Daily Sepsis Research Analysis
Mechanistic and translational studies advance sepsis care along three fronts: preserving endothelial integrity, preventing device-associated thrombosis, and accelerating antimicrobial susceptibility testing. A mechanistic study links SGLT2 inhibition to ApoM preservation and reduced vascular leak; a nano-selenium hydrogel coating suppresses thrombosis even under septic conditions; and direct AST from positive blood cultures shows high agreement with standard methods while cutting turnaround by 2
Summary
Mechanistic and translational studies advance sepsis care along three fronts: preserving endothelial integrity, preventing device-associated thrombosis, and accelerating antimicrobial susceptibility testing. A mechanistic study links SGLT2 inhibition to ApoM preservation and reduced vascular leak; a nano-selenium hydrogel coating suppresses thrombosis even under septic conditions; and direct AST from positive blood cultures shows high agreement with standard methods while cutting turnaround by 24 hours.
Research Themes
- Endothelial barrier protection in systemic inflammation and sepsis
- Device-associated thrombosis mitigation under inflammatory/septic conditions
- Rapid antimicrobial susceptibility testing directly from positive blood cultures
Selected Articles
1. In situ self-growth nano-selenium hydrogel coating alleviates surface thrombosis of blood-contacting devices by inactivating inflammatory cells.
An in situ self-growing nano-selenium hydrogel coating reprogrammed macrophages (↓M1, ↑M2; +146% M2/M1) and reduced procoagulant activity (↓TF release, ↓thrombin). It suppressed coagulation and thrombus formation in an LPS-induced rabbit model and in patients with clinical sepsis, and reduced thrombosis and inflammatory activation on CVCs in rabbit and pig models.
Impact: Introduces a mechanistically grounded, anti-inflammatory device coating that mitigates thrombosis under intense inflammatory/septic conditions, spanning small and large animal models with translational signals in patients.
Clinical Implications: If validated clinically, such coatings could reduce catheter-related thrombosis and inflammation in critically ill and septic patients, potentially lowering complications and device failure. Implementation would require safety profiling (e.g., selenium exposure), durability testing, and infection-control assessment.
Key Findings
- Nano-selenium coating shifted macrophages toward an anti-inflammatory phenotype (M2/M1 ratio increased by 146%) and reduced pro-inflammatory cytokines.
- The coating decreased macrophage tissue factor release and thrombin production, suppressing coagulation in an LPS-induced rabbit model and in patients with clinical sepsis.
- Central venous catheters with the coating reduced thrombosis and vascular inflammatory activation in rabbit and pig vascular models.
Methodological Strengths
- Convergent evidence across in vitro assays, small (rabbit) and large (pig) animal models, and translational observations in septic patients.
- Mechanistic linkage to macrophage polarization and coagulation pathways (tissue factor/thrombin).
Limitations
- Human data are limited; no randomized clinical outcomes were reported.
- Long-term biocompatibility, durability, and potential selenium toxicity were not fully characterized.
Future Directions: Conduct multicenter safety and efficacy trials in high-risk ICU/sepsis populations, assess infection risk and device colonization, and optimize coating composition and growth parameters.
The formation of thrombi in blood-contacting devices is accompanied by a several risks that can be life-threatening. Specifically, the process of blood exposure immediately after implantation triggers an immune response aimed at removing foreign substances, which can lead to thrombosis, inflammation and device malfunction. To confer anticoagulant properties to the implanted devices, a nano-selenium hydrogel coating which was in-situ self-growing on implant devices had been developed that inhibited thrombosis by intervening in the inflammatory cell activation pathway, possibly by decreasing tissue factor activity and thrombin production expressed by inflammatory cells. Compared with the selenium-free coating, the nano-selenium hydrogel coating significantly inhibited macrophage activation, as demonstrated by reduced M1 phenotype and increased M2 phenotype polarization, resulting in a 146 % increase in the M2/M1 ratio, together with the reduction of secretion of pro-inflammatory cytokines. More importantly, the selenium coating reduced macrophage procoagulant activity through macrophage inactivation, resulting in decreased tissue factor (TF) release and thrombin production. Remarkably, the coating suppressed the coagulation response in a rabbit model of LPS-induced inflammation and in patients with clinical sepsis, thereby reducing thrombus formation manifested by decreased fibrin deposition and reduced monocyte markers. Further studies demonstrated that coated central venous catheters (CVCs) in rabbit and pig vascular models diminished thrombosis and vascular inflammatory activation. Overall, this active anti-inflammatory hydrogel coating strategy is effective in inhibiting thrombus formation on blood-contacting device surfaces, especially in more challenging bloodstream environments.
