INTRODUCTION:Increasing chronological age drives dynamic changes in platelet functionality, bringing unique biologic challenges to the injured older adult. While platelets play an indispensable role in injury response, the impact of age on platelet dynamics after injury remains elusive. We examine the associations of age and platelet dynamics for injured patients not on antiplatelet therapy, hypothesizing that aging is associated with decreases in platelet count and function in injured patients. METHODS:We performed a secondary analysis of injured patients from a prospective observational study of coagulation and inflammation (2010-2024). Patients taking anticoagulants, antiplatelets, and/or with isolated traumatic brain injury were excluded. Univariable and multivariable associations of age and platelet count and function profiles (impedance aggregometry and viscoelastic testing) at presentation and up to seven days post-injury were analyzed. Platelet profiles, thromboembolic events, and mortality relationships were analyzed by stratifying age to <55 and ≥55 years. RESULTS:716 patients were examined. Median age was 36 years (range 15-97 years). On multivariable analyses platelet count and functional profiles demonstrated independent associations with increasing age at all time points measured - reduced platelet count, aggregation responses, and hypercoagulable clotting dynamics. In patients ≥55 years low platelet count and reduced aggregation responses on presentation were suggestive of increased mortality (all p<0.05). CONCLUSION:Following injury, increasing chronological age is independently associated with altered platelet profiles - reduced platelet count and aggregation responses with concurrent hypercoagulable clotting dynamics. These age-related cellular changes may portend worse outcomes, including mortality, and should be considered for intervenable biologic targets in future study.
Post cardiac arrest Syndrome (PCAS) is a systemic ischemia-reperfusion injury (IRI) that occurs after the return of spontaneous circulation (ROSC), characterized by endothelial dysfunction, systemic inflammatory response syndrome (SIRS), and multiple organ failure (MOF). This review focuses on the pathophysiological mechanisms, dynamic change patterns, and prognostic predictive value of three key categories of biomarkers in PCAS: inflammatory factors, endothelial injury biomarkers, and neuronal injury biomarkers. It covers the dual roles of inflammatory mediators such as Interleukin-6 (IL-6), Interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-α), and procalcitonin (PCT); the early warning value of syndecan-1 (SDC-1), hyaluronic acid (HA), heparan sulfate (HS) and other endothelial injury markers; as well as the prognostic characteristics of neuronal biomarkers including neuron-specific enolase (NSE), s100 calcium binding protein beta subunit (S100-B), Tau proteins, neurofilament light chain (NFL), ubiquitin carboxyl-terminal hydrolase-L1 (UCH-L1), and glial fibrillary acidic protein (GFAP). The review proposes that an integrated strategy of multi-omics and multimodal biomarkers can significantly improve the accuracy of prognostic assessment, thereby providing a new theoretical basis and development direction for the early intervention and individualized treatment of PCAS.
BACKGROUND:Traumatic brain injury (TBI) is an underrecognized public health threat. Significant long-term complications can occur resulting in motor, cognitive, and behavioral deficits. Trauma occurs predominately in male populations, skewing studies towards men. Creating a critical unmet research need to better understand the pathophysiologic differences in traumatic injury between sexes. Women TBI patients differ in severity and mortality, often suffering from greater long-term neuropsychiatric disorders as compared to men. Sex hormones may account for the observed differences. We hypothesized that microglia would adopt a divergent, sex-dependent, TBI- associated transcriptional profile after TBI. METHODS:Young-adult male and female mice underwent a severe TBI via controlled cortical impact or sham injury. Behavioral phenotyping was performed at 30-days post injury to assess anxiety, memory and motor deficits. A second cohort of mice had brains harvested, microglia sorted via flow cytometry, and single- cell RNA sequencing performed. RESULTS:Female mice demonstrated disinhibition of normal anxiety-like and exploratory behavior in comparison to male mice post TBI. Additionally, female TBI mice had attenuation of memory deficits as compared to male TBI mice. Lastly, we observed a marked divergence in the transcriptional profiles of microglia at baseline and after TBI in female mice as compared to male mice. CONCLUSION:Our data showed a significant difference in anxiety and memory deficits after TBI between male and female mice. Which was associated with a marked difference in the transcriptional profile of microglia between male and female mice. These data suggest that sex needs to be an a priori consideration in clinical TBI trials.
