Critical Care

Background: Many patients in the ICU receive oxygen to secure blood and tissue oxygenation. Increasing evidence shows exposure to high fractions of inhaled oxygen (FiO2) being associated with adverse effects. In patients with severe ARDS, veno-venous Extracorporeal Membrane Oxygenation (VV-ECMO) can be implemented as a rescue therapy and PaO2 levels can be controlled by the blood flow of the VV-ECMO. Yet, optimal oxygenation targets in ARDS patients treated with VV-ECMO are unknown. Methods: Retrospective analysis of 443 patients with severe ARDS treated with VV-ECMO. Regression analyses were performed for mortality and time-weighted averages of PaO2 and FiO2. Furthermore, considering a possible non-linear relationship, a restricted cubic spline (RCS) model was performed for PaO2. Results: A simple logistic regression for mean PaO2 and ICU mortality showed a significant positive association (per mmHg OR 0.99 [95%CI 0.98-1.00], p=0.002). RCS analysis showed a U-shaped association of mortality and mean paO2 (paO2 69.70-90.24mmHg: OR 0.92 [95%CI 0.89-0.94], p<0.001; paO2 90.24-123.40mmHg: OR 1.09 [95%CI 1.06-1.13], p<0.001). A model including PaO2 as RCS variable and FiO2 showed significant associations of mortality with both variables (PaO2 69.70-90.24mmHg: OR 0.94 [95%CI 0.91-0.97], p<0.001; paO2 90.24-123.40 mmHg: OR 1.07 [95%CI 1.04-1.11], p<0.001; FiO2: OR 35.98 [95%CI 8.67-158.60], p<0.001, VIF<1.11). Conclusions: PaO2-levels in patients with ARDS and VV-ECMO have a U-shaped association with mortality. Optimal outcomes are observed in the 90-123 mmHg range, which is higher compared to non-ECMO settings. Whether this is explainable by increased tissue oxygenation with concurrent avoidance of pulmonary hypoxia should be subject of future research.

RationaleSepsis is a life-threatening syndrome causing significant morbidity and mortality especially in the aging population. Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition of clonal expansion of hematopoietic stem cells harboring somatic mutations associated with increased incidence of chronic illness and all-cause mortality. ObjectiveEvaluate the association of pre-illness CHIP with mortality and morbidity in patients admitted to the ICU with sepsis. MethodsWe performed a retrospective study using a de-identified electronic health record linked with a DNA biorepository. We identified adult patients with sepsis who had DNA collected prior to ICU admission. We tested the association between CHIP status, determined from whole-genome sequencing, and ICU mortality, organ support-free days, and long-term survival adjusting for age, sex, race and Sequential Organ Failure Assessment (SOFA) score on ICU admission. Measurements and Main ResultsPre-illness CHIP was associated with increased sepsis mortality (OR = 1.54, 95% CI 1.13 to 2.07, P = 0.005) and fewer days alive and free of organ support (-1.7 days, 95% CI -3.2 to -0.2, P = 0.028) after adjusting for age, sex, race, and SOFA score. In sepsis survivors, CHIP was also associated with increased long-term mortality after discharge (HR 1.40, 95% CI 1.01 to 1.93, P = 0.041). ConclusionsPre-illness CHIP was independently associated with increased mortality and morbidity in critically-ill adults with sepsis. These findings suggest that CHIP is a risk factor for sepsis severity. Elucidating the mechanism underlying this association could uncover new therapeutic interventions for sepsis.

Rationale: Fibrinolysis resistance in sepsis associates with thrombotic burden, multi-organ failure and death. The degrees and dynamics of resistance that associate with mortality in acute sepsis are unknown, and a simple tool to aid clinician interpretation of fibrinolysis measurements is lacking. Objectives: To establish a point of care grading tool of fibrinolysis resistance that aligns with scoring systems for disease acuity, is substantiated by plasma fibrinolysis markers and enables rapid investigation of the fibrinolysis state at the point of care. Methods: Prospective observational study of 116 adult sepsis/septic shock patients with sequential measurements of fibrinolysis resistance during Intensive Care Unit (ICU) admission using tissue plasminogen activator (tPA) enhanced viscoelastic testing (VET). The clot lysis time (TPA-LT) adjusted for fibrin clot amplitude (TPA-LT/FIBA10, sec/mm) underwent cluster analysis and was evaluated against disease severity scores, standard pathology, clinical outcomes and fibrinolysis markers. Measurements and Main Results: Three clusters of progressively increasing fibrinolysis resistance were identified (Grades 1-3). At admission, Grade 3 associated with the highest disease severity, organ failure, haematological and biochemical perturbations, fibrinolysis marker inhibitory profile and mortality (42% versus 24% and 15% in Grade 2 and Grade 1, respectively) with a 3.9-fold [95% CI 1.4-11] increased hazard ratio for death at 28 days compared to Grade 1. Transitions between grades were frequent over 7 days with a reduced Grade associated with decreased risk of death. Conclusions: Grading of fibrinolysis resistance in sepsis enables rapid identification of patients at greatest mortality risk with any dynamic improvement corresponding to favourable clinical outcomes.