2. Sodium-Glucose Cotransporter Inhibition Preserves Apolipoprotein M During Acute Inflammation in Mice and Humans.
Dapagliflozin preserved ApoM during acute inflammation by maintaining renal LRP2, increased ApoM in randomized human participants, and reduced LPS-induced vascular leak in an ApoM-dependent manner. The findings provide a mechanistic link between SGLT2 inhibition, ApoM biology, and endothelial barrier integrity relevant to sepsis pathophysiology.
Impact: This is a novel mechanistic demonstration that SGLT2 inhibition preserves ApoM via LRP2 and stabilizes the endothelial barrier, connecting a widely used cardiometabolic drug class to a sepsis-relevant survival pathway.
Clinical Implications: Supports testing SGLT2 inhibitors as adjunctive therapy to preserve endothelial integrity in sepsis or systemic inflammation. ApoM may serve as a pharmacodynamic biomarker to enrich and monitor such trials.
Key Findings
- Dapagliflozin restored circulating ApoM in LPS-treated mice (0.017 vs 0.035 a.u./μL; P=0.0489).
- In randomized human participants receiving SGLT2 inhibitors, ApoM increased (0.5240 vs 0.6537 μM; P=0.0101).
- LRP2 knockout abrogated the ApoM effect; in vitro Lrp2-dependent ApoM uptake increased; vascular leak reduction was ApoM-dependent.
Methodological Strengths
- Triangulation across mouse models, randomized human cohort, and mechanistic in vitro assays.
- Genetic validation using proximal tubule-specific Lrp2 knockout.
Limitations
- Clinical outcomes (e.g., mortality, organ failure) were not assessed.
- Human sample size and sepsis-specific cohorts were not detailed; human data derived from COVID-19 context.
Future Directions: Randomized controlled trials in sepsis to test SGLT2 inhibitors for endothelial leak reduction and improved outcomes, with ApoM as a mechanistic biomarker.
BACKGROUND: Sodium-glucose cotransporter inhibitors (SGLT2is) reduce inflammation and maintain vascular integrity. Apolipoprotein M (ApoM) is crucial for vascular integrity via sphingosine-1-phosphate (S1P) signaling and is inversely linked with mortality in sepsis and COVID-19. OBJECTIVES: The authors tested if SGLT2i (dapagliflozin [Dapa]) increases ApoM in mice using lipopolysaccharide (LPS) and in humans with COVID-19. METHODS: Diet-induced obese mice (n = 14-15/group), proximal tubule-specific knockout of the multiligand protein receptor Lrp2 (Lrp2 RESULTS: Dapa restored circulating ApoM levels in LPS-treated mice (0.017 vs 0.035 [a.u./μL], P = 0.0489) and increased ApoM levels in patients randomized to SGLT2i (0.5240 vs 0.6537 [μM], P = 0.0101). LRP2 knockout blocked Dapa's effect on ApoM. In vitro, Dapa stimulated Lrp2-dependent uptake of ApoM-GFP. Dapa attenuated vascular leak induced by LPS in an ApoM-dependent manner. CONCLUSIONS: SGLT2i maintains Lrp2 levels, preserving ApoM and promoting endothelial barrier integrity in acute inflammation, indicating a novel protective mechanism of SGLT2i through ApoM preservation.