Delirium is a frequent neuropsychiatric complication in critical illness associated with increased risk of long-term cognitive impairment and mortality. We hypothesized that lower cerebral tissue oxygen saturation (cStO2) levels measured with near infrared spectroscopy (NIRS) associate with worse outcome, including mortality, and the risk for developing delirium in circulatory shock. We conducted the prospective, observational, multi-center study (ASSESS-SHOCK, ClinicalTrials.gov: NCT03814564), from April 2019 to May 2023. We enrolled adult circulatory shock patients within 24 hours of intensive care unit (ICU) admission. We registered cStO2 continuously for 48 hours using INVOS™ NIRS devices. We calculated the time-weighted mean cStO2 values and areas under the predefined thresholds of 60%, 50%, and 40% respectively. The primary objective was the association of time-weighted mean cStO2 during 0-48 hours with development of delirium during days 1-7. Secondary endpoints were ICU- and 90-day mortality. We included 256 patients, of whom 87 (34%) developed delirium. The 0-48 h mean cStO2 values did not differ between patients with and without delirium: 61.6% (interquartile range [IQR] 57.3 to 67.7) vs 63.1% (IQR 57.7 to 68.1, p=0.716), respectively. Lower time-weighted mean cStO2 during 48 hours was, however, associated with higher 90-day mortality: in non-survivors cStO2 was 60.0% (IQR 52.8 to 64.7) compared to 63.9% (IQR 58.1 to 68.9) in survivors (p<0.001). Conclusions: In circulatory shock, lower mean cStO2 values were not associated with delirium but they were associated with 90-d mortality. NIRS monitoring could serve as an adjunct method for identifying patients at risk for developing adverse outcomes, including mortality. Trial registration: ClinicalTrials.gov Identifier: NCT03814564, registered 15 January 2019. The ASSESS-SHOCK study: Assessment of peripheral perfusion, tissue oxygen saturation, endothelial function, and coagulation disorder in circulatory shock.
BACKGROUND:Sex-based differences in trauma outcomes are well documented, but the early molecular programs distinguishing male and female responses remain incompletely defined. We hypothesized that biological sex shapes the circulating proteomic and metabolomic response at emergency department arrival and that these signatures interact with age, injury severity, and shock physiology. METHODS:Patients meeting the highest level of trauma activation criteria were prospectively enrolled. Blood samples were collected upon arrival to the emergency department within one hour of injury and before transfusion. Plasma proteomics and metabolomics were performed by liquid chromatography-mass spectrometry. Sex differences were assessed by feature-level testing with Benjamini-Hochberg FDR correction. Multivariable linear models adjusted for age, ISS, base deficit, lactate, mechanism, and head/neck injury. Spearman correlations and network visualization integrated omics and clinical variables. RESULTS:Among 292 patients (236 male, 56 female), baseline characteristics were similar. Unadjusted analyses identified 45 proteins and 9 metabolites differing by sex. Female-enriched proteins included PZP, CERU, SHBG, VTNC, ITIH3, and IGHM; male-enriched included FCN3, AMPN, APOD, GELS, NCAM1, ANTR2, MASP1, and GPX3. After adjustment, sex remained independently associated with FCN3, SHBG, PTPRG, CERU, FUCO, PZP, and APOD. Sex-associated metabolite differences were more strongly coupled to injury severity and shock physiology than to sex alone. CONCLUSION:Male and female trauma patients demonstrate distinct early multi-omic signatures, including sex-associated immune, complement, redox, and metabolic programs that persist after adjustment for injury severity and shock physiology. Sex-informed omics may improve biological endotyping and precision approaches to trauma care.