Purpose: Polypharmacy is highly prevalent among critically ill patients, yet it's independent impact on intensive care unit (ICU) outcomes in sepsis remains critically unexplored. We aimed to evaluate whether pre-admission polypharmacy independently predicts ICU mortality and provides incremental prognostic value using the medication reconciliation module of the MIMIC-IV-ED linked database. Materials and Methods: We conducted a retrospective cohort study of 3,347 adults admitted to the ICU who met Sepsis-3 criteria. Pre-admission polypharmacy was categorized as none (0-4), standard (5-9), or high (>=10 medications). Multivariable logistic regression, propensity score matching, and reclassification analyses (NRI/IDI) were performed. The primary outcome was in-hospital ICU mortality. Results: High polypharmacy was present in 58.9% of patients. Crude ICU mortality increased sequentially: 18.5% (none), 26.0% (standard), and 27.5% (high; p < 0.001). After multivariable adjustment, high polypharmacy independently predicted in-hospital ICU mortality (aOR 1.45, 95% CI (1.10-1.91)), and 28-day mortality (aOR 1.47). Drug-class analysis identified statins as significantly protective (aOR 0.56), whereas RAS blockers combined with diuretics increased acute kidney injury risk (aOR 1.49). Propensity matching confirmed the primary mortality association (matched aOR 1.28). Conclusions: By utilizing the ED medication reconciliation table, this study proves high polypharmacy represents a distinct 'pharmacologic frailty', independent of acute severity. Available instantly at triage, this zero-latency metric provides significant early prognostic value (SOFA NRI = 0.24) and identifies actionable high-risk interactions (e.g., RAS blockers plus diuretics) for immediate, targeted pharmacist-led intervention upon ICU admission.

The Sequential Organ Failure Assessment (SOFA)-2 score was recently validated for ICU mortality prediction across more than 3 million admissions but was not evaluated across demographic subgroups. We assessed the discrimination and calibration of the SOFA-2 score for ICU mortality across subgroups defined by age, sex, race and ethnicity, primary language, and insurance status. We conducted a retrospective cohort study of adult patients (aged 18 years or older) admitted to ICUs at Beth Israel Deaconess Medical Center between 2008 and 2022 (MIMIC-IV, version 3.1), selecting the first ICU admission per patient. First-day SOFA-2 scores (range, 0-24) were calculated using worst recorded values across 6 organ systems. Discrimination was assessed using AUROC, calibration using intercepts and slopes, and subgroup differences using bootstrap resampling. Among 64,015 ICU admissions (median age, 66 years [IQR, 54-78]; 56.1% male; 66.1% White), overall ICU mortality was 7.2% (n=4,596). Overall AUROC was acceptable at 0.77 (95% CI, 0.76-0.77). Notably, discrimination declined significantly with age: AUROC was 0.85 (95% CI, 0.83-0.87) for ages 18-44 and 0.72 (95% CI, 0.70-0.73) for ages 75 and older (difference in AUROC, -0.14; 95% CI, -0.16 to -0.11), with systematic underprediction of mortality in older patients (calibration intercept, 0.39). Discrimination was also significantly lower among non-English speakers (difference in AUROC, -0.04; 95% CI, -0.07 to -0.01) but did not differ significantly across documented racial and ethnic groups. Patients with unknown race/ethnicity (14.3% of the cohort) had nearly double the overall mortality rate and poor calibration. SOFA-2 demonstrated good overall performance for ICU mortality prediction but with clinically meaningful variation across demographic subgroups, particularly a substantial decline in discrimination with advancing age. These findings underscore the need for routine equity evaluation of clinical prediction tools before widespread implementation.