3. Evaluation of BD Phoenix and VITEK 2 for direct and routine antimicrobial susceptibility from positive blood culture bottles.
In 128 ESKAPE isolates from positive blood cultures, direct AST (DAST) using BD Phoenix and VITEK 2 showed high categorical agreement with routine and standard testing. VITEK 2 was consistently reliable for Gram-negative bacteria, and BD Phoenix performed strongly for direct AST across organisms. Implementing DAST reduced turnaround time by 24 hours.
Impact: Rapid, accurate AST directly from positive blood cultures can accelerate effective therapy in sepsis, potentially improving outcomes while informing stewardship.
Clinical Implications: Clinical microbiology labs can adopt DAST workflows to shorten time-to-result by 24 hours. Platform choice may be tailored: VITEK 2 for Gram-negative reliability, BD Phoenix for robust direct testing performance, with local verification and protocols for discordance resolution.
Key Findings
- DAST vs RAST categorical agreement (BD Phoenix): 95.3% (Enterobacterales), 100% (non-fermenters), 100% (Gram-positive cocci).
- DAST vs RAST categorical agreement (VITEK 2): 94.8%, 94.7%, 80%, and 100% across Enterobacterales, non-fermenters, S. aureus, and Enterococci spp.
- RAST vs SAST categorical agreement: BD Phoenix 86.9%, 95.3%, 100%, 82.3%; VITEK 2 91.8%, 91.9%, 85.7%, 84.6% across the same groups; DAST reduced turnaround time by 24 hours.
Methodological Strengths
- Head-to-head comparison of two automated platforms using DAST, RAST, and SAST with explicit categorical agreement metrics.
- Focus on clinically relevant ESKAPE pathogens from positive blood cultures.
Limitations
- Single-laboratory methodology study with 128 isolates; external validity may be limited.
- Clinical impact (time to effective therapy, outcomes) not directly measured.
Future Directions: Multicenter validation including outcome-linked implementation studies; expand organism/antibiotic panels and harmonize DAST protocols.
OBJECTIVES: This study aims to comparatively evaluate the reliability of BD Phoenix and VITEK 2 systems for direct, routine and standard antimicrobial susceptibility testing (AST) of ESKAPE isolates from positive blood culture bottles, with a primary focus on the interpretation of results into susceptible, intermediate, or resistant categories. METHODS: A total of 128 ESKAPE isolates from positive blood culture bottles were subjected to direct, routine and standard AST. Direct AST (DAST) and routine AST (RAST) were performed using BD Phoenix and VITEK 2 automated systems. DAST was conducted using a bacterial pellet obtained directly from positive blood cultures, while RAST used a colony after subculture. Results of both were compared based on categorical agreement (CA) and discrepancies. RAST results were further evaluated against standard AST (SAST), performed via the Kirby-Bauer disc diffusion assay using 24 h-grown colonies. FINDINGS AND RESULTS: The AST categorical agreements (CA) of DAST with the RAST using BD Phoenix automated system for Enterobacterales, Non-fermenting, and Gram-positive cocci (S. aureus and Enterococci spp.) were 95.3 %, 100 %, and 100 % respectively, while 94.8 %, 94.7 %, 80 % and 100 % respectively in VITEK 2. CA between RAST and SAST is 86.9 %, 95.3 %, 100 %, and 82.3 % respectively with BD Phoenix, while 91.8 %, 91.9 %, 85.7 %, and 84.6 % respectively with VITEK 2, on the same group of bacteria. The VITEK 2 automated system showed consistency of results with >90 % CA suggesting high reliability for both direct and routine AST in Gram-negative bacteria. CONCLUSION: VITEK 2 demonstrated consistently high reliability for both direct and routine AST in Gram-negative bacteria. The BD ph