Daily Sepsis Research Analysis

BACKGROUND: Sepsis survivors often experience sustained muscle weakness, leading to physical disability, with no pharmacological treatments available. Despite these well-documented long-term clinical consequences, research exploring the cellular and molecular mechanisms is sorely lacking. METHODS: Bioinformatic analysis was performed in the vastus lateralis transcriptome of human ICU survivors 7 days after ICU discharge (D7), 6 months (M6) and age- and sex-matched controls. Enrichment analysis using Gene Ontology (GO) terms and Mitocarta3.0 was performed at D7 and M6 on differentially expressed genes (DEGs) and modules identified by weighted gene co-expression network analysis (WGCNA). Using a murine model of resuscitated sepsis induced by caecal slurry injection, pathways identified by the bioinformatics analysis were explored in 18- to 24-week-old sepsis-surviving (SS) mice at Day 10. Autophagy flux was investigated both in vivo and in vitro with chloroquine, a lysosomal inhibitor and urolithin A (UA), an autophagy inducer. Systemic metabolism was evaluated with indirect calorimetry, muscle phenotype with in situ and ex vivo contractility, muscle mass, myofibre cross-sectional area and typing and mitochondrial population with transmission electron microscopy (TEM), as well as mitochondrial function with high-resolution respirometry. Autophagic vacuole (AV) level was monitored using LC3B-II and P62 protein expression and TEM. RESULTS: Pathways related to 'mitochondrion' were the only ones whose deregulation persisted between D7 and M6 (p < 0.05) and characterized WGCNA modules correlated with muscle mass, strength and physical function. Shared mitochondrial DEGs between D7 and M6 encoded matrix mitochondrial proteins related to 'metabolism' and 'mitochondrial dynamics'. SS mice exhibited reduced complex I-driven oxygen consumption (CI-J CONCLUSION: Mitochondrial and autophagy disruption contributes to long-term muscle dysfunction in human and mouse sepsis survivors. We demonstrate for the first time that sepsis induces an autophagy flux blockade. Urolithin A prevents mitochondrial and muscle impairments both in vivo and in vitro by improving autophagy flux.

Implant-associated infections remain a significant complication in medicine. often leading to chronic infection, tissue damage, or implant failure. To address this, this work develops a modular, triple-action titanium implant that integrates bacterial repellency, bactericidal activity, and enhanced tissue integration. The implant comprises medical-grade titanium with a co-deposited layer of bacteriophages and collagen stably embedded within a repellent lubricant layer. The collagen layer promotes cell deposition and spreading in vitro. When tested against Pseudomonas aeruginosa, the coating reduces bacterial load by 3.2 logs on the surface and 1.9 logs in the medium, outperforming conventional liquid-infused surfaces. A modified version targeting Staphylococcus aureus achieves 4.1-log and 5.2-log reductions, respectively, after a 6-h incubation. When challenging the coating in a sepsis survival model of Pseudomonas aeruginosa infection, mice with the phage-activated implants exhibit a 100% survival rate and fully recover from the infection. In comparison, those with pathogen-repellent and untreated titanium implants show survival rates of only 30% and 10%, respectively. Furthermore, phage, but no bacteria, are detected in the bloodstream of mice implanted with phage-activated titanium, suggesting that locally implanted phage-biomaterials can distribute systemically to control blood infections. Therefore, the engineered phage-activated, triple-action biomaterials may prevent implant-associated infections locally and systemically.

BACKGROUND: Systemic inflammation is a critical clinical condition regularly observed in the context of surgery-induced trauma or infection. Systemic inflammation induces an ubiquitous activation of the vasculature and vascular dysfunction related to organ damage and adverse outcomes. The dipeptidyl peptidase-4 (DPP4) modulates the receptor preferences and activity of a multitude of humoral substrates mediating the systemic inflammatory response. We here determined whether DPP4 inhibition is a means to beneficially modulate systemic inflammatory responses affecting vascular and organ integrity. METHODS: In cardiac surgery patients medicated with DPP4 inhibitors, we used a systems biology approach for in-depth characterization of the perioperative immune response and assessment of macro- and microvascular dynamics compared to control patients. In parallel, we mechanistically evaluated the efficacy of DPP4 inhibition on modulating immune responses, capillary leakage, vasoplegia and endothelial transcriptomic profiles in mice with severe systemic inflammation. RESULTS: Preoperative oral intake of the DPP4 inhibitor sitagliptin modulated innate and adaptive immune phenotypes and was associated with augmented microvascluar integrity, reduced vasoplegia and improved clinical parameters of capillary leakage in patients undergoing cardiac surgery. In mice, DPP4 inhibition curbed the inflammatory response to a polymicrobial sepsis resulting in a massive reduction in endothelial gene activation assoicated with preserved vascular barrier function, augmented vasopressor responses and organ integrity. CONCLUSIONS: We conclude that DPP4 inhibition may be a safe and potent means to curb immune responses to surgery or infection, resulting in a preservation of vascular integrity that translates into organ protection and improved clinical outcomes. TRIAL REGISTRATION: https://www. CLINICALTRIALS: gov ; Unique identifier: NCT05725798, study start: 2022-02-01.