BackgroundImmune dysfunction in sepsis and critical illness is biologically heterogeneous, yet available stratification frameworks leave many patients unclassified. We hypothesized that ex vivo cytokine-induction responses would define a continuous axis of functional immune responsiveness and identify a low-response state enriched in sepsis. MethodsIn this prospective observational study, 39 critically ill adults enrolled within 48 hours of ICU admission and 6 healthy controls underwent standardized whole-blood stimulation with lipopolysaccharide, anti-CD3/anti-CD28 antibodies, and PMA/ionomycin, with selected wells additionally supplemented with interleukin-7 or granulocyte-macrophage colony-stimulating factor. Interleukin-6, tumor necrosis factor, and interferon-gamma responses were quantified and referenced to subject-specific unstimulated baselines. A patient-anchored primary feature matrix was used to derive a continuous immune axis by principal component analysis, and a cross-validated 5-feature MiniResponder score was developed as a portable summary measure. ResultsAmong critically ill patients, induced cytokine responses organized along a dominant continuous axis of functional immune responsiveness; the first principal component explained 53.3% of between-patient variance. MiniResponder captured this axis and showed a lower-shifted distribution in sepsis. Using a control-referenced threshold defined by the 10th percentile of the healthy-control distribution, 19 of 39 patients (48.7%) were classified as low-response, including 15 of 21 patients with sepsis (71.4%) and 4 of 18 critically ill patients without sepsis (22.2%) (odds ratio 8.75, Fisher exact P=0.004). In exploratory analyses, lower MiniResponder scores were associated with greater unadjusted improvement in Sequential Organ Failure Assessment score from day 1 to days 3-9 (rho=-0.33; P=0.046), but this association attenuated after adjustment for baseline SOFA score (beta=-0.10; 95% CI-0.36 to 0.27). ConclusionsEx vivo immune profiling identified a continuous patient-anchored axis of functional immune responsiveness in critical illness that can be summarized by a compact 5-feature score. A control-referenced low-response state was enriched in sepsis. This framework may complement existing biomarker-based stratification approaches and support future enrichment strategies in sepsis trials.

Functional capacity, muscle strength, and patient-reported outcome measures are important indicators of health. In chronic obstructive pulmonary disease (COPD), these traits are often impaired beyond normal age-related decline. Substantial variability exists in both COPD and healthy populations, the biological basis of which remains poorly understood. Given the known contribution of genetics to complex traits, genetic factors may partly explain this variability. This study aimed to identify genetic variants associated with measures used to characterise extrapulmonary traits in COPD. Genome-wide association studies were conducted on the Lab3R-ESSUA cohort for the 6-minute walk test (6MWT), the 1-minute sit-to-stand test (1-min STS), the quadriceps maximal voluntary contraction (QMVC), the handgrip muscle strength, and the chronic airways assessment test (CAAT), adjusting for age, sex, body mass index, pack-years and ancestry. Variants with P<1E-05 were selected for replication in the EARLYCOPD cohort, and effects compared between COPD and healthy populations (two-way ANOVA). A total of 639 participants (364 people with COPD, 275 healthy; 75% male, median age 67 years; BMI of 27 Kg/m2; 10 pack-years) were included. Significant variants were identified for the 6MWT (rs1108983:G, {beta}=-186.5m, P=4.8E-08), the 1-min STS (rs5889103:GTT, {beta}=4.2reps, P=4.8E-08), the Handgrip (rs67352743:A, {beta}=-4.4Kg, P=2.8E-08), and for the CAAT (rs11747040:C, {beta}=4.4points, P=4.0E-09; rs11041680:A, {beta}=-2.6points, P=2.5E-08). Effects were independent of COPD diagnosis. Replication in EARLYCOPD (n=282) confirmed one SNP for 6MWT and three for CAAT. These findings highlight genetic contributions to functional capacity, muscle strength, and disease burden. COPD-related impairments appear to build on pre-existing genetic predisposition, contributing to disease heterogeneity.

Background Acute respiratory distress syndrome (ARDS) is characterised by substantial physiological heterogeneity, which contribute to a very variable clinical outcomes and therefore inconsistent responses to ventilatory strategies. We aimed to externally validate physiological ARDS subphenotypes previously identified using routine ventilatory and gas-exchange variables, assess their prognostic relevance across independent cohorts, and examine heterogeneity of treatment effect according to PEEP strategy. Methods Unsupervised Gaussian Mixture Modelling was used to identify physiological subphenotypes based on ventilatory mechanics and gas-exchange parameters. Labels were subsequently used to train and validate supervised classifiers using XGBoost. Prognostic relevance was assessed across three independent cohorts, including two randomised controlled trials (ALVEOLI and LOVS). Predictive enrichment for PEEP strategy was evaluated using individual patient data from ALVEOLI and LOVS (n = 1,532) using intention-to-treat analyses, applying both one-stage and two-stage fixed-effects IPD meta-analytic approaches to test for interaction between physiological subphenotype and PEEP strategy. Results Two distinct physiological subphenotypes, termed Efficient and Restrictive, were replicated across independent cohorts. Across each cohort, patients classified as Restrictive consistently exhibited higher all-cause 28-day mortality compared to Efficient patients. When pooled across studies, the Restrictive subphenotype was associated with a significantly increased risk of death (pooled odds ratio 1.75, 95% CI 1.36-2.24), with no evidence of between-study heterogeneity. Predictive analyses showed a statistically significant interaction between physiological subphenotype and PEEP strategy in the one-stage IPD model (p for interaction = 0.037), with concordant findings in the two-stage fixed-effects IPD meta-analysis (interaction OR 1.91, 95% CI 1.00-3.66; I2 = 0%). Higher PEEP was associated with increased mortality in Efficient patients and reduced mortality in Restrictive patients, indicating effect modification by physiological subphenotype. Interpretation Physiological ARDS subphenotypes derived from routinely collected bedside data provide robust and externally validated prognostic stratification across observational and randomised trial cohorts. The observed interaction with PEEP strategy suggests that underlying physiological profiles may influence treatment response, supporting the concept that physiology-based be a starting point for personalized medicine and therefore better ventilatory strategies in future clinical trials.

