Critical Care

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.

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: 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.

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.

BACKGROUND: Cerebral ischemia following subarachnoid hemorrhage (SAH) has traditionally been considered transient because functional alterations of the cerebral microcirculation are thought to be self-limiting. However, we identified a previously unrecognized vasculopathy, perivascular fibrosis of the cerebral microcirculation (PFCM), characterized by excessive type I collagen deposition after SAH. This study investigated the mechanisms underlying PFCM and its subsequent effects on cerebral hemodynamics. METHODS: In vivo SAH was modeled in mice by autologous blood injection, whereas oxygenated hemoglobin (OxyHb) exposure was used to mimic SAH in vitro. Pericyte-deficient mice (Pdgfr{beta}+/-) and pericyte-specific vestigial-like family member 3 (VGLL3) conditional knockout mice (Vgll3{Delta}PC) were generated. Pericyte contractility was measured by nanoindentation and traction force microscopy. Molecular mechanisms were examined using Western blotting, immunofluorescence, CUT&Tag, RNA-seq, transmission electron microscopy, and molecular docking. PFCM, impaired dilation of the cerebral microcirculation, and cerebral autoregulation were assessed by two-photon imaging, transcranial Doppler with continuous blood pressure monitoring, super-resolution ultrasound imaging, and photoacoustic imaging. RESULTS: After SAH, mice developed long-term cerebral autoregulation dysfunction marked by impaired dilation of the cerebral microcirculation, with the abnormality being most evident within the relatively lower blood pressure range. The marked reduction in PFCM in Pdgfr{beta}+/- mice indicated that pericytes were the principal cellular contributors. Mechanistically, OxyHb-induced cytoskeletal remodeling in vitro increased pericyte contractility and promoted nuclear translocation of SAH-upregulated VGLL3. This was followed by increased genomic occupancy, Col1a1 transcriptional activation, and type I collagen deposition. Pericyte-specific VGLL3 knockout abolished PFCM and, consequently, significantly alleviated long-term cerebral autoregulation dysfunction. CONCLUSIONS: Our findings identify PFCM mediated by pericytic VGLL3 as a novel vasculopathy leading to long-term cerebral autoregulation dysfunction after SAH.

Purpose To estimate the per-protocol effect of red blood cell (RBC) transfusion strategies on ICU-acquired infection in critically ill adults with sepsis using a target trial emulation framework. We evaluated whether restrictive strategy and liberal strategy, defined by hemoglobin (Hgb) thresholds, differ in their effect on ICU-acquired infection during ICU stay. Methods We conducted a target trial emulation using the MIMIC-IV database and included adults who met Sepsis criteria at ICU admission. Clones were assigned to restrictive or liberal transfusion strategies. Under the restrictive strategy, RBC transfusion was permitted only when Hgb was [&le;]7.0 g/dL, whereas under the liberal strategy, transfusion was permitted when Hgb was >7.0 g/dL. The primary outcome was the first ICU-acquired infection occurring at least 72 hours after ICU admission. Per-protocol effects were estimated using a clone-censor-weight approach with a marginal structural model. A parametric g-formula was used as a complementary analysis that jointly modeled ICU discharge and ICU mortality as competing events to derive strategy-specific 28-day cumulative incidences and risk differences. Results 8 Among 4,013 eligible ICU stays, the liberal-versus-restrictive comparison provided little evidence of a difference in the risk of ICU-acquired infection (adjusted conditional OR, 0.954; 95% CI, 0.797 to 1.142). In the complementary g-formula analysis, the 28-day risk difference for the liberal versus restrictive comparison was -0.02 percentage points (95% CI, -0.15 to 0.11), consistent with the primary analysis. Findings were generally robust across prespecified subgroup and sensitivity analyses. Conclusion In this target trial emulation of adults with sepsis, we observed no clinically meaningful difference in ICU-acquired infection between RBC transfusion strategies defined by hemoglobin thresholds.

