Causal Association Between Heart Failure and Sepsis: Insights from Mendelian Randomization and Observational Studies. Clinical epidemiology Purpose:We aimed to identify the association between heart failure (HF) with sepsis and its mortality through Mendelian randomization (MR) and observational studies. Patients and Methods:In MR study, we utilized public summary statistics from genome-wide association studies (GWAS). We conducted univariable, multivariable and network MR analyses to investigate causal relationships between HF and sepsis, and mediating roles of cytokines and growth factors. We performed an observational analysis using the MIMIC-IV database. Propensity score matching (PSM) and logistic regression models were employed to explore causal relationships between HF and sepsis, besides short-, medium-, and long-term mortality associated with sepsis. Results:In univariable MR analysis, there was a causal relationship between genetically predicted HF (OR = 1.15, 95% CI = 1.02-1.29, P = 0.025) and sepsis. In multivariable and network MR analyses, βNGF was independently associated with sepsis. And it mediated 17.6% (95% CI 2.45-30.72%) of HF effect on sepsis. In the real-world observational study, acute on chronic diastolic (congestive) heart failure (DCHF) (OR = 1.59, 95% CI = 1.31-1.93, P < 0.001), acute DCHF (OR = 2.52, 95% CI = 1.61-3.95, P = 0.010), and acute diastolic heart failure (DHF) (OR = 1.52, 95% CI = 1.06-2.19, P = 0.024) after PSM were associated with occurrence of sepsis. Chronic systolic (congestive) heart failure (SCHF) was associated with increased 28-day (OR = 1.75, 95% CI = 1.06-2.91, P = 0.030), 1-year (OR = 1.80, 95% CI = 1.08-3.00, P = 0.023), and 2-year (OR = 1.86, 95% CI = 1.12-3.10, P = 0.018) mortality in sepsis. Conclusion:Observational and MR analyses showed a causal relationship between HF and sepsis. Chronic SCHF was related to increased short/long-term mortality in sepsis. Our study indicated βNGF a key factor in HF-induced sepsis. 10.2147/CLEP.S487118

An early and stable mouse model of polymyxin-induced acute kidney injury. Intensive care medicine experimental BACKGROUND:Polymyxins have been revived as a last-line therapeutic option for multi-drug resistant bacteria and continue to account for a significant proportion of global antibiotic usage. However, kidney injury is often a treatment limiting event with kidney failure rates ranging from 5 to 13%. The mechanisms underlying polymyxin-induced nephrotoxicity are currently unclear. Researches of polymyxin-associated acute kidney injury (AKI) models need to be more standardized, which is crucial for obtaining consistent and robust mechanistic results. METHODS:In this study, male C57BL/6 mice received different doses of polymyxin B (PB) and polymyxin E (PE, also known as colistin) by different routes once daily (QD), twice daily (BID), and thrice daily (TID) for 3 days. We continuously monitored the glomerular filtration rate (GFR) and the AKI biomarkers, including serum creatinine (Scr), blood urea nitrogen (BUN), neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1). We also performed histopathological examinations to assess the extent of kidney injury. RESULTS:Mice receiving PB (35 mg/kg/day subcutaneously) once daily exhibited a significant decrease in GFR and a notable increase in KIM-1 two hours after the first dose. Changes in GFR and KIM-1 at 24, 48 and 72 h were consistent and demonstrated the occurrence of kidney injury. Histopathological assessments showed a positive correlation between the severity of kidney injury and the changes in GFR and KIM-1 (Spearman's rho = 0.3167, P = 0.0264). The other groups of mice injected with PB and PE did not show significant changes in GFR and AKI biomarkers compared to the control group. CONCLUSION:The group receiving PB (35 mg/kg/day subcutaneously) once daily consistently developed AKI at 2 h after the first dose. Establishing an early and stable AKI model facilitates researches into the mechanisms of early-stage kidney injury. In addition, our results indicated that PE had less toxicity than PB and mice receiving the same dose of PB in the QD group exhibited more severe kidney injury than the BID and TID groups. 10.1186/s40635-024-00667-y