Pulmonary vascular remodelling is common in patients with chronic obstructive pulmonary disease (COPD). Vascular endothelial growth factors (VEGFs) are key mediators in angiogenesis and vascular remodelling and exist in different isoforms. VEGF-A is the most potent angiogenic member binding to VEGF receptor 2 (VEGFR2). There are, however, few studies on other isoforms, as VEGF-C, and its receptor VEGFR3 in COPD and subsequent impact of cAMP therapies on VEGF isoforms. Our aim was to evaluate the VEGF isoform synthesis in primary distal lung fibroblasts from control subjects (non-smokers (n=6) and ex-smokers (n=4), and COPD subjects with GOLD stage II (n=4) or GOLD stage IV (n=6), and the expression of VEGFR2 and VEGFR3 in human lung tissue. Primary lung fibroblasts were exposed to the cAMP generating therapies formoterol, iloprost, or roflumilast, the adenylyl cyclase activator forskolin or to transforming growth factor (TGF)-b1. VEGF isoforms were evaluated with ELISA. VEGF-C release was not significantly altered by TGF-{beta}1, in contrast to the increased levels of VEGF-A, in all fibroblasts. VEGF-C was significantly decreased by iloprost, forskolin and formoterol, whereas VEGF-A was significantly increased by iloprost and forskolin, with differences in release pattern between and within fibroblasts from control and COPD subjects. Exposure to VEGF-C specifically towards VEGFR3 decreased proliferative rate in human lung fibroblasts and bronchial epithelial cells. VEGFR2 and VEGFR3 were both present in parenchymal lung tissue and VEGFR2 in pulmonary blood vessels. in both healthy and COPD, whereas there was elevated expression of VEGFR3 in bronchial epithelium. In conclusion, TGF-{beta}1 and cAMP generating compounds have significant effects on VEGF-C and VEGF-A synthesis, which appear dysregulated in lung fibroblasts from ex-smokers and patients with COPD. Increased VEGFR3 expression in the bronchial epithelium in lung tissue, and studies into their functional impact, warrants further investigations.

ObjectiveTo develop and validate a predictive model incorporating behavioral telemetry signals--documentation pattern anomalies derived from routine EHR charting--alongside clinical variables for ICU mortality prediction in patients with low acute physiologic derangement. Materials and MethodsRetrospective cohort study of 46,002 adult ICU stays from MIMIC-IV v3.1 (2008-2022) with SOFA scores 0-2, excluding neurological units. We extracted 66 variables spanning demographics, acuity, behavioral telemetry, clinical enrichment, and temporal factors. Progressive logistic regression models (M1-M7) were compared using cross-validation, DeLong tests, net reclassification improvement, and calibration analysis. ResultsOverall mortality was 9.34% (4,295 deaths). The clinical model (M5) achieved cross-validated AUROC 0.691 versus 0.639 for demographics alone (M2; {Delta}AUROC = 0.052, DeLong p = 4.41x10-47). NRI was 24.3%. Discordant care patients received 30.5% more chart events than concordant patients, with the sole deficit in neurological assessments (-15.4%), refuting the neglect hypothesis. Kaplan-Meier analysis confirmed survival separation (log-rank {chi}2 = 138.6, p = 5.32x10-32). In the most conservative subgroup (SOFA 0, no sedation, no ventilation, N = 11,158), orientation omission remained associated with mortality (adjusted OR 1.52, p = 0.027). DiscussionDeep sedation and mechanical ventilation function as mediators on the causal pathway rather than traditional confounders; the discordant care signal retains significance after full sedation adjustment. ConclusionDocumentation pattern analysis adds measurable predictive value for ICU mortality risk stratification and represents a novel signal for real-time EHR-based clinical decision support.