BACKGROUND: Subarachnoid hemorrhage (SAH) induces inflammatory responses and subsequent immune cell activation, which may contribute in cerebral vasospasm, microcirculatory impairment and poor neurological outcomes. Although cerebral vasospasm has traditionally been considered a major cause of delayed cerebral ischemia after SAH, therapies targeting angiographic vasospasm have not consistently improved functional outcomes. Early inflammatory responses may contribute to microcirculatory impairment, cerebral vasospasm, and subsequent neurological injury. Herein, we investigated whether interleukin-10 (IL-10), an anti-inflammatory cytokine, improves these outcomes in an experimental SAH model. METHODS: Mice received intramuscular injections of either an adeno-associated virus encoding IL-10 (AAV/IL-10) vector or an AAV expressing green fluorescent protein (AAV/GFP) vector (control). India ink angiography was performed to assess the diameter of the sphenoidal segment of the middle cerebral artery (MCA), the total length of the visible cortical arteries, and cortical staining intensity, as indices of cerebral vasospasm, microcirculatory impairment, and cerebral perfusion, respectively. Perivascular inflammatory cell infiltration and cytokine levels were assessed using immunohistochemistry and ELISA. We also evaluated the therapeutic efficacy of the AAV/IL-10 vector when administered immediately after SAH induction. RESULTS: IL-10 overexpression significantly improved neurological outcomes after SAH and was associated with attenuated cerebral vasospasm and microcirculatory impairment, as well as preservation of cerebral perfusion. It also significantly reduced neutrophil and macrophage infiltration around the internal carotid artery and attenuated SAH-induced elevations in IL-6 and matrix metalloproteinase-3 levels. Mice treated with the AAV/IL-10 vector immediately after SAH induction showed significant improvements in neurological scores and cerebral perfusion. CONCLUSIONS: AAV-mediated IL-10 overexpression improves neurological outcomes after SAH, likely by attenuating inflammatory responses, cerebral vasospasm, and microcirculatory impairment. These findings suggest that IL-10-based anti-inflammatory therapy is a promising therapeutic strategy for SAH.

Severe dengue can damage the liver through unestablished mechanisms. We investigated the role of myeloperoxidase (MPO), a neutrophil enzyme, in dengue through patients, fatal liver samples, and mouse infection models. Observations from two independent clinical cohorts revealed elevated plasma MPO levels in dengue and, in one cohort, MPO was further linked to liver injury markers during the critical phase of disease, whereas livers from dengue fatal cases revealed MPO build-up in the vicinity of CD177+ activated neutrophils. In mice, dengue led to MPO overexpression, oxidative damage, and broad activation of innate and systemic inflammatory pathways in livers. Blocking MPO activity alleviated these and improved survival in one model and delayed disease progression without preventing death in another. These findings establish MPO as a functional mediator of severe dengue-associated liver injury and inflammation, which warrants further preclinical investigation into its hepatic pathogenic mechanism and its validity as target for therapeutic intervention.

Offline reinforcement learning (RL) provides a promising framework for learning and evaluating treatment policies from logged clinical data, particularly in sequential decision-making settings where prospective exploration would be unsafe. In ICU sepsis management, however, it remains unclear whether offline RL policies retain stable behavior under increasingly severe out-of-distribution (OOD) patient cohorts. In this paper, we evaluate standard offline RL methods on three severity-enriched OOD test mixtures from the MIMIC-III benchmark dataset to determine whether offline policies retain a stable, actionsensitive decision-support signal. Under the shared learned-dynamics offpolicy evaluation (OPE) protocol, as the severe-OOD ratio increases from 25% to 75%, observed clinical survival declines from 67% to 49%, while the best offline method in each mixture receives model-predicted terminal survival values of 87%, 86%, and 85%, respectively. Because observed clinical survival and model-predicted terminal survival are different quantities, this contrast suggests a stable model-based decision-support signal under severity shift. We further present a secondary physiological stabilization analysis using an episode-level physiological stabilization score (EPSS), a heuristic summary of whether selected physiological variables move in favorable directions during follow-up. In this analysis, model-generated rollouts under offline policies receive higher EPSS values than matched logged clinical trajectories for several physiological components. Together, these results support learned-dynamics OPE as a useful severity-OOD stress test for offline RL policies in ICU sepsis, while leaving prospective and causal validation as necessary next steps.

In early sepsis the direction in which blood immune-cell transcriptional programmes move may carry prognostic information beyond a single baseline measurement, but whether such trajectory associations survive independent testing is unknown. We scored five immune modules, frozen before analysis, in three public longitudinal whole-blood microarray sepsis cohorts and fitted a logistic model ladder fixed in advance to the change per 24 hours in the two cohorts with mortality data (82 patients, 24 deaths), pooling by inverse-variance fixed-effect meta-analysis with Benjamini-Hochberg control. No association survived