Persistent inflammation, immunosuppression, and catabolism syndrome (PIICS) is a major cause of prolonged morbidity and poor outcomes among critical illness survivors. We established long-term murine PIICS models using two peritonitis-induced sepsis methods-cecal ligation and puncture (CLP) and fecal suspension intraperitoneal injection (FSI)-and investigated their immunological and histopathological features over 2 months. Survivors were defined as PIICS model mice, with unoperated mice serving as controls. Following an intraperitoneal lipopolysaccharide (LPS; 10 mg/kg) challenge, 27 plasma cytokines and chemokines were quantified before and 20 h after administration, and survival was monitored for 14 days. Survivors of CLP and FSI exhibited sustained baseline elevations in inflammatory mediators (G-CSF, IL-7, CCL3/4) and reductions in anti-inflammatory cytokines (IL-13, TGF-β2) compared with those in controls. Following the LPS challenge, control mice showed robust cytokine induction, and 4 of 13 died, whereas both PIICS groups exhibited globally suppressed cytokine responses with no mortality (p = 0.011 vs. controls). Histopathological staining showed mild splenic macrophage infiltration at baseline in both PIICS groups. Upon LPS administration, pulmonary congestion, splenic macrophage infiltration, and neutrophil infiltration into the portal vein were observed. Intra-abdominal abscesses or granuloma-like masses occurred in 50% of CLP-PIICS mice. Collectively, these long-term PIICS models recapitulate key clinical features, including persistent dysregulated inflammation, impaired responsiveness to secondary stimuli, and chronic tissue pathology, providing a platform to investigate the transition from acute sepsis to PIICS and for preclinical testing of immune-restorative or metabolic interventions in survivors of sepsis.
Approximately 50% of sepsis patients develop acute skeletal muscle atrophy and dysfunction. Autophagy plays an important role in skeletal muscle atrophy and dysfunction, and skeletal muscle autophagy is known to be regulated by multiple miRNAs. In this study, we found that miR-15a-3p was significantly upregulated in published Gene Expression Omnibus (GEO) datasets of septic patients and septic mouse skeletal muscle. Correlation analysis revealed that miR-15a-3p was associated with autophagy activation in septic patients and septic mouse skeletal muscle. Inhibition of miR-15a-3p attenuated excessive autophagy and ameliorated skeletal muscle atrophy in septic mice and differentiated C2C12 myotubes. Overexpression of miR-15a-3p increased autophagy and skeletal muscle atrophy in mice and differentiated C2C12 myotubes. Furthermore, we identified peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1α) as a direct target of miR-15a-3p. Our findings elucidate the molecular mechanisms underlying miR-15a-3p in sepsis-induced autophagy and skeletal muscle injury, highlighting its potential as a therapeutic target.
Over the past five decades, advances in acute burn care have markedly improved early survival following severe thermal injury. However, long-term epidemiologic studies demonstrate that burn survivors remain at increased risk for metabolic disease, cardiovascular pathology, malignancy, cognitive impairment, and accelerated aging, well beyond wound closure. These observations suggest that severe burn injury can initiate a chronic disease state characterized by persistent physiologic dysregulation in a subset of patients. Emerging evidence indicates that this phenotype is driven by sustained immunometabolic dysfunction, in which immune and metabolic pathways are tightly coupled and mutually reinforcing. Severe burn injury induces durable reprogramming of innate and adaptive immune cells alongside prolonged hypermetabolism, mitochondrial dysfunction, and neuroendocrine stress signaling. This results in a persistent inflammatory, immunosuppressed, catabolic syndrome (PIICS), where chronic inflammation coexists with impaired adaptive immunity and ongoing amino acid depletion. In this review, we synthesize population-based, clinical, and experimental data supporting burn injury as a chronic immunometabolic disease. We highlight key mechanisms linking immune dysfunction with altered substrate utilization, mitochondrial bioenergetics, and neuroimmune signaling, and discuss how these pathways contribute to long-term organ dysfunction. Finally, we outline emerging opportunities for risk stratification and therapeutic interventions targeting integrated immunometabolic pathways.
