Daily ReportSep 25, 2026
Sepsis, September 25 edition
We read 37 papers and selected 3.
Summary
Today’s most impactful sepsis research spans three complementary advances: real-world evaluation of an electronic early-warning model, discovery of a circular RNA-mediated inflammatory mechanism, and prospective assessment of a point-of-care immune-function assay. Together, these studies address implementation safety, biological mechanism, and earlier risk stratification, while emphasizing the need for external validation and prospective outcome trials.
Research Themes
- Real-world implementation and safety of artificial intelligence for sepsis detection
- Circular RNA regulation of innate inflammatory signaling
- Point-of-care immune-function testing for early sepsis risk stratification
Selected Articles
1. Real-world effects of a sepsis early detection model integrated into clinical workflow: a quasi-experimental study.
In 89,469 inpatient encounters, visibility of Epic’s Early Detection of Sepsis Model was associated with lower inpatient mortality, prolonged hospitalization, antibiotic use, and false-positive treatment harm than expected under a counterfactual model. Observed mortality was 1.21% versus an expected 1.94%, while antibiotic use was 43.52% versus 47.74%.
Impact: This is one of the largest real-world evaluations of an integrated sepsis artificial-intelligence model and directly examines both benefit and potential overtreatment harm. The counterfactual analysis strengthens causal interpretation beyond a simple before-and-after comparison.
Clinical Implications: Workflow-integrated sepsis prediction may improve recognition and reduce unnecessary antibiotic use when paired with appropriate clinician oversight. The findings support prospective, multicenter evaluation before broad adoption and do not justify treating an algorithm alert as a diagnostic substitute.
Key Findings
- The study included 89,469 inpatient encounters: 75,215 before model visibility and 14,254 during the online period.
- Observed inpatient mortality was 1.21% versus 1.94% expected without the model, and prolonged hospitalization was 5.56% versus 8.14%.
- Antibiotic use decreased to 43.52% from 47.74% expected, while false-positive harm decreased to 37.72% from 42.31%.
Methodological Strengths
- Large encounter-level real-world dataset with a counterfactual framework estimating outcomes without model exposure.
- Assessment included both patient outcomes and potential harms related to antibiotic overtreatment and delayed treatment.
Limitations
- The study was conducted within a single healthcare system and may have limited transportability to other hospitals or populations.
- The quasi-experimental design cannot fully exclude residual confounding, secular trends, or concurrent workflow changes.
Future Directions: Future studies should use multicenter prospective or stepped-wedge designs, evaluate subgroup performance and alert burden, and determine whether benefits persist across different electronic health record systems and sepsis prevalence settings.
BACKGROUND: Sepsis is a life-threatening condition in which delayed recognition and treatment are associated with increased mortality. While predictive models such as Epic's Early Detection of Sepsis Model (ESM) were developed to support early intervention, their real-world effects after integration into clinical workflows remain difficult to evaluate. OBJECTIVES: To evaluate the real-world effects of ESM integrated into clinical workflow on clinical outcomes, antibiotic use, and harm-benefit tradeoffs. METHODS: We conducted a quasi-experimental study in a single healthcare system using encounter-level data from inpatient settings.
2. A circular RNA modulates IL-6 transcription via HuR-dependent stabilization of C/EBPβ mRNA.
Sequencing identified 1,298 high-confidence circular RNAs in lipopolysaccharide-stimulated murine macrophages, including 54 with significant expression changes. Mechanistic experiments showed that circNav1 binds HuR and stabilizes C/EBPβ mRNA, thereby enhancing interleukin-6 transcription; circNav1 was reduced in murine colitis and septic shock models.
Impact: The study identifies a previously uncharacterized circRNA–RNA-binding protein–transcription factor axis that links post-transcriptional RNA regulation to IL-6-driven inflammation. It provides a mechanistic framework for exploring circRNA-based modulation of sepsis biology.
Clinical Implications: The circNav1–HuR–C/EBPβ pathway is a potential mechanistic target for immunomodulatory therapy or biomarker development, but no immediate clinical application is established. Translational work must determine whether the pathway is conserved in human sepsis and whether its manipulation improves outcomes without impairing host defense.
Key Findings
- Among 1,298 high-confidence circRNAs in LPS-stimulated murine macrophages, 54 showed significant stimulus-associated expression changes.
