Sepsis, October 25 edition

This translational study combined longitudinal biomarker assessment in septic patients with mechanistic experiments in a murine cecal ligation and puncture model. Several glycocalyx-related abnormalities persisted after organ dysfunction and standard inflammatory markers normalized, while injectable melatonin reduced cytokine responses and partially restored circulating and tissue glycocalyx components.

Impact: The study identifies persistent endothelial injury as a potentially actionable component of post-acute sepsis biology rather than merely a transient consequence of shock. Its combination of human longitudinal data and animal mechanistic validation provides a credible rationale for testing endothelial-protective therapies.

Clinical Implications: Persistent glycocalyx biomarkers could eventually support monitoring of vascular recovery after apparent clinical stabilization. Melatonin should not yet be used routinely for sepsis vascular protection, but the findings justify controlled dose-finding and clinical outcome trials.

Future Directions: Future studies should validate persistent glycocalyx biomarkers in large, serially sampled patient cohorts and test melatonin or other endothelial-protective interventions in randomized trials using organ failure, vascular function, and long-term recovery outcomes.

Using plasma from patients with sepsis or septic shock and in vitro human platelet experiments, the study showed that septic plasma reduced platelet mitochondrial respiration and Complex I activity while increasing epinephrine-induced platelet activation. The mitochondria-targeted ROS scavenger MitoTEMPO reversed these effects, suggesting a mechanistic link between mitochondrial oxidative injury and thromboinflammation.

Impact: This study provides a direct human experimental mechanism connecting septic plasma, platelet mitochondrial dysfunction, and platelet hyperactivation. It identifies mitochondrial ROS handling as a potentially targetable pathway for limiting sepsis-associated thromboinflammatory organ injury.

Clinical Implications: The findings support further investigation of mitochondrial antioxidants as adjunctive therapies in sepsis, but they do not establish clinical efficacy or safety. Future interventions will need to preserve host hemostasis while reducing pathological platelet activation.

Future Directions: The mechanism should be validated in larger patient cohorts and in vivo sepsis models, followed by studies defining therapeutic timing, platelet-specific effects, interactions with antithrombotic treatment, and clinically relevant outcomes.

In this prospective multisite study of 110 neonates evaluated for late-onset sepsis, culture-proven sepsis showed significant proteomic differences from non-sepsis, whereas culture-negative sepsis did not. Extracellular particle concentration and type did not differ between groups, supporting the biological distinction between culture-proven and culture-negative diagnoses and suggesting that identified proteins may help define neonatal sepsis endotypes.

Impact: The study challenges the common practice of treating culture-negative and culture-proven neonatal sepsis as biologically equivalent. It provides a prospective molecular basis for developing endotype-specific diagnostics and reducing unnecessary antimicrobial exposure in neonates.

Clinical Implications: Proteomic signatures may eventually improve diagnostic classification when blood cultures are negative, but they require independent validation before guiding antibiotic initiation or discontinuation. The findings reinforce the need for a standardized definition of culture-negative neonatal sepsis.

Future Directions: Future research should validate the protein signatures in larger, internationally diverse neonatal cohorts, establish prespecified diagnostic thresholds, and test whether proteomic classification can safely guide antimicrobial stewardship and risk-adapted treatment.