Critical Care

We have previously shown that fresh frozen plasma (FFP) and fibrinogen have protective effects in mice with hemorrhagic shock through restoration of endothelial syndecan-1 and reversal of endothelial injury. In the current study, we tested the hypothesis that a combined model of abdominal sepsis and hemorrhagic shock would induce endothelial syndecan-1 shedding and lung injury which could be attenuated by both FFP and fibrinogen. C57BL/6 mice underwent cecal ligation and puncture (CLP) followed by hemorrhagic shock (HS) and fluid resuscitation with lactated Ringers (LR), fibrinogen (5 mg/mouse), and FFP, all at 1X shed blood volume. After 24 hours, lung tissues and plasma were harvested for assays. CLP+HS induced an increase in alveolar thickness and decreases in lung syndecan-1 and lung neutrophil granule-enzymes (myeloperoxidase, neutrophil elastase, and MMP9), with reciprocal elevations in plasma syndecan-1 and plasma neutrophil granule-enzymes (myeloperoxidase, neutrophil elastase, and MMP9). All these alterations were significantly attenuated by FFP but not by fibrinogen. Additionally, CLP+HS-induced hypotension at 24 hours was partially reversed by FFP but not by fibrinogen. FFP administration inhibits CLP+HS-induced neutrophil degranulation to prevent syndecan-1 shedding and lung injury. The current study supports that FFP has therapeutic benefit in a combined septic and hemorrhage shock model.

Sepsis mimics resemble sepsis clinically but may require different treatments. We evaluated whether inflammatory protein profiles could distinguish these conditions in a retrospective case-control study using 4 prospective Japanese cohorts. The study included 34 adults with sepsis and 46 with sepsis mimics. We measured 92 proteins using Olink, assessed between-group differences with false discovery rate (FDR) adjustment, and evaluated 3 prediction models using repeated nested cross-validation. No protein met the FDR threshold; the lowest FDR-adjusted P value was 0.345. The primary elastic-net model had an area under the receiver operating characteristic curve of 0.442 (95% confidence interval, 0.315-0.574), based on cross-validation predictions averaged for each participant. Random forest and gradient boosting also showed no clear evidence of discrimination above chance. Confidence intervals included chance performance in both the all-serum and quality-control-Pass sensitivity analyses. In this cohort, a single measurement of an inflammation-focused protein panel showed limited discrimination between sepsis and sepsis mimics. Integration with clinical information and longitudinal measurements warrants further investigation.

Sepsis causes approximately 11 million deaths globally each year. Whole-genome sequencing (WGS) of founder populations offers a unique opportunity for discovery of genes related to susceptibility of sepsis. We performed GWAS and EXWAS on WGS data for n=210 Arab ICU patients (n=68 sepsis cases, n=142 controls, other ICU-related disorders) and prioritized n=40 associated deleterious founder variants in n=31 genes (REGENIE Firth regression p < 0.05; CADD score > 20; enriched AAF vs AllofUs/gnomAD), including a novel start-loss variant in UBE2L3 (c.2T>G; p.Met1?; CADD = 25.6; SIFT = 0.001) in sepsis cases (3/68 vs 0/142 controls; Fisher's exact P = 0.026). In All of Us (AoU), UBE2L3 missense burden was associated with bacterial infection (n=26,939 cases; SKAT-O P = 2.38x10-3; OR=23.10; 95% CI = [0.63-845.27]). LLM AI models fine-tuned for drug development scored UBE2L3 a 7.8 of 10 as a drug target for sepsis, consistent with mouse UBE2L3 KO showing increased IL-1Beta mediated inflammation in sepsis.

Background Sepsis is the primary driver of mortality in intensive care. Personalized medicine requires an accurate understanding of the syndrome, and plasma proteomics is increasingly used to characterize its molecular alterations. Comorbidities, demographics and postoperative sterile inflammation complicate this task, and proteins associated with them may be mistaken as sepsis-specific. Methods We compared 343 sepsis patients with two independent perioperative control cohorts (n = 73 and n = 75) sampled before and after surgery. Plasma was analyzed by mass spectrometry, and analyzed using linear models adjusted for age, sex and cohort-specific comorbidities. Propensity score matching was used to characterize renal comorbidities and Elastic Net classifiers were trained per cohort and time point. Results We show that renal comorbidities had the strongest impact on the plasma proteome and affected sepsis-associated proteins including Cystatin-C and Beta-2-microglobulin. Eleven proteins were robustly associated with sepsis, among them established acute phase proteins and the less well characterized Beta-1,4-galactosyltransferase 1. Feature importance analysis confirmed this core set and identified further proteins that contributed in a cohort- and time point-specific manner. Classifiers performed very well except against control patients at day 3 after surgery, when sterile inflammation peaked. Conclusions Sepsis, comorbidities and sterile inflammation may alter the same acute phase and renal proteins, differing in magnitude rather than in the type of response. We disentangled these influences and report a robust set of sepsis-associated proteins together with confounder-associated proteins, providing a basis for future studies and the development of diagnostic and therapeutic strategies.