BackgroundSepsis is a recognized risk factor for upper gastrointestinal bleeding, yet sepsis-specific randomized evidence informing stress ulcer prophylaxis remains limited. ObjectiveTo describe the rationale, methods, and statistical analysis plan for a post hoc subgroup analysis evaluating pantoprazole versus placebo in invasively ventilated critically ill adults with septic shock enrolled in the REVISE trial (NCT03374800). MethodsThis study will be a post hoc extended subgroup analysis of the international, blinded, randomized REVISE trial, which enrolled 4,821 mechanically ventilated adults in 68 ICUs across 8 countries. Patients were randomized to intravenous pantoprazole 40 mg once daily or placebo during invasive mechanical ventilation. Septic shock will be defined as receipt of vasopressors or inotropes at baseline together with an admitting diagnosis of infection according to APACHE III diagnostic categories. ResultsThe primary efficacy outcome will be clinically important upper gastrointestinal bleeding in the ICU within 90 days after randomization, and the primary safety outcome will be all-cause mortality within 90 days. Additional trial outcomes will include patient-important upper gastrointestinal bleeding, ventilator-associated pneumonia, Clostridioides difficile infection during hospitalization, new renal replacement therapy, mortality in the ICU and hospital, and duration of ICU and hospital stay. Analyses will be adjusted for prehospital acid suppression; the mortality analyses will be additionally adjusted for APACHE II score. ConclusionThis protocol and statistical analysis plan describes an evaluation of the efficacy and safety of pantoprazole in patients with septic shock within a large randomized trial dataset.

IntroductionCardiopulmonary exercise testing (CPET) quantifies exercise limitation and helps differentiate cardiovascular dysfunction from deconditioning in patients with exertional dyspnoea. In mild pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH), traditional CPET oxygen delivery parameters may not adequately distinguish cardiac limitation. We evaluated whether oxygen pulse (O2 pulse) kinetics and the ratio of ventilation-carbon dioxide slope to peak oxygen uptake (VEVCO2/peakVO2) improve identification of cardiovascular limitation and prognostication. MethodsWe retrospectively analysed 289 consecutive patients referred for CPET. Patients were categorised into pre-capillary PH, no PH, or "unclassified" PH based on haemodynamics. O2 pulse slopes were calculated across exercise phases, and qualitative curve patterns were classified. VEVCO2/peakVO2 was derived from standard CPET parameters. Logistic regression assessed predictors of cardiac dysfunction (peak O2 pulse <65% predicted). Survival was evaluated using Kaplan-Meier and Cox regression analyses. ResultsPre-capillary PH patients demonstrated more impaired aerobic capacity and ventilatory efficiency than those without PH. Abnormal O2 pulse patterns (early plateauing or down-sloping) were associated with shallower slopes, lower peak O2 pulse, and greater chronotropic index. A work-phase O2 pulse slope < 0.40 identified impaired oxygen delivery but was not independently predictive in multivariable analysis. VEVCO2/peakVO2 independently predicted cardiac dysfunction (OR 3.9 [2.6-6.2], p < 0.001) and showed strong discrimination (AUC 0.83). VEVCO2/peakVO2 [&ge;] 2.7 independently predicted mortality (HR 13.6, 95% CI 3.8-48.5, p<0.001) outperforming peak O2 pulse and VE/VCO2 slope. ConclusionO2 pulse kinetics, particularly a work-phase slope < 0.40 and plateauing or decreasing trajectories, are associated with cardiac dysfunction in patients with pre-capillary PH. VEVCO2/peakVO2 appears to be a marker of cardiovascular limitation and mortality and may aid differentiation between cardiac dysfunction and deconditioning in this population when conventional CPET parameters are inconclusive.

IntroductionIntraoperative glycemic dysregulation, including unrecognized hypoglycemia and stress-induced hyperglycemia, is common during elective surgery. Conventional point-of-care (POC) monitoring provides only intermittent measurements, limiting the anesthesiologists ability to detect rapid glucose fluctuations. Continuous glucose monitoring (CGM) enables real-time, trend-based assessment, potentially shifting intraoperative glycemic management from reactive to proactive. ObjectiveTo meta-analyze the analytical accuracy, intraoperative glycemic efficacy, and feasibility of subcutaneous CGM in adults undergoing elective surgery, informing anesthesiology practice. MethodsThis systematic review and meta-analysis followed the PRISMA 2020 statement. Searches were conducted in PubMed, Embase, and Cochrane Central Register of Controlled Trials from January 2010 to May 2025. Eligible studies included randomized controlled trials and prospective cohorts of adults undergoing elective surgery under general or neuraxial anesthesia using subcutaneous CGM. Primary outcomes were pooled mean absolute relative difference (MARD) and time in range (TIR, 70-180 mg/dL). Random-effects models were applied. ResultsTen studies (3 RCTs, 7 cohorts; N=557) were included. Pooled MARD was 14.1% (95% CI 11.3-16.9%; I{superscript 2}=78%), lower in non-cardiac surgery (12.7%) than cardiac procedures with hypothermia (19.2%; p=0.03). CGM improved TIR by +14.9 percentage points (95% CI 7.2-22.6; p<0.001). Clinically significant hypoglycemia was detected in 43% of patients, all missed by POC. Sensor availability exceeded 96%, with no serious device-related events. ConclusionSubcutaneous CGM provides acceptable intraoperative accuracy and improves glycemic control, supporting its integration into anesthetic management.