Sepsis-induced acute intestinal cell injury disrupts the normal barrier function of the intestine and leads to systemic inflammation and organ dysfunction. This study aims to investigate the molecular mechanism of Kruppel-like factor 4 (KLF4) in lipopolysaccharide (LPS)-induced intestinal epithelial cell injury. A human colonic mucosal epithelial cell line was treated with LPS to establish a model of intestinal epithelial injury. Real-time quantitative polymerase chain reaction and Western blot assay were performed to detect the expression of KLF4/microRNA (miR)-1306-5p/homeodomain interacting protein kinase 2 (HIPK2). Cell injury and apoptosis were detected. The levels of Occludin and zonula occludens-1 (ZO-1) were measured. The permeability was evaluated. The binding between KLF4 and the miR-1306-5p promoter, and between miR-1306-5p and HIPK2, was analyzed. The role of the miR-1306-5p/HIPK2 axis in cells was demonstrated by co-experiments. KLF4 and HIPK2 were downregulated, while miR-1306-5p was upregulated in LPS-treated cells. Overexpression of KLF4 increased cell viability and reduced apoptosis. Mechanistically, KLF4 could bind to the miR-1306-5p promoter, suppressing miR-1306-5p expression and thereby promoting HIPK2 expression. Overexpression of miR-1306-5p or downregulation of HIPK2 attenuated the protective effect of KLF4 overexpression on LPS-induced intestinal epithelial cell injury. In conclusion, KLF4 inhibits LPS-induced intestinal epithelial cell injury through the miR-1306-5p/HIPK2 axis.
BACKGROUND:Sepsis exhibits marked biological heterogeneity, yet the causal pathways linking host immune mediators to clinically relevant endotypes remain poorly defined, particularly in pathogen-specific contexts. METHODS:We applied Mendelian randomization (MR) to investigate the causal effects of circulating immune mediators on the risk of Haemophilus septicemia, identifying interleukin-7 (IL-7) and vascular endothelial growth factor A (VEGFA) as putative causal factors. To elucidate the biological context underlying these genetic associations, we integrated pathogen-informed gene sets with bulk blood transcriptomic data from a large sepsis cohort (GSE185263). Single-sample gene set enrichment analysis and Pathway responsive genes (PROGENy) were used to infer pathway activities, which were subsequently aligned with previously reported sepsis endotypes. RESULTS:A Haemophilus-informed transcriptional score captured a distinct signaling hierarchy dominated by TGFβ, TNFα/NFκB, hypoxia, and cell death pathways, accompanied by suppression of regenerative signaling. These pathway activities aligned most closely with the neutrophil-dominated, immunosuppressive (NeutroSupp) endotype described in the original cohort. While VEGFA expression showed strong coupling with VEGF and hypoxia signaling, IL-7-related immune maintenance pathways, inferred through Janus Kinase-signal transducer and activator of transcription activity, were only modestly engaged, consistent with impaired adaptive immune recovery. CONCLUSIONS:By integrating genetic causality with transcriptomic and endotype-level analyses, our findings suggest that IL-7 and VEGFA contribute to sepsis risk through distinct immune-endothelial axes that converge on an immunosuppressive sepsis endotype. This work provides a pathogen-informed framework for interpreting genetic associations within clinically relevant sepsis phenotypes.
BACKGROUND:Coronavirus disease 2019 (COVID-19) is characterized by dysregulated immune responses and excessive inflammation, contributing to severe disease and mortality. Interleukin-1 receptor type 2 (IL1R2), a decoy receptor for interleukin-1 (IL-1), regulates inflammatory responses; however, its cellular distribution and clinical significance in COVID-19 remain unclear. METHODS:Publicly available single-cell RNA sequencing (scRNA-seq) dataset (GSE149689) of peripheral blood mononuclear cells (PBMCs) from COVID-19 patients were analyzed. An independent monocyte transcriptomic dataset (GSE198256) was analyzed to evaluate IL1R2 dynamics during COVID-19 and recovery. Differential expression, functional enrichment, regulon activity, and CellChat analyses were performed to characterize IL1R2⁺ monocytes. Serum IL1R2 levels were measured in COVID-19 patients and healthy controls (HCs), and their associations with disease severity and mortality were evaluated. RESULTS:Single-cell analysis revealed that IL1R2 was predominantly expressed in monocytes from COVID-19 patients. IL1R2 expression was increased during active COVID-19 and decreased after recovery. IL1R2⁺ monocytes exhibited enhanced inflammatory transcriptional programs, increased activity of inflammation-associated regulons, and activation of TNFα/NF-κB, interferon, and IL6-JAK-STAT3 pathways. Cell-cell communication analysis identified IL1R2⁺ monocytes as active mediators of CCL, CXCL, IL1, and TNF signaling networks. Serum IL1R2 levels were elevated in COVID-19 patients, further increased in non-survivors, and correlated with inflammatory markers, tissue injury indicators, and coagulation abnormalities. IL1R2 showed predictive performance for mortality comparable to procalcitonin and D-dimer. CONCLUSIONS:IL1R2 identifies a highly inflammatory monocyte state associated with COVID-19 immune dysregulation. Elevated IL1R2 levels reflect disease activity and poor outcomes, supporting its potential role as a complementary prognostic biomarker and therapeutic target.