Objective We aimed to evaluate the performance of the recently updated Sequential Organ Failure Assessment Score-2 (SOFA-2) on organ dysfunction classification and prognostication compared to SOFA-1 in critically injured trauma patients. Methods Adult trauma patients admitted to critical care at four urban Major Trauma Centres between 2011 and 2024 were included. Daily organ dysfunction scoring was performed using SOFA-1 and SOFA-2 until death or discharge. The primary outcome was MODS, defined as SOFA score [&ge;]6. Results In 2162 severely injured patients (median Injury Severity Score 25 [IQR, 17-34]), SOFA-2 reduced the proportion of patients classified as having MODS compared with SOFA-1 (61.6% vs 68.5%, p<0.001). SOFA-2 scores on the first day after admission were lower than SOFA-1 (median 6 [IQR, 3-8] vs 7 [IQR, 4-10], p<0.001), driven predominantly by lower respiratory and cardiovascular scoring. Critical care mortality in trauma patients was increased in respiratory, cardiovascular and renal components of SOFA-2 at the higher ends of the scores, consistent with the aims of the SOFA-2 reclassification. A group of 159 severely injured patients (7.3%) classified as MODS by SOFA-1 were reclassified to no-MODS by SOFA-2. Despite this reclassification, these patients had substantially higher ICU mortality (7.5% vs 0.7%, p<0.01), greater ventilator and vasopressor requirements, and longer hospital stays than patients classified as no-MODS by both systems. Conclusions SOFA-2 reduces MODS prevalence in severely injured patients and changes organ dysfunction classification, with lower rates of severe respiratory and cardiovascular dysfunction. This represents an important update in trauma MODS measurement and has implications for future trauma trial design. However SOFA-2 reclassification generates a small cohort a small but clinically significant group with occult MODS that warrants further evaluation in severely injured trauma patients.

OBJECTIVE: Sepsis-associated encephalopathy (SAE) and sepsis-associated delirium (SAD) lack confirmatory laboratory tests or biomarkers. We evaluated whether the Th17/interleukin (IL)-17 axis or neuroglial-injury biomarkers reflect acute brain dysfunction beyond systemic inflammation and whether biomarker profiles differ between these phenotypes. DATA SOURCES: EMBASE, MEDLINE/PubMed, and the Cochrane Library from inception to August 1, 2026, supplemented by backward and forward citation searching, following PRISMA 2020. STUDY SELECTION: Observational studies of adults with sepsis classified by SAE or SAD status and reporting circulating biomarker concentrations by neurological group or biomarker-outcome associations. Eighteen studies (2,388 participants; 1,863 with sepsis) were included. DATA EXTRACTION: Two reviewers independently extracted study, phenotype, assay, and outcome data. Risk of bias was assessed with the Newcastle-Ottawa Scale and certainty with GRADE. DATA SYNTHESIS: Random-effects models pooled standardized mean differences (SMDs) separately against non-septic and septic controls and odds ratios (ORs) for biomarker-outcome associations. IL-6 was the only mediator elevated in both comparative frameworks and associated with outcomes (non-septic controls: SMD, 0.54 [0.25-0.82]; septic controls: SMD, 1.05 [0.51-1.59]; OR, 1.85 [1.50-2.29]). S100B, neuron-specific enolase, IL-10, tumor necrosis factor; and interferon-gamma; were elevated versus septic controls, whereas IL-17 was modestly elevated only versus non-septic controls (SMD, 0.37 [0.01-0.73]). The IL-6 septic-control effect was concentrated in SAE (p<0.0001) and remained robust in leave-one-out and risk-of-bias sensitivity analyses. Certainty was low to very low, and all 14 computable prediction intervals included the null. CONCLUSIONS: IL-6 emerges as the leading circulating candidate biomarker of sepsis-associated brain dysfunction, while S100B and NSE capture neuroglial injury beyond sepsis. Current evidence does not establish a discriminating role for the Th17 axis. Future studies require standardized neurological phenotyping and appropriately matched septic controls to establish diagnostic value.

