culture-confirmed sepsis, and 13 with clinical sepsis. For mortality, the 5 strongest associations were weak, abnormal, or absent cry (OR, 20.48; 95% CI, 6.59-63.67); not able to feed at all (OR, 18.32; 95% CI, 6.00-55.97); not feeding well (OR, 13.39; 95% CI, 6.97-25.72); drowsiness or unconsciousness (OR, 12.46; 95% CI, 6.06-25.62); and prolonged capillary refill (OR, 12.06; 95% CI, 2.77-52.53). The top 5 signs associated with culture-confirmed sepsis were not feeding well (OR, 4.52; 95% CI, 1.10-18.59); prolonged capillary refill (OR, 3.59; 95% CI, 2.05-6.28); lethargy (OR, 3.44; 95% CI, 1.89-6.26); drowsiness or unconsciousness (OR, 3.07; 95% CI, 2.01-4.68); and feeding intolerance (OR, 2.95; 95% CI, 1.67-5.21). CONCLUSIONS AND RELEVANCE: All current WHO IMCI clinical signs were significantly associated with mortality or culture-confirmed sepsis. Several signs not in IMCI were identified that may improve identification of life-threatening illness in young infants in resource-limited settings where clinical sign algorithms are the primary diagnostic tool.

This study aims to estimate the association between the splenic Doppler resistive index (SDRI) and in-hospital mortality in patients with sepsis. A prospective analytic cohort study was conducted on 109 consecutive adult patients with sepsis or septic shock, admitted to the emergency resuscitation room of a 4th-level referral center in Bogotá, Colombia, between November 2023 and October 2024, until the required statistical sample size was reached. A total of 109 consecutive adult patients (aged ≥18 years) with a diagnosis of sepsis or septic shock, based on the Sepsis-3 definition, were admitted to the emergency resuscitation room. Exclusion criteria included pregnancy, breastfeeding, inability to perform an apnea maneuver for Doppler measurement, severe hyperactive delirium, abdominal conditions limiting ultrasound access, severe peripheral arterial disease, disorders affecting hepatosplanchnic circulation, and permanent cardiac arrhythmias. The SDRI was measured within the 1st 6 hours after admission to the emergency resuscitation unit. The principal investigator received standardized training from the affiliated radiologist. Additional clinical variables were simultaneously recorded using a standardized data collection tool, including demographic characteristics, vital signs, site of infection, laboratory tests, blood culture, capillary refill time, Glasgow Coma Scale, and mottling score. In sepsis, SDRI of >0.7 showed lower survival from day 0 to day 38 of hospitalization. Thus, an association between SDRI of >0.7 and in-hospital mortality is suggested. Further studies are required to confirm these findings.