PURPOSE:To systematically review preclinical studies to determine whether biological sex alters outcomes after severe trauma with hemorrhagic shock (T/HS), identify the mechanistic drivers of any sex dimorphism, and define key gaps that limit translation to critical care. METHODS:Following PRISMA guidance, we searched PubMed and Google Scholar through December 2025 for original animal or veterinary T/HS studies, comparing biological sexes or manipulating sex hormones. Exclusions included non-hemorrhagic shock, traumatic brain injury, and reviews. Two reviewers independently screened 1,450 records and assessed risk of bias via SYRCLE. Data were extracted on species, hormonal status, survival, organ function, and mechanisms. A structured narrative synthesis was performed as study heterogeneity precluded quantitative meta-analysis. RESULTS:Of the 1,450 records, 66 met the inclusion criteria. In rodents, females, particularly during proestrus, exhibited superior survival, preserved organ function, and reduced inflammation. These advantages were typically reversed by ovariectomy and mimicked by estrogen or ER-β agonists. Conversely, male vulnerability was linked to androgen-driven immune dysfunction and mitigated by castration or flutamide. Age and sepsis often reverse female benefits. Emerging research highlighted non-classical pathways, such as autophagy and pyroptosis. High model heterogeneity and reporting gaps precluded meta-analysis. CONCLUSION:Preclinical evidence confirms sex-dependent resilience in T/HS, primarily driven by sex steroids and immune-vascular modulation. To bridge the translational gap, clinical studies should adopt sex-stratified analyses and prospectively record hormonal status. Future preclinical research must prioritize standardized reporting and the use of large-animal or uncontrolled hemorrhage models to validate these findings for critical care.
BACKGROUND:Sepsis is heterogeneous, and early emergency department (ED) management is constrained by limited information and dynamic clinical trajectories. METHODS:Using the nationwide Korean Sepsis Alliance (KSA) registry, we applied k-means clustering to nine routine ED variables (demographics, vital signs, Clinical Frailty Scale, mental status, lactate). The model was developed in KSA 3 (2019-2021) and tested for temporal reproducibility in the independent KSA 5 cohort (2022-2023). Phenotypes were compared on 7-day mortality, early sepsis-bundle compliance, and SOFA trajectories; stability was assessed by bootstrap resampling and alternative clustering. One-hour vasopressor non-compliance was decomposed into criterion-not-met versus delivered-with-delay. RESULTS:Six phenotypes were identified in 9,430 patients and reproduced in 7,184 (mortality-rank ρ = 1.00; calibration drift, O/E 0.83-1.32). Seven-day mortality ranged 6.7%-31.8%. Extreme-severity phenotypes (A, F, E) were bootstrap-robust (Jaccard 0.65-0.91), whereas intermediate phenotypes (B, D) were less stable (0.21-0.47), consistent with a continuous severity spectrum. Non-compliance composition separated phenotypes that severity scores rank together: predominantly criterion-not-met (appropriate withholding) in low-acuity phenotype C versus delivered-with-delay in high-acuity phenotype E. Phenotypes B and F, matched on presenting physiology and mortality but differing in frailty and mental status, still differed in composition (criterion-not-met 49.6% vs 28.3%; p < 0.001). SOFA trajectories were highest in phenotype E. CONCLUSIONS:ED-presentation phenotyping using routine variables identifies six cross-sectional signatures along the sepsis severity spectrum rather than definitive subtypes. Decomposing bundle non-compliance shows that it combines appropriate withholding and urgency-associated delay in phenotype-dependent proportions, a distinction one-dimensional severity scores cannot make, relevant to phenotype-stratified resuscitation warranting prospective evaluation.