Background: Molecular markers and mediators of adverse post-hospital outcomes following critical illness remain incompletely characterized. Anemia and red blood cell (RBC) indices integrate inflammation, nutritional status, and hematopoietic function, and may represent biological processes that influence long-term outcomes. We therefore examined whether pre-discharge anemia and hematologic clusters derived from correlated RBC indices were associated with one-year mortality among critical illness survivors. Methods: We conducted an exploratory, retrospective cohort study of adult ICU patients discharged alive using MIMICIV. Pre-hospital discharge RBC indices (hemoglobin, red cell distribution width (RDW), mean corpuscular volume (MCV), mean cell hemoglobin (MCH), mean cell hemoglobin concentration (MCHC), and RBC count) were analyzed. Hemoglobin and anemia were first evaluated, followed by Gaussian mixture modeling of standardized RBC indices to identify patient clusters in a derivation cohort (70%) and validated findings in a held-out cohort (30%). Associations with one-year mortality were assessed using multivariable-adjusted Cox models. Results: Among 20,233 ICU survivors with available pre-discharge hemoglobin (median age, 67 years), based on the WHO definition of anemia, 17,247 (85.2%) critical illness survivors were anemic at hospital discharge. Anemia was associated with higher one-year mortality (adjusted HR 1.42, p<0.001). Mortality was 20% overall and decreased across increasing hemoglobin quartiles, from 28.8% to 12.5% (log-rank P<0.005); lower hemoglobin was associated with progressively higher adjusted one-year mortality risk. Six hematologic clusters derived from RBC indices were identified with one-year mortality ranging from 10.1% to 31.4% (log-rank p<0.005). Compared with the lowest-risk group, the cluster characterized by elevated RDW and MCV had a twofold higher adjusted mortality risk (HR 2.14; 95% CI, 1.81-2.53). Conclusion: Both anemia and hematologic clusters derived from standard RBC indices at hospital discharge are associated with one-year mortality following critical illness. These hypothesis-generating findings support further investigation of RBC indices as potential biomarkers for post-discharge risk stratification and of the underlying biological pathways as possible therapeutic targets.

Background: Intracerebral hemorrhage (ICH) is associated with high early mortality. Although routine coagulation markers are clinically relevant, their incremental value for mortality prediction beyond neurologic and physiologic information is uncertain. We developed and externally validated models using first-24-hour ICU data and evaluated the added predictive value of routine coagulation measurements. Methods: We used MIMIC-IV for model development and eICU-CRD for external validation. The development cohort included 2,669 adults with non-traumatic ICH and 388 ICU deaths. Logistic regression, random forest, and XGBoost were evaluated using a patient-level 70:30 holdout split and 5-fold stratified cross-validation. External validation used a high-specificity primary eICU cohort (396 patients; 39 deaths) and a broader secondary hemorrhagic-stroke/likely-ICH cohort (1,555 patients; 168 deaths). Performance was assessed using AUROC, AUPRC, Brier score, calibration, and paired bootstrap comparisons. GCS-only and age-plus-GCS models served as clinical benchmarks. Coagulation-only, clinical-only, and combined XGBoost models were compared to assess incremental value. Results: In the internal holdout cohort, AUROCs were 0.870 for logistic regression, 0.859 for random forest, and 0.867 for XGBoost. In the primary external cohort, corresponding AUROCs were 0.804, 0.839, and 0.817; AUPRCs were 0.342, 0.419, and 0.406; and Brier scores were 0.080, 0.072, and 0.074. In the broader cohort, AUROCs were 0.826, 0.848, and 0.838. Random forest showed the numerically strongest external performance, but pairwise AUROC differences among multivariable models were not clearly supported. GCS-only achieved AUROCs of 0.780 and 0.813 in the primary and broader cohorts. Coagulation-only XGBoost showed weak discrimination (AUROC 0.598 internally, 0.598 primary external, and 0.566 broader external). Adding coagulation variables to the clinical model produced AUROC differences of 0.014 (95% CI -0.009 to 0.037) and 0.003 (95% CI -0.007 to 0.013) in the two external cohorts. Conclusions: Multivariable models based on first-24-hour ICU data retained useful discrimination across external cohorts and provided modest gains over simple GCS-based benchmarks. Routine coagulation markers alone were weak predictors and did not provide clearly supported incremental discrimination beyond broader clinical information. Cross-database transportability should be interpreted together with phenotype alignment and calibration.

BACKGROUND: Liberation from invasive mechanical ventilation (IMV) is a central therapeutic objective in acute respiratory failure (ARF). While lung-protective ventilation strategies and diaphragm function have received considerable attention as determinants of liberation success, the prognostic role of extrapulmonary thoracic tissue composition remains poorly defined. We examined whether chest computed tomography (CT)-derived thoracic skeletal muscle mass (TMM), subcutaneous fat mass (SFM), and their ratio (muscle-fat ratio: MFR) are associated with IMV outcomes in ARF. METHODS: This secondary analysis of a prospective observational ARF cohort includes patients with a chest CT obtained within 7 days before or 3 days after intubation. TMM, SFM and MFR were derived using validated three-dimensional convolutional neural network-based volumetric segmentation spanning the lung apices to bases. Co-primary outcomes were time to successful ventilator liberation within 60 days and 60-day all-cause mortality. Multivariable Cox and logistic regression models with restricted cubic splines assessed linear and non-linear associations, adjusted for age, sex, and key comorbidities. We performed prespecified BMI-stratified and ARDS subgroup analyses. RESULTS: Among 826 patients with ARF requiring IMV, 238 patients with CT imaging were included for analysis (median age 59.5 years, median BMI 28.7 kg/m^2). A higher MFR was independently associated with faster ventilator liberation (hazard ratio 1.16, 95% confidence interval [CI] 1.02 to 1.32, p=0.023). TMM demonstrated a significant J-shaped non-linear relationship with time to liberation (p for non-linearity=0.019), with delayed liberation at both low and high extremes of TMM. Higher SFM was independently associated with increased 60-day mortality (odds ratio 1.09, 95% CI 1.00 to 1.18, p=0.049). In 81 patients with ARDS, TMM also demonstrated a significant J-shaped non-linear relationship with 60-day mortality (p for non-linearity=0.037). BMI was not significantly associated with either outcome. CONCLUSIONS: Volumetric CT-derived thoracic body composition metrics, particularly MFR and TMM, are independently associated with ventilator liberation and 60-day mortality in ARF, capturing prognostic information not reflected by BMI alone. These findings support the incorporation of automated thoracic body composition analysis into early risk stratification frameworks for mechanically ventilated patients and highlight extrapulmonary tissue composition as an underexplored determinant of IMV outcomes.