BackgroundPatent ductus arteriosus (PDA) is a common and potentially serious cardiovascular condition in preterm infants, particularly those with low gestational age and birth weight. Its management remains controversial due to variability in screening, diagnostic criteria, and treatment strategies. This study aimed to evaluate risk factors, outcomes, and management strategies for PDA in preterm infants, and to identify predictors of clinical and echocardiographic response to therapy. MethodsWe conducted a retrospective cohort study over a 4-year period (2016-2019) in the neonatal intensive care unit (NICU) of a tertiary care center. All consecutive preterm infants admitted during the study period were eligible. Infants with echocardiographically confirmed PDA who received pharmacological treatment with intravenous paracetamol or ibuprofen were included in the analysis. Missing data were minimal and handled using available-case analysis. Statistical analyses included descriptive statistics, Pearsons chi-square test, and multivariable logistic regression. ResultsAmong 2154 preterm infants admitted to the NICU, 60 were diagnosed with PDA (incidence : 2.8%). The mean gestational age was 29 {+/-} 2.6 weeks, and the median birth weight was 1200 g. Respiratory distress occurred in 95% of cases, mainly due to hyaline membrane disease (86.7%). PDA was symptomatic in 80% of infants. First-line treatment resulted in clinical improvement in 77% and ductal closure in 83.3% of cases, most within 3 days. Predictors of successful closure included gestational age [&ge;] 28 weeks (OR = 5.9; 95% CI : 1.7-20.2) and antenatal corticosteroid exposure (OR = 1.2; 95% CI : 1.0-1.6). Overall mortality was 35% and was significantly higher in infants < 28 weeks (OR = 5.0; 95% CI : 2.4-10.3). Clinical improvement (OR = 3.7) and echocardiographic closure (OR = 4.5) after first-line treatment were associated with reduced mortality. ConclusionsPDA in preterm infants is associated with substantial morbidity and mortality, particularly in those born before 28 weeks of gestation. Early diagnosis, antenatal corticosteroid exposure, and timely pharmacological treatment may improve outcomes. Systematic echocardiographic screening in high-risk neonates should be considered.

RationaleAutonomic dysfunction is a hallmark of sepsis pathophysiology, yet its quantification remains challenging. Multiscale entropy (MSE) derived from heart rate variability (HRV) offers a dynamic measure of physiological complexity and may serve as a biomarker of early deterioration associated with subsequent organ failure, vasopressor escalation, or mortality. ObjectiveTo determine whether MSE computed across multiple temporal scales during the first 24 hours of Intensive Care Unit (ICU) admission is associated with short-term mortality and longer-term organ dysfunction in patients with sepsis, and whether these relationships vary across vasopressor exposure. Unlike prior studies that focused on short-term HRV metrics, we applied MSE across multiple temporal scales and incorporated these features into machine learning models to evaluate their prognostic utility in septic shock. MethodsThis retrospective cohort study included adult ICU sepsis patients at Emory University Hospital from January 2016 to December 2019. Of 2,076 eligible patients, 958 were propensity matched into two cohorts: fluids-only and fluids-plus-vasopressor, with norepinephrine as the primary vasopressor. High-resolution electrocardiogram (ECG) waveforms were analyzed to compute MSE across 20 temporal scales. Machine learning models using (1) MSE features alone and (2) MSE combined with demographic and vital sign data (MSE-DV) were compared against traditional HRV measures based model and severity of illness scores for predicting outcomes. Model performance was assessed using the area under the receiver operating characteristic curve (AUROC), with a primary outcome of mortality at day 7 and secondary outcome of persistent organ dysfunction at day 28. ResultsIn the fluids-plus-vasopressor cohort, MSE-based models demonstrated superior predictive performance for 7-day mortality (AUROC 0.84) compared to severity of illness scores (AUROC 0.64). MSE-DV models also predicted organ dysfunction including 28-day renal (AUROC 0.75), neurological (AUROC 0.79), and respiratory (AUROC 0.71) dysfunction. Patients receiving second-line and third-line vasopressors and corticosteroids exhibited progressively lower MSE values, particularly at mid-range and long-range scales. ConclusionMSE features in the first 24 hours of ICU stay predict mortality and organ dysfunction with higher discrimination than traditional severity of illness scores. Future work should validate these findings, assess longitudinal MSE trends, and race-specific autonomic patterns to refine predictive models.