BACKGROUND:The Sequential Organ Failure Assessment-2 (SOFA-2) score is a recently developed update of the conventional SOFA score that incorporates contemporary patterns of organ support in the intensive care unit (ICU). However, the association between SOFA-2 and long-term mortality in patients with sepsis has not been well characterized. METHODS:This retrospective cohort study extracted adult sepsis ICU data from MIMIC-IV v3.1. ICU admission SOFA-2 scores (0-24) were calculated. Boruta algorithm selected confounders; binary logistic regression and restricted cubic splines (RCS) analyzed linear association between SOFA-2 and 90-/365-day all-cause mortality. Random forest (RF) combined key predictors, SHAP interpreted feature importance, and AUC evaluated discriminative performance. RESULTS:8,779 patients were enrolled. Fully adjusted regression showed SOFA-2 independently elevated 90-day mortality (OR=1.17, 95%CI 1.15-1.18) and 365-day mortality (OR=1.16, 95%CI 1.14-1.18). RCS confirmed an approximately linear correlation (all nonlinearity p>0.05). Single SOFA-2 yielded modest AUCs: 0.65 (90-day) and 0.64 (365-day). The RF model improved prediction (validation AUC: 0.68 for 90-day, 0.67 for 365-day). SHAP analysis identified SOFA-2 as the most influential predictor. CONCLUSIONS:SOFA-2 provides moderate, stable long-term mortality discrimination for sepsis patients. Further external validation and optimization are required to improve its risk stratification utility.
BACKGROUND:Sepsis is a life-threatening syndrome characterized by dysregulated immune responses, while the molecular basis of immune dysfunction remains unclear. Increasing evidence suggests that R-loop accumulation and DNA damage may contribute to immune disorders, but their roles in sepsis have not been systematically investigated. METHODS:Four GEO microarray datasets were integrated after batch-effect correction and normalization. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were performed to identify sepsis-related genes. Overlapping R-loop-related genes (RLRGs) were obtained by intersecting differentially expressed genes, key module genes, and curated RLRGs. Machine learning was then applied to prioritize hub genes and construct an optimal diagnostic model, which was validated in external cohorts. A nomogram, single-cell RNA-sequencing analysis, survival analysis, and in vivo/in vitro experiments were further used for validation. RESULTS:Five overlapping RLRGs (EXOSC4, GADD45A, HMGB2, LDHA, and PRKDC) were identified, and all were consistently retained by top-performing machine learning models, supporting their robustness. The five-gene nomogram showed good calibration and clinical utility. Single-cell analysis revealed cell-type-specific expression across neutrophils, monocytes, and T cells. Among the five genes, only GADD45A was significantly associated with poor survival. Experimental validation showed that GADD45A was upregulated in a CLP-induced sepsis mouse model. In HL-60 cells, GADD45A silencing reduced LPS-induced inflammatory cytokine expression, R-loop accumulation, and DNA damage. CONCLUSIONS:GADD45A is a promising biomarker for the diagnosis and prognosis of sepsis and may promote disease progression by enhancing R-loop accumulation and DNA damage.