Abstract Background: Chronic subdural hematoma (cSDH) remains a significant and increasingly prevalent cause of morbidity in older adults. Disease progression is sustained by de novo formed highly vascularized pseudomembranes and a persistent cycle of fluid accumulation and hematoma expansion. Although inflammatory and angiogenic pathways have been implicated in cSDH pathogenesis, the endothelial mechanisms underlying persistent vascular leak remain poorly understood. We investigated the cSDH vascular microenvironment in human patients and examined the role of vascular endothelial cadherin (VECAD) remodeling in cSDH endothelial dysfunction. Methods: Human cSDH membranes and fluid were evaluated by multiplex profiling, histology, immunofluorescence, immunoprecipitation, western blotting and exploratory bulk RNA sequencing. A human brain endothelial cell (HBEC) line was exposed to patient-derived cSDH fluid to assess VECAD remodeling, endothelial barrier permeability, and proliferation. Results: Multiplex profiling of patient-derived cSDH fluid detected mediators associated with endothelial cell (EC) activation, extracellular matrix remodeling, inflammation, and angiogenesis. In patient pseudomembranes, discontinuous VECAD coincided with erythrocyte extravasation. Two hyperdense (high-risk) specimens showed more extensive disruption than the hypodense (low-risk) specimen while vessel counts appeared similar. Bulk RNA sequencing identified an angiogenic environment and enrichment in cadherin regulation. A soluble VECAD (sVECAD) isoform was detected in cSDH fluid. Exposure of HBECs to patient-derived cSDH fluid increased EC proliferation, cytoplasmic VECAD (cVECAD) accumulation, and EC barrier permeability. Concurrent dexamethasone or minocycline treatment attenuated VECAD cleavage. Conclusions: VECAD disruption is a prominent feature of cSDH and is associated with EC barrier dysfunction. These findings support further evaluation of soluble VECAD as a candidate biomarker and of junction-preserving pathways as potential therapeutic targets.

Importance: Pharmacological targeting of host mechanisms that limit sepsis-induced organ dysfunction represents a new therapeutic approach. Preclinical studies showed that low-dose epirubicin enhances tissue damage control and attenuates sepsis severity independently of pathogen burden, thereby promoting disease tolerance to infection. Yet epirubicin can cause myelotoxicity when used in cancer therapy. Objective: To investigate whether low-dose epirubicin can safely be administered to patients with sepsis and septic shock. Design, Setting, and Participants: A randomized, double-blind, placebo-controlled clinical trial conducted in five German University hospitals. Patients with sepsis, defined by Sepsis-3 criteria, were eligible within 48 hours after diagnosis. The first patient was enrolled on October 19, 2022, and the last follow-up was conducted on May 21, 2025. Interventions: Eligible patients were randomized in a 4:1 ratio to receive either placebo or low-dose epirubicin in addition to standard care. There were three consecutive phases. Patients in the epirubicin group received a single dose of epirubicin (either 3.75 mg/m2, 7.5 mg/m2 or 15 mg/m2, depending on study phase). Main Outcomes and Measures: The primary endpoint of the trial was the 14-day myelotoxicity. Secondary and explorative outcomes included 90-day mortality, the degree of organ dysfunction as assessed by SOFA score, PK/PD modelling and cytokine release. Results: Of 854 patients assessed for eligibility, 32 were randomized and 31 were included in the primary analysis population. Six participants received placebo, nine participants received 3.75 mg/m2, nine received 7.5 mg/m2 and eight individuals received 15 mg/m2 epirubicin, respectively. There was no myelotoxicity in any group. Mortality at 90 days and SOFA-scores were not significantly different between groups. Two of 39 SAEs in the epirubicin group were assessed by the investigators as possibly related to epirubicin, Conclusions and Relevance Among patients with sepsis and septic shock, low dose epirubicin was not associated with increased myelotoxicity.

