Daily Sepsis Research Analysis

BACKGROUND: Antimicrobial resistant (AMR) pathogens represent urgent threats to human health, and their surveillance is of paramount importance. Metagenomic next-generation sequencing (mNGS) has revolutionized such efforts, but remains challenging due to the lack of open-access bioinformatics tools capable of simultaneously analyzing both microbial and AMR gene sequences. RESULTS: To address this need, we developed the Chan Zuckerberg ID (CZ ID) AMR module, an open-access, cloud-based workflow designed to integrate detection of both microbes and AMR genes in mNGS and single-isolate whole-genome sequencing (WGS) data. It leverages the Comprehensive Antibiotic Resistance Database and associated Resistance Gene Identifier software, and works synergistically with the CZ ID short-read mNGS module to enable broad detection of both microbes and AMR genes from Illumina data. We highlight diverse applications of the AMR module through analysis of both publicly available and newly generated mNGS and single-isolate WGS data from four clinical cohort studies and an environmental surveillance project. Through genomic investigations of bacterial sepsis and pneumonia cases, hospital outbreaks, and wastewater surveillance data, we gain a deeper understanding of infectious agents and their resistomes, highlighting the value of integrating microbial identification and AMR profiling for both research and public health. We leverage additional functionalities of the CZ ID mNGS platform to couple resistome profiling with the assessment of phylogenetic relationships between nosocomial pathogens, and further demonstrate the potential to capture the longitudinal dynamics of pathogen and AMR genes in hospital acquired bacterial infections. CONCLUSIONS: In sum, the new AMR module advances the capabilities of the open-access CZ ID microbial bioinformatics platform by integrating pathogen detection and AMR profiling from mNGS and single-isolate WGS data. Its development represents an important step toward democratizing pathogen genomic analysis and supporting collaborative efforts to combat the growing threat of AMR.

BACKGROUND: The optimal timing for initiating norepinephrine in septic shock is debated. This updated systematic review and meta-analysis aimed to evaluate the impact of early versus delayed norepinephrine initiation on mortality and clinical outcomes in adults with septic shock. METHODS: A systematic search in Pubmed, EMbase and the Cochrane Library to identify eligible randomized controlled trials, propensity score matching (PSM) and observational studies that compare early norepinephrine initiation with non-early norepinephrine initiation in patients with acute circulatory failure. The primary outcome was mortality in intensive care unit. Secondary outcomes included intensive care unit length of stay, fluid volume received at 6 h, norepinephrine dose, mechanical ventilation-free days, renal replacement therapy free days, and time to achieve a targeted mean arterial pressure (MAP). Meta-analysis and subgroup analysis were conducted to calculate odds ratio (OR) or mean difference with 95% confidence interval (95%CI) using random-effect model. Trial sequential analysis was conducted to evaluate the conclusiveness of evidence. RESULTS: Ten studies (two RCT, three PSM and five observational studies) involving 4767 patients were included. Early norepinephrine significantly reduced mortality in RCT (OR 0.49, 95%CI 0.25-0.96; I CONCLUSION: Early norepinephrine introduction in septic shock is associated with reduced mortality, decreased fluid volume administered at 6 h, faster time to achieve MAP target and more mechanical ventilation-free days. However, the trial sequential analysis indicates that further RCT are still needed to confirm these findings.

BACKGROUND: Sepsis is a critical and life-threatening clinical syndrome. Abnormal plasma lipid levels are associated with disease progression. However, causal links remain uncertain due to limitations of observational studies. METHODS: This study conducted a comprehensive two-sample Mendelian randomization (MR) analysis utilizing publicly available pooled genome-wide association study (GWAS) data on 179 plasma phospholipid subtypes, 731 immune cell phenotypes, and genetic data related to sepsis-related mortality outcomes. The causal associations between plasma lipids, immune cell phenotypes, and the risk of sepsis-related death were investigated. RESULTS: MR results demonstrated significant causal associations between five subtypes of phosphatidylcholine (PC) and one sphingomyelin (SM) and the clinical outcome of 28-day mortality in sepsis patients. Notably, PC(16:0_18:2), PC(18:0_18:1), PC(18:0_20:4), PC(O-16:1_16:0), and SM(d34:0) demonstrated a protective effect in reducing the risk of 28-day mortality(P < 0.05). Conversely, PC(16:1_20:4) was associated with an increased risk of 28-day mortality in sepsis patients(P < 0.05). Comprehensive sensitivity analyses confirmed the robustness of these results. The inverse Mendelian randomization analysis did not reveal a significant causal effect of sepsis on the aforementioned lipid profile. Mediation analysis identified two key immune cell-mediated factors, including circulating CD39 on CD39 + CD8br cells and CX3CR1 on CD14+ CD16+ monocytes, as mediators of the reduced risk of sepsis-associated mortality due to PC(O-16:1_16:0), with mediation proportions of 17.4% and 13.6%, respectively. CONCLUSIONS: Our study supports a causal relationship between plasma lipid metabolism disorders and sepsis-associated mortality and provides new insights into the critical role of immune cell alterations induced by lipid metabolism disorders in sepsis progression.