ObjectiveTo systematically review and characterize methodological heterogeneity in sepsis case detection using the MIMIC-III and eICU-CRD databases. Materials and MethodsWe conducted a PRISMA-guided systematic review of PubMed and Web of Science (publication years 2016-2024). We extracted methodological details on sepsis case detection across six domains: parameter coverage, temporal windows, aggregation methods, missing-data handling, SOFA calculation, and infection detection methods. For studies with available source code, we additionally examined code structure and repository dependencies to identify methodological decisions across these domains. ResultsOf 396 publications screened, 64 met the inclusion criteria and 12 provided available source code. Sepsis detection rates ranged from 3.4% to 65.2% in MIMIC-III and from 9.8% to 47.9% in eICU-CRD. Substantial variability persisted among studies using identical cohort definitions within both databases (MIMIC-III: 16.9%-42.2%; eICU-CRD: 13.9%-31.4%). The overall proportion of studies reporting methodological details varied by domain: SOFA calculation (53.1%), infection detection methods (42.2%), temporal windows (37.5%), aggregation methods (26.6%) and missing-data handling (17.2%). Source code analysis identified 321 implementation decisions, revealing heterogeneity in baseline SOFA definitions (SOFA=0 vs dynamic baseline), temporal windows (infection-centered vs ICU-admission-centered) and infection detection methods (antibiotic-culture matching vs APACHE-based diagnosis). Dependencies among several MIMIC-III repositories suggested propagation of implementation decisions across studies. DiscussionClinically validated sepsis definitions yield substantially different detection rates across studies using identical datasets, indicating heterogeneity in computational implementation. ConclusionTo improve reproducibility in sepsis research and the robustness of sepsis prediction models, we recommend standardized reporting of sepsis case detection methodology and the publication of version-controlled source code.

BackgroundThe cardiovascular (CV) benefit of CPAP in OSA remains debated and its effects on new OSA-related CV risk markers are unclear. We aimed to quantify short-term CPAP effects on these markers along with vascular and autonomic phenotypes. MethodsIn a 2-week withdrawal study, patients on long-standing effective CPAP took part in three visits (V1-V3: on/off/back-on CPAP) with overnight polygraphy followed by vascular and autonomic phenotyping. Co-primary endpoints included endothelial function assessed by flow-mediated dilation (FMD) and baroreflex sensitivity (BRS), hypoxic burden (HB), pulse wave amplitude drop index (PWADi) and spontaneous-PWADi (excl. apnoea-triggered drops), and event-related heart-rate response ({Delta}HR). Between-visit differences were tested in adjusted mixed models, with visit or within-participant changes in AHI/HB as fixed effects. ResultsIn 42 participants (61{+/-}10 years, 83% male), CPAP withdrawal reinstated OSA (medians [IQR] V1 to V3: AHI 3.9[1.5, 8.8] to 33.4[19.5, 42.1] to 4.0[2.0, 8.8] events/h, HB 4.3[1.1, 8.7] to 51.3[19.7, 83.7] to 2.0[1.2, 6.5] %{middle dot}min/h, p<0.001) and increased total PWADi (mean{+/-}SD 42.25{+/-}18.73 to 50.22{+/-}17.77 to 41.29{+/-}17.14 drops/h, p<0.001), while spontaneous PWADi decreased as respiratory-events recurred (-1.17 drops/h per 10 events/h, p=0.015) along with FMD (3.7{+/-}1.9% to 3.2{+/-}2.5% to 4.2{+/-}2.7%, V2 vs V3 p=0.047). {Delta}HR and BRS were stable across visits. ConclusionShort-term CPAP re-initiation improved endothelial function (FMD), with no significant effects on autonomic measures (BRS, {Delta}HR) or structural vascular indices. This supports a temporal dissociation between rapidly reversible exposure metrics (AHI, HB) and slower dynamics of autonomic markers. Changes in spontaneous PWADi suggests that it may track physiological CPAP benefits beyond indices driven primarily by respiratory-event frequency.