BACKGROUND Traditional organ dysfunction classifications after severe trauma rely on binary categories (e.g., chronic critical illness [CCI] versus rapid recovery), which likely oversimplify the true heterogeneity of postinjury organ dysfunction trajectories and their underlying immune-biologic drivers. We hypothesized that severely injured trauma patients demonstrate multiple, distinct organ dysfunction phenotypes distinguished by unique immune signatures. METHODS We performed a prospective, longitudinal, observational cohort study of severely injured trauma patients at high risk for multiple organ dysfunction at a single Level 1 trauma center. Organ dysfunction was quantified daily through 28 days, death, or discharge using a trauma-specific modified Sequential Organ Failure Assessment (mSOFA) score excluding the neurologic subdomain to isolate systemic organ dysfunction from traumatic brain injury. We utilized group-based trajectory modeling to identify longitudinal mSOFA phenotypes. Plasma immune protein trajectories were compared across phenotypes using mixed-effects models with time interaction. RESULTS Sixty-nine patients were enrolled. Trajectory modeling identified five mSOFA phenotypes (c1-c5) with differences in resuscitation requirements, shock severity, and 28-day mortality, but not baseline demographics, injury severity, or early physiologic parameters. The phenotypes revealed organ dysfunction heterogeneity not fully captured by CCI/rapid recovery classification. Forty of 92 measured immune markers showed phenotype-differentiated trajectories (FDR<0.1). The most fulminant phenotype (c5) was distinguished by IL-17C, CXCL5, and CXCL6, implicating epithelial-barrier and neutrophil-trafficking mechanisms. The phenotype with highest CCI incidence (c3) was distinguished by rising CXCL9, ARTN, and TWEAK, implicating Th1 polarization and tissue-inflammation/repair signaling. The clinically distinct, older-age phenotype (c4) carried the largest differentiating signature (29 proteins), spanning renal injury/repair, endothelial activation, and adaptive lymphocyte modulation. CONCLUSIONS Organ dysfunction after severe trauma is more biologically heterogeneous than traditional clinical classifications suggest. Distinct mSOFA trajectory phenotypes correspond to distinct immune signatures, supporting separable pathobiology rather than a single axis of injury severity, with implications for phenotype-targeted precision immunomodulatory approaches in critical illness.

Background: Risk adjustment for disease severity in pediatric intensive care research commonly relies on clinical organ dysfunction scores requiring detailed clinical and laboratory information, which is often unavailable in administrative healthcare datasets. We therefore evaluated the feasibility of a coding-based Pediatric Organ Dysfunction Index (PODI) derived from International Classification of Diseases (ICD-10) and Operation and Procedure System (OPS) codes, for approximating sepsis-related organ dysfunction and adjusting for disease severity, using the pediatric Sequential Organ Failure Assessment (pSOFA) score as a reference standard. Methods: In this retrospective single-center cohort study, pediatric sepsis episodes treated between November 2011 and November 2021 were identified. Discrimination for in-hospital mortality and calibration were assessed. Agreement between PODI and pSOFA was quantified using Spearman's rank correlation, and organ-specific agreement using sensitivity, specificity, and predictive values. An expanded PODI incorporating additional ICD-10 and OPS codes was evaluated in sensitivity analyses. Results: A total of 488 pediatric sepsis episodes were included, with an in-hospital mortality of 14.1%. The PODI showed good discrimination for in-hospital mortality (AUC 0.85, 95% CI 0.80-0.89), comparable to the maximum pSOFA (pSOFAmax) (AUC 0.78, 95% CI 0.72-0.83) and superior to pSOFA at sepsis onset (pSOFAonset) (AUC 0.73, 95% CI 0.67-0.80). Agreement between PODI and pSOFA organ-specific components varied considerably across organ systems, with the highest sensitivity to detect pulmonary dysfunction. Correlation between both scores was moderate (0.54 for pSOFAonset and 0.60 for pSOFAmax), indicating that comparable predictive performance does not render the scores interchangeable. The expanded PODI improved organ-level sensitivity for selected components but did not meaningfully improve mortality discrimination. Conclusions: The standard PODI may represent a practical approach to adjust for organ dysfunction and therapy intensity in administrative datasets with ICD-10 coding where clinical and laboratory information is unavailable. Given only moderate agreement with the pSOFA, the PODI should be understood as a covariate for risk adjustment at the group level rather than as a substitute for clinical organ dysfunction scores in individual patients. Further validation and refinement in non-sepsis cohorts are required before broader implementation in large-scale administrative research can be recommended.

