Daily Sepsis Research Analysis

BACKGROUND: Maternal infection and sepsis are major causes of maternal death and severe illness worldwide, particularly in low- and middle-income countries. Inconsistent implementation of evidence-based recommendations for infection prevention and management and delays in detection and treatment of maternal sepsis contribute to the number of preventable deaths. METHODS: We conducted a cluster-randomized trial to assess a multicomponent intervention, the Active Prevention and Treatment of Maternal Sepsis (APT-Sepsis) program. This program was designed to support health care providers in achieving three goals: adherence to World Health Organization (WHO) hand-hygiene standards; adoption of evidence-based practices for maternal infection prevention and management; and early detection of sepsis and use of the FAST-M (fluids, antibiotics, source control, transfer if required, and monitoring) treatment bundle. Usual care was provided in the control group, along with dissemination of guidelines. The primary outcome was a composite of infection-related maternal death, infection-related near-miss event (events in which women survived a life-threatening complication), or severe infection-related illness (deep surgical-site, deep perineal, or body-cavity infection) among women who were pregnant or had recently been pregnant. RESULTS: We randomly assigned 59 health facilities (where 431,394 women gave birth during the trial) in Malawi and Uganda to the intervention group (30 clusters) or the usual-care group (29 clusters). A primary-outcome event occurred in 1.4% of the patients in the intervention group and in 1.9% of those in the usual-care group (risk ratio, 0.68; 95% confidence interval, 0.55 to 0.83; P<0.001). This effect was generally consistent between countries and among facilities of difference sizes and was sustained over time. CONCLUSIONS: Implementation of the APT-Sepsis program led to a significantly lower risk of a composite of infection-related maternal death, infection-related near-miss event, or severe infection-related illness than usual care. (Funded by the Joint Global Health Trials scheme and others; APT-Sepsis ISRCTN number, ISRCTN42347014.).

BACKGROUND: Vascular leakage is a major cause of multiple organ failure and mortality in sepsis, and factors that regulate endothelial integrity could serve as promising biomarkers of septic shock development. Copine family members (CPNEs) are well-characterized as soluble membrane-binding proteins, whether CPNEs play a critical role in maintaining vascular integrity during sepsis, however, remains unclear. METHODS: Human aorta single-nucleus RNA-sequencing data were analyzed for the expression profile of all Copine family members (CPNE1-9). Plasma levels of CPNE5, Ang-II, sICAM-1, and SDC-1 were measured in human sepsis patients at admission and healthy donors as well as in septic mice induced by injection i.p. with cecal slurry. The correlation of CPNE5 levels to other three factors (Ang-II, sICAM-1, SDC-1) were analyzed. CPNE5-knockdown endothelial cells (ECs) and global CPNE5-knockout (KO) mice were utilized to determine the critical role of CPNE5 in sepsis-triggered vascular leakage, organ damage and mortality. RESULTS: Among nine CPNEs, only CPNE5 is predominantly expressed in human aorta endothelial cells. In sepsis patients (n = 77), plasma levels of CPNE5 were significantly reduced, whereas plasma levels of Ang-II, sICAM-1, and SDC-1 were markedly elevated, compared to healthy donors (n = 44; p < 0.01). Similar findings were also observed in a murine sepsis model induced by cecal slurry (CS)-injection intraperitoneally. Furthermore, in the supernatants of cultured ECs treated with LPS or pro-inflammatory cytokine mixture (Cytomix: TNFα/IL-1β/IFNγ, each 10 ng/mL), the concentrations of CPNE5 were significantly lower, which was negatively correlated with the higher EC permeability, compared to the control group. Accordingly, siRNA-mediated knockdown of CPNE5 in ECs caused hyperpermeability upon stimulation with LPS or Cytomix. In vivo, we observed that loss of CPNE5 increased vascular leakage, leading to severe organ injury and higher mortality, compared to WT mice upon septic conditions. The initial mechanistic analysis showed that the reduction of CPNE5 in cardiac and pulmonary ECs was linked to the increased cleavage of membrane tight junctions and adherens junctions. CONCLUSIONS: These observations from human sepsis patients and a murine sepsis model suggest that reduced plasma levels of CPNE5 may contribute to sepsis-induced vascular leakage and mortality.

INTRODUCTION: Intestinal barrier injury plays a significant role in the development and progression of sepsis. However, the underlying mechanisms remain unclear. METHODS: The "intestinal immune network for IgA production" pathway (KEGG ID: hsa04672) is closely associated with the intestinal barrier. This study integrated bulk and single-cell RNA sequencing data, a clinical trial, an animal study and Mendelian randomization (MR) analyses to elucidate the role of hsa04672 during sepsis. RESULTS: Enrichment analyses confirmed the relationship between hsa04672 and sepsis. Four machine learning algorithms identified HLA-DPA1 (area under the curve [AUC] = 0.995), ITGB7 (AUC = 0.967), and CXCR4 (AUC = 0.942) as hsa04672-associated diagnostic biomarkers. Gene Set Variation Analysis (GSVA) revealed suppressed activity of hsa04672 in sepsis patients. Two independent methods (GSVA scores and consensus clustering) generated hsa04672-associated sepsis subgroups. Kaplan-Meier analyses subsequently confirmed significant survival differences between these subgroups, indicating a relationship between hsa04672 and sepsis prognosis. Afterwards, univariable Cox, LASSO, and multivariable Cox regression analyses identified ANKRD55, CX3CR1, and GIMAP4 as hsa04672-associated prognostic biomarkers. Based on these prognostic biomarkers, we constructed a nomogram model, whose accuracy and robustness were demonstrated through calibration curves, decision curve analyses, and time-dependent ROC curves. In the animal study, reduced intestinal IgA production was observed in severe sepsis. Single-cell analyses revealed the activities of hsa04672 and the expression patterns of biomarkers within each immune cell type across healthy controls, sepsis survivors, and sepsis nonsurvivors. MR analyses suggested that elevated CXCR4 expression was a risk factor of sepsis (OR = 1.27, 95% CI: 1.02-1.58, P = 0.036), and decreased GIMAP4 expression was a risk factor of 28-day death in sepsis (OR = 0.76, 95% CI: 0.60-0.98, P = 0.032). CONCLUSION: The "intestinal immune network for IgA production" is deeply involved in the development and progression of sepsis.