RationaleFibrotic lung diseases, such as idiopathic pulmonary fibrosis (IPF) and fibroproliferative remodeling in acute respiratory distress syndrome (ARDS), are characterized by increased extracellular matrix (ECM) deposition. However, measuring collagen accumulation alone does not capture differences in ECM organization or biochemical maturation that may distinguish persistent fibrosis from potentially reversible remodeling. ObjectivesTo examine collagen organization characteristics and mature (pyridinoline) collagen crosslinking amount in established end stage fibrotic lung disease (IPF) and fibroproliferation following an acutely damaged lung (non-resolving (NR) ARDS) and to investigate any relationships in these parameters and temporal tissue remodeling. MethodsHuman lung tissue samples from control subjects, patients with IPF, and NR-ARDS were analyzed. Collagen amount and fiber organization were digitally quantified using picrosirius red staining. Mature collagen crosslinking was assessed by quantification of pyridinoline crosslinks. Measurements and Main ResultsLung tissue from both IPF and NR-ARDS lungs had higher collagen content compared with controls. Collagen fiber organization differed between groups. IPF lungs exhibited collagen architectures consistent with established fibrosis, whereas NR-ARDS lungs showed altered but less stabilized collagen organization despite similarly elevated collagen levels. Mature collagen crosslinks were significantly higher in IPF lungs but not in NR-ARDS lungs compared to controls. Integrated analyses identified distinct disease-associated ECM phenotypes, indicating that higher collagen abundance in NR-ARDS, unlike IPF, is not accompanied by more mature and persistent collagen crosslinking. ConclusionsDespite shared increases in collagen content, IPF and NR-ARDS lungs differ fundamentally in collagen organization and crosslinking maturity, suggesting differences in the reversibility of these conditions.

Premature very low birth weight (VLBW) infants have high rates of mortality and morbidity from sepsis, necrotizing enterocolitis, and respiratory failure requiring intubation and mechanical ventilation. Earlier detection of cardiorespiratory deterioration using vital signs from continuous physiological monitoring may lead to more timely interventions and improved outcomes. To further this research area, we present PreMo, a publicly available dataset of continuous heart rate and oxygen saturation, demographics, clinical events, and outcomes for 3,829 VLBW patients from four Neonatal Intensive Care Units (NICUs) in the United States. The PreMo dataset consists of a collection of parquet files, RO-Crate metadata, and sample usage code scripts hosted on the University of Virginia LibraData Dataverse website.

Sepsis is a complex condition with a time-dependent evolution. Longitudinal biomarker dynamics could help us to better characterise sepsis. We hypothesised that the kinetics of biomarkers are associated with sepsis and with the intensity of organ dysfunction, and may have predictive capacity for patient survival. This single-centre, prospective, observational study included adult patients presenting to the Emergency Department (ED) with suspected infection. Patients were included in the study if they had a National Early Warning Score 2 (NEWS 2) of 3 or higher. Blood samples were obtained at baseline, 4hs and 24 hs. Linear mixed models were constructed to analyse the association between biomarker concentrations over time, sepsis diagnosis and organ dysfunction severity. Joint models were used to evaluate the predictive ability of individual biomarker kinetics during the first 24 hours for in-hospital mortality Of 214 screened patients, 173 patients were analysed, and 137 (79%) developed sepsis. Linear mixed models revealed time-dependent decreases in IL10 ({beta} -0.016, 95%CI -0.028 to -0.004), IL1RN ({beta} -0.014, 95%CI -0.024 to -0.004), and IL6 ({beta} -0.012, 95%CI -0.024 to 0.00). Sepsis was associated with higher IL1RN ({beta} 0.378, 95%CI 0.153-0.603), and TNFRSF1A ({beta} 0.40, 95%CI 0.21-0.58); only models evaluating IL6 showed significant interaction between sepsis and time ({beta} -0.14, 95%CI -0.028 to 0.00). SOFA correlated with elevated IL10 ({beta} 0.048, 95%CI 0.021-0.075), IL1RN ({beta} 0.044, 95%CI 0.017-0.071), CCL2 ({beta} 0.046, 95%CI 0.021-0.071), TNFRSF1A ({beta} 0.050, 95%CI 0.030-0.070), and PCT ({beta} 2.63, 95%CI 1.32-3.93); the interaction between SOFA score and time was significant only for IL6 ({beta} -0.003, 95%CI -0.005 to -0.001). Joint survival models (adjusted for age and highest SOFA) identified IL8 (HR 0.655, 95% CrI 0.582-0.728), TNFRSF1A (HR 0.505, 95% CrI 0.419-0.682), and PCT (HR 1.004, 95% CrI 1.001-1.008) as predictors. ConclusionSepsis diagnosis and severity of organ dysfunction may be associated with higher levels and kinetic values of inflammatory biomarkers such as IL1RN and TNFRSF1A. IL6 levels showed a significant association for the interaction of time with both sepsis diagnosis and SOFA score. TNFRSF1A, IL8 and PCT dynamics were found to be associated with survival and could be useful in developing prognosis tools.