Abstract Background: In patients with sepsis and pre-existing hypertension, admission findings may not adequately describe the subsequent course of circulatory support and organ dysfunction. We developed and externally validated a model to reassess in-hospital mortality risk after the first 72 hours of intensive care. Methods: This retrospective study used MIMIC-IV for development and eICU-CRD for external validation. Patients had received vasoactive agents and remained in the ICU for at least 72 hours. Static variables were combined with features from six consecutive 12-hour windows. Imputation, feature selection, model fitting, and calibration were performed within training folds during five-fold cross-validation. The final XGBoost model was applied externally without refitting. Evaluation included discrimination, calibration, decision curves, and risk stratification, with an exploratory comparison of static-only and static-plus-dynamic feature sets. Results: The development and external cohorts included 1019 and 1747 patients, with 338 (33.2%) and 516 (29.5%) deaths, respectively. Internal area under the receiver operating characteristic curve (AUC) was 0.752 (95% CI 0.720-0.784). External AUC was 0.713 (95% CI 0.687-0.739), average precision was 0.536, the Brier score was 0.185, and the calibration slope was 0.744. Mortality increased across external risk tertiles from 13.7% to 47.3%. In an exploratory feature-set comparison, the static-plus-dynamic feature set showed a 0.071 higher internal AUC than the static feature set (95% CI 0.042-0.109). Conclusions: Information accumulated during the first 72 hours supported subsequent mortality risk stratification in this selected population. The model retained moderate discrimination externally, supporting further evaluation as an adjunct to clinical reassessment. Local calibration and the clinical consequences of acting on model predictions require evaluation before routine use.

Introduction Norepinephrine remains first-line vasopressor therapy for septic shock despite its association at high doses with undesirable cardiovascular, kidney, and immune effects. Angiotensin-II (Ang-II) is a non-catecholamine vasopressor of the renin-angiotensin-aldosterone system (RAAS) now approved to increase blood pressure in vasodilatory shock. RAAS dysregulation is common in septic shock and may represent a treatable trait. However, few prospective investigations evaluate the effect of early Ang-II use in septic shock on dysfunctional RAAS biology, host-response, or clinical outcomes. Therefore, we designed a mechanistic clinical trial to test the hypothesis that early Ang-II therapy in septic shock normalizes systemic RAAS abnormalities and modulates innate immune responses. Methods and Analysis The Mechanistic Assessment of Norepinephrine TheRapy vs. Angiotensin-II in Septic Shock (MANTRA) trial is an investigator-initiated, prospective, multicenter, open-label, randomized mechanistic clinical trial. Adults with septic shock by Sepsis-3 criteria receiving a norepinephrine-equivalent dose (NED) of 0.10-0.50 mcg/kg/min will be randomized 1:1 to primary Ang-II (to a maximum of 40 ng/kg/min) or norepinephrine (to a maximum 35 mcg/min) treatment strategies over a 48-hour period. The primary outcome is the between-group difference in plasma renin trajectory from baseline to 24 hours, analyzed using a linear mixed-effects model with a treatment-by-time interaction term. With n=78, the trial has 90% power (at two-sided =0.05) to detect a 25% between-group difference in 24-hour renin. Secondary clinical outcomes include longitudinal NED, hours alive and vasopressor-free at 72 hours, a 28-day composite outcome (days alive and free of vasopressors, renal replacement therapy, and mechanical ventilation), treatment failure requiring crossover or protocol discontinuation, and thrombotic and arrhythmia events through 28 days. Secondary mechanistic outcomes include serial RAAS biomarkers (prorenin, soluble prorenin receptor, angiotensinogen, ACE, ACE2, Ang-II, angiotensin-(1-7), aldosterone, and DPP3), immune measures (ex vivo monocyte function, monocyte gene expression, plasma cytokines), and organ injury biomarkers. Enrollment is planned from 5/2026-7/2030. Strengths and limitations of this study MANTRA is a randomized trial comparing angiotensin-II against an active standard-of-care norepinephrine strategy rather than placebo, enrolling patients earlier in septic shock than prior trials restricted to catecholamine-resistant shock. Serial sampling profiles RAAS peptides, innate immune function, and organ-injury biomarkers, which will generate rich mechanistic data on how vasopressor strategy shapes the host response. The sample size is adequate for the biomarker primary endpoints and will establish feasibility for a larger trial, but it does not provide sufficient power for hard clinical endpoints, which remain exploratory. MANTRA compares two open-label vasopressor strategies rather than monotherapies; clinician retain discretion over background and rescue vasopressors, steroids, and crossover, which may attenuate differences between-arms. The 48-hour intervention window limit inference about clinician-assessed outcomes and the durability of treatment effect.