Background: Illness severity scores such as SAPS II implicitly assume that condition-specific mortality contributions — including that of sepsis — remain constant across the severity spectrum. From a shock pathophysiology perspective, distributive shock from sepsis may carry different reversibility profiles than cardiogenic or neurogenic shock at equivalent severity. Whether illness severity modifies the mortality burden of sepsis remains unevaluated. Methods: We conducted a retrospective cohort study of 64,703 ICU admissions from MIMIC-IV (2008–2019). Sepsis was defined by Sepsis-3 criteria; baseline severity by SAPS II with fractional polynomial modeling. Multivariable logistic regression with interaction terms assessed effect modification; average marginal effects (AMEs) were estimated across the SAPS II spectrum. ICU-type interaction heterogeneity was tested. Results: Sepsis occurred in 42.7% of admissions; 30-day mortality was 12.9%. The sepsis–mortality association varied significantly by severity (interaction p<0.001). At SAPS II 30, sepsis was associated with higher mortality (AME +3.8%, 95%CI 3.2–4.3%); this attenuated and became non-significant at SAPS II 50–55. At SAPS II 80, septic patients had lower adjusted mortality (AME −7.3%, 95%CI −9.6 to −5.0%). This crossover was present in unadjusted data (SAPS II ≥70: 61.5% vs 69.2%) and consistent across eight sensitivity analyses. Conclusions: The mortality burden of sepsis is not constant across the severity spectrum: it confers additional risk at low-to-moderate severity, but a crossover pattern emerges with lower mortality at high severity — robust in crude and adjusted analyses and consistent across ICU types. These findings implicate severity-dependent shock reversibility and have implications for prognostication, clinical trial design, and quality benchmarking.
OBJECTIVE:This study aims to explore the role of miR-340-5p in sepsis-related acute lung injury (ALI). METHODS:Firstly, ROC curve and binary logistic regression were employed to assess the correlation between the level of miR-340-5p in patients with sepsis and the risk of ARDS. ALI was induced in mice through cecal ligation and puncture (CLP), and then the number of neutrophils and inflammatory factors and pulmonary edema were observed. Furthermore, the effects of miR-340-5p on the cell viability, apoptosis and inflammatory factors of lung epithelial cells induced by LPS were observed through CCK-8, flow cytometry and ELISA. Moreover, the binding relationship between miR-340-5p and ROCK1 was verified through dual luciferase reporter assay. RESULTS:miR-340-5p is an important risk factor affecting ARDS. After overexpression of miR-340-5p, the lung injury in CLP mice was significantly alleviated, as evidenced by the inhibition of inflammatory factors and pulmonary edema. miR-340-5p also has a significant protective effect on lung epithelial cells, manifested as reduced cell apoptosis and decreased inflammatory factors. Moreover, overexpression of ROCK1 weakened the protective effect of miR-340-5p on alveolar epithelial cells. CONCLUSION:Patients with sepsis who have low expression of miR-340-5p are associated with a higher risk of developing ARDS. During ALI, miR-340-5p exerts a protective effect by inhibiting ROCK1.
BACKGROUND:Blockade of the urotensin II receptor (UT; G protein-coupled receptor [GPR]14) has been reported to confer protective effects against impaired cardiovascular response, inflammatory tissue injury, and mortality induced by lipopolysaccharide (LPS)-induced endotoxic shock or remote ischemic preconditioning (RIPC). This study aimed to test the hypothesis that SB-710411, a selective UT antagonist, has a protective effect on RIPC in a rat model of LPS-induced endotoxic shock. METHODS:The endotoxic shock model was established by injecting LPS into rats. RIPC was induced with three 10-minute ischemia/10-minute reperfusion cycles of both hind limbs of rats using tourniquets before saline or LPS injection. The rats were treated with SB-710411 (0.01 mg/kg) 1 hour after saline or LPS injection. The mean arterial pressure and heart rate values of the rats were measured during the experiments. RESULTS:SB-710411 prevented hypotensive and tachycardic responses to LPS or RIPC, but not to the RIPC/LPS. While RIPC ameliorated LPS-induced hypotension, but not tachycardia, it also caused a 33% mortality rate. The increase in the expression/activity of U-II, GPR14, nuclear factor-κB, inducible nitric oxide (NO) synthase, vasodilator-stimulated phosphoprotein, gp91 phox, p47 phox, 3-nitrotyrosine, and IL-1β as well as the decrease in endothelial NO synthase expression/activity in the arterial, cardiac, renal, pulmonary, and/or cerebral tissues of endotoxemic rats was prevented by SB-710411. SB-710411 also attenuated the elevation in scores for histopathological changes induced by LPS or RIPC/LPS in the heart, as well as LPS in the lung and brain. CONCLUSION:Our findings revealed that SB-710411 prevents deterioration of cardiovascular response and inflammatory tissue injury in rat models of LPS-induced endotoxic shock or RIPC, but not that of RIPC/LPS. It also seems that RIPC does not confer protection against LPS-induced endotoxic shock.