- circNav1 interacted with HuR and promoted HuR-dependent stabilization of Cebpb mRNA.
- The circNav1–HuR–C/EBPβ axis enhanced Il6 transcription, while circNav1 expression was reduced in murine colitis and septic shock models.
Methodological Strengths
- Integrated circRNA sequencing, transcriptomic analysis, functional assays, and molecular interaction studies to investigate mechanism.
- Findings were examined in both cellular systems and murine inflammatory or septic shock models.
Limitations
- The reported experiments were predominantly murine and cellular, limiting direct extrapolation to human sepsis.
- The abstract does not establish whether manipulating circNav1 improves survival or organ dysfunction in a clinically relevant therapeutic setting.
Future Directions: Future research should validate circNav1 expression and pathway activity in longitudinal human sepsis cohorts, define cell-type-specific effects, and test targeted modulation in adequately powered in vivo models with survival and organ-function endpoints.
Inflammatory responses require precise posttranscriptional control of gene expression, yet the contribution of circular RNAs (circRNAs) to this process remains poorly understood. Here, we performed circRNA sequencing in murine macrophages stimulated with lipopolysaccharide (LPS) and identified dynamic and stimulus-dependent changes in circRNA expression. Among 1,298 high-confidence circRNAs, 54 showed significant expression changes upon LPS stimulation. We focused on circNav1, which was downregulated upon LPS stimulation. Functional analyses revealed that circNav1 enhances LPS-induced Il6 expression in macrophages.
3. Point-of-care LPS-induced TNF-α release testing for early sepsis risk stratification in the emergency department.
In a prospective emergency-department cohort of 203 adults with suspected infection and NEWS2 of at least 3, 180 had valid paired TARA measurements and 142 met Sepsis-3 criteria within 24 hours. Reduced LPS-induced TNF-α responsiveness was common; a parallel 0- or 4-hour negative TARA rule yielded 78.9% sensitivity but only 39.5% specificity, supporting an adjunctive rather than stand-alone role.
Impact: This study evaluates a biologically informed immune-function assay at the point of emergency presentation, including patients with relatively low clinical severity. Its main contribution is a realistic definition of utility: high sensitivity but low specificity, requiring integration with clinical assessment rather than replacement of it.
Clinical Implications: TARA may help identify patients with suspected infection who warrant closer sepsis assessment, including some patients with low NEWS2 or qSOFA scores. Because specificity and the negative predictive value were limited, TARA should not be used alone to rule in or rule out sepsis or to determine antibiotic therapy.
Key Findings
- Of 203 enrolled emergency-department patients, 180 had valid paired TARA results and 142 fulfilled Sepsis-3 criteria within 24 hours.
- Reduced LPS-induced TNF-α responsiveness was frequent, occurring in 75% of patients with valid paired testing.
- A parallel negative TARA rule had 78.9% sensitivity, 39.5% specificity, 83.0% positive predictive value, and 33.3% negative predictive value for Sepsis-3.
Methodological Strengths
- Prospective consecutive enrollment in the emergency department with repeated point-of-care immune-function measurements.
- Diagnostic performance was reported with confidence intervals, likelihood ratios, subgroup analyses, and adjustment for age and qSOFA.
Limitations
- The single-center or limited-setting observational design and selected inclusion criteria may restrict generalizability to unselected emergency populations.
- The assay had low specificity and negative predictive value, and predictive values may change substantially with sepsis prevalence.
Future Directions: Multicenter studies should assess TARA across broader emergency-department case mixes, evaluate serial testing and clinically relevant decision thresholds, and determine whether TARA-guided care improves time to treatment, antibiotic appropriateness, organ dysfunction, or mortality.
BACKGROUND AND OBJECTIVE: Early changes in innate immune responsiveness precede overt organ dysfunction in sepsis. In emergency department (ED) patients with suspected infection and physiological deterioration, we estimated the prevalence of reduced LPS-induced TNF-α responsiveness, characterized the associated clinical outcomes, and assessed the diagnostic accuracy of a point-of-care LPS-induced TNF-α release assay (TARA) for Sepsis-3 adjudicated at 24 h. METHODS: In this prospective observational cohort, adults with suspected infection and NEWS2 ≥3 were consecutively enrolled. Whole-blood samples collected at ED arrival (0 h) and 4 h later were stimulated