Early risk stratification of COVID-19 patients at admission informs triage and resource allocation, particularly in low- and middle-income settings where intensive-care capacity is constrained. Most published models are not interpretable, rarely externally validated, and developed almost exclusively in high-income cohorts. We developed an interpretable random-forest classifier for three-class COVID-19 severity (Mild: not ventilated, survived; Severe: ventilated, survived; Fatal: died) using only data available within 24 hours of admission in 321 hospitalised PCR-confirmed COVID-19 patients in Pakistan. From 2,278 raw variables we retained 20 predictors by clinical screening and permutation-importance selection, with leakage-controlled multiple imputation by chained equations and SHapley Additive exPlanations (SHAP) for interpretation. A 15-feature variant was evaluated in two independent public cohorts: the Chinese iCTCF cohort (n = 894) and an Italian complete-blood-count cohort (n = 1,218). The development model achieved a macro F1 of 0.55, identifying the Fatal class most reliably (F1 0.67, recall 0.73) and Mild cases least well. SHAP identified a parsimonious set of admission-time predictors (oxygen saturation, lactate dehydrogenase, urea, C-reactive protein, age and radiographic pneumonia), including a raised urea-to-creatinine ratio in fatal cases most consistent with dehydration (median urea 80 vs 50 mg/dL, fatal vs mild; p < 0.001). Externally, the model retained useful discrimination in the Chinese cohort (mortality AUC 0.82 in 719 patients with recorded outcomes; severe-or-worse AUC 0.75; macro F1 0.50) but only modest discrimination in the Italian cohort (AUC 0.62, 95% CI 0.56-0.68), which we treat as a feature-availability stress test rather than a second validation. Cross-cohort SHAP rankings correlated strongly in China (Spearman {rho} = 0.91) and moderately in Italy ({rho} = 0.76), where most laboratory predictors were imputed and carried no information beyond the complete blood count; discrimination tracked how many predictors were actually measured. The admission-time signature converges with established markers of hypoperfusion and inflammation.

BackgroundReactive oxygen species (ROS) overproduction, inflammatory cytokines, and plasma mediators disrupt alveolar tight junction integrity and perpetuate oxidative injury in acute respiratory distress syndrome (ARDS). Biological heterogeneity of ARDS, reflected by hyper- and hypoinflammatory subphenotypes with distinct plasma mediator profiles, may contribute to heterogeneity of treatment effect. Stem cell-derived EVs have been shown to exert regenerative and immunomodulatory effects by horizontal transfer of proteins, lipids and genetic material to injured target cells. This study investigated whether extracellular vesicles derived from bone marrow (MSC-EVs) and adipose tissue (ASC-EVs) mesenchymal stem cells restore barrier integrity and redox homeostasis, and whether efficacy differs across subphenotypes. MethodsBronchial epithelial cells (BEAS-2B), microvascular endothelial cells (HMEC-1), and small airway epithelial cells (SAEC) were challenged with plasma from patients with hyperinflammatory or hypoinflammatory ARDS subphenotypes, including those treated with venovenous ECMO. MSC-EVs or ASC-EVs were added concomitantly with plasma exposure or six hours later, at a dose of 5,000 particles/cell. After 24 h, the expression of actin and tight junction proteins, zonula occludens (ZO)-1, occludin, and vascular endothelial (VE)-cadherin, was evaluated by immunofluorescence. Oxidative stress parameters, antioxidant defenses, and antioxidant enzyme activities, were measured. ResultsPlasma from patients with the hyperinflammatory ARDS subphenotype induced marked disruption of ZO-1, occludin, and VE-cadherin expression, together with actin cytoskeletal rearrangement, across BEAS-2B, HMEC-1, and SAEC cells. Barrier disruption was accompanied by increased oxidative stress markers and altered antioxidant enzyme activity. Both MSC-EVs and ASC-EVs restored tight junction protein expression and cytoskeletal organization when administered either concurrently with ARDS plasma or 6 hours after exposure, and both effectively modulated redox parameters. Delayed administration 6 hours after injury produced greater effects for several oxidative stress endpoints, particularly in cells challenged with hypoinflammatory plasma. ConclusionARDS-associated plasma mediators induce subphenotype-dependent impairment of epithelial-endothelial barrier integrity through oxidative mechanisms. Both MSC-EVs and ASC-EVs mitigate this injury, with efficacy that varies according to ARDS subphenotype and timing of administration.

Incidence of ventilator-associated pneumonia (VAP) is increased in patients admitted for brain injury. Staphylococcus aureus appears to be a particularly common pathogen in these respiratory infections. Our aim was to confirm the extent of S. aureus involvement in VAP among patients with neurological injuries. We conducted a retrospective, multicenter study including patients with and without neurological injuries who developed VAP during their ICU stay. Among 15 702 patients admitted in the participant centers during the study period. 407 were finally included in the study. S. aureus was involved in 122 (61.6%) VAP in brain-injured patients and 63 (30.1%) of non-brain-injured patients. In brain-injured patients, multivariate analysis identified age (0.97 [0.95; 0.98]), antibioprophylaxis (0.31 [0.18; 0.53]; p < 0.0001), subarachnoid hemorrhage (2.18 [1.01; 4.68]; p=0.0461), lower Glasgow coma score (0.92 [0.87; 0.97]; p= 0.004) and SAPS II (0.98 [0.97; 1]; p=0.0174) as critical factors associated with the risk of S. aureus in VAP. In the non-brain-injured population, multivariate analysis identified antibioprophylaxis (0.38 [0.22; 0.65]; p=0.0006), age (0.96 [0.95; 0.98]; p<0.0001), SAPS II (0.98 [0.97; 1]; p=0.0265), thoracic surgery (0.21 [0.09; 0.48]; p=0.0002) and peripheral neurosurgery (1.95 [1.2; 3.19]; p=0.0076) as critical factors. A total of 172 patients (42.3%) died during their ICU stay and 90-days mortality was 194 (47.7%). No difference of mortality was noticed function of VAP-associated pathogen.