OBJECTIVES:To evaluate the association between metabolic syndrome (MetS) and in-hospital mortality in sepsis patients and to determine whether this association varies according to disease severity and individual MetS-related components. DESIGN:Multicenter retrospective cohort study. SETTING:Three tertiary hospitals in China. PATIENTS:A total of 2,973 adult patients with sepsis admitted between September 2015 and May 2023. INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:MetS was defined according to the criteria of the Chinese Diabetes Society. The primary outcome was in-hospital mortality. Multivariable Cox regression, subgroup analyses, interaction analyses, and Kaplan-Meier survival analyses were performed. MetS was present in 1,309 patients (44.0%). Patients with MetS had a higher in-hospital survival rate than those without MetS (78.4% vs. 72.8%, p = 0.001). After adjustment for potential confounders, MetS remained independently associated with lower in-hospital mortality. A significant interaction was observed between MetS and SOFA-defined severity strata, indicating a severity-dependent association. The survival advantage of MetS was mainly confined to patients with mild-to-moderate sepsis and was primarily driven by overweight and hyperlipidemia. In addition, these 2 metabolic features were associated with more favorable physiologic profiles, including lower inflammatory burden and better preservation of nutritional and cardiometabolic indices. CONCLUSIONS:MetS was associated with lower in-hospital mortality in sepsis, particularly in patients with mild-to-moderate disease severity. This association appeared to be largely driven by overweight and hyperlipidemia, supporting a stage-specific prognostic role of metabolic phenotypes in sepsis.
BACKGROUND:Milrinone is established in the management of heart failure. However, its therapeutic role in patients with sepsis remains uncertain and warrants further investigation. Objective: To examine the association between milrinone administration and mortality in patients diagnosed with sepsis. METHODS:This retrospective cohort study utilized data from the MIMIC-IV database. The primary exposure of interest was milrinone use. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were employed to balance baseline characteristics. The association between milrinone use and 7-，14-，and 28-day mortality in sepsis patients was assessed using multivariate Cox proportional hazards models, restricted cubic spline (RCS) curves, and longitudinal targeted maximum likelihood estimation (TMLE). RESULTS:Among 27,070 sepsis patients, 523 received milrinone at a median interval of 5.24 hours after ICU admission. In the unadjusted Cox model, milrinone use was associated with significantly lower mortality at 7 days (HR = 0.53, 95% CI: 0.33-0.85), 14 days (HR = 0.54, 95% CI: 0.38-0.78), and 28 days (HR = 0.60, 95% CI: 0.45-0.82). This association remained consistent after adjusting for multiple confounders. In the IPTW-adjusted cohort, Cox regression showed no significant association between milrinone use and mortality at day 7 or day 14; however, a statistically significant association was observed at day 28. Longitudinal TMLE analyses further indicated a protective effect for both 14-day (RR = 0.65, 95% CI: 0.48-0.88; P = 0.01) and 28-day mortality (RR = 0.58, 95% CI: 0.45-0.74; P < 0.001). RCS analysis demonstrated a linear inverse relationship between cumulative milrinone dosage and 7-day mortality risk, while a non-linear association was observed with 14-day and 28-day mortality. Subgroup analysis revealed a significant interaction between milrinone use and heart failure status, with reduced mortality associated with milrinone use only in patients with heart failure. CONCLUSION:Milrinone use appeared to be associated with reduced mortality risk at 7, 14, and 28 days in sepsis patients. This association was linear for 7‑day mortality, but nonlinear and potentially indicative of a threshold effect for 14‑and 28‑day mortality.