Background Despite numerous randomized controlled trials (RCTs) and systematic reviews (SRs), current sepsis guidelines continue to issue only weak recommendations for corticosteroids. We examined the clinical scope, underlying study pools, and mortality conclusions of SRs evaluating corticosteroids for sepsis. Methods We conducted a meta-research study of SRs on corticosteroids in sepsis (2015 to 2025), extracting SR characteristics, mortality results, and included RCTs. Study-pool overlap was assessed using an SRxRCT inclusion matrix, Jaccard similarity (J), and hierarchical clustering. SRs and RCTs were classified according to standardized Population, Intervention, Comparison, Outcome (PICO) profiles. We explored discordance in short-term mortality conclusions among clinically comparable SRs and potential associations with study-pool composition, target populations, and methodological characteristics. Results Forty-two SRs including 121 unique RCTs were identified. More than half of pairwise SR comparisons shared no RCTs, and only three pairs showed high overlap (J>0.8). SRs addressing similar intervention and target population profiles frequently relied on different study pools. Among 38 SRs with short-term mortality meta-analyses, 15 (39%) reported benefit and 23 (61%) no evidence of effect. Discordance occurred exclusively among SRs evaluating broad, non-specific corticosteroid strategies; conclusions were consistent for hydrocortisone plus fludrocortisone (benefit) and hydrocortisone, ascorbic acid, and thiamine (no evidence of effect). SRs including sepsis +/- shock populations more frequently reported benefit than those restricted to septic shock (62% vs 22%), although estimates were imprecise. No single methodological or clinical factor consistently explained discordance. Conclusions SRs addressing apparently similar clinical questions frequently synthesized different underlying evidence bases and reported discordant conclusions. Guideline developers should therefore consider not only methodological quality and reported PICO, but also whether the RCTs included in an SR adequately represent the intended clinical question. Clinically coherent evidence syntheses may improve the interpretability of pooled treatment effects and support more targeted corticosteroid therapy in sepsis.

BACKGROUD: Sepsis is a life-threatening condition characterized by a dysregulated host response to infection. It frequently precipitates sepsis-associated acute kidney injury (SA-AKI). 20-Hydroxyeicosatetraenoic acid (20-HETE), is an important regulator of vascular tone. We aim to investigate whether disruption of 20-HETE signaling contributes to septic renal dysfunction. METHODS: In the animal study, Sprague-Dawley rats underwent the cecal ligation and puncture to induce sepsis and SA-AKI. Comprehensive cardiac and renal ultrasonographic assessments were performed in all animals. Blood samples were collected for biochemical assessment of renal function and quantification of circulating 20-HETE levels. Kidney tissues were harvested for analysis of the 20-HETE-GPR75-PLC/PKC signaling pathway and histological evaluation by hematoxylin and eosin staining. In the clinical study, circulating 20-HETE levels and renal hemodynamic parameters derived from point-of-care ultrasound were evaluated in healthy individuals and patients with sepsis. Venous blood samples were collected for quantification of serum 20-HETE concentrations. RESULTS: Firstly, CLP-induced septic rats produced a biphasic hemodynamic response, with early compensation followed by late cardiovascular decompensation, accompanied by progressive renal dysfunction, tubular injury, depletion of circulating and renal 20-HETE, and reduced renal GPR75 expression. Secondly, Restoration of 20-HETE signaling with a pharmacological analog improved systemic and renal hemodynamics, increased MAP, reduced serum creatinine, blood urea nitrogen, and ameliorated renal pathological injury. These protective effects were partially attenuated by PKC inhibition, implicating PKC-dependent signaling in 20-HETE-mediated renal protection. Moreover, in septic patients, circulating 20-HETE concentrations were reduced compared with healthy individuals and were lowest among those with SA-AKI, paralleling alterations in renal hemodynamic parameters measured by point-of-care ultrasound. CONCLUSIONS: Sepsis-associated depletion of 20-HETE accompanies impaired systemic and renal hemodynamic regulation and is associated with the development of SA-AKI. Restoration of 20-HETE signaling improves hemodynamic function and attenuates renal injury, potentially involving GPR75-associated PLC/PKC signaling. KEY WORDS: sepsis-associated acute kidney injury, 20-hydroxyeicosatetraenoic acid, GPR75, renal hemodynamics, point-of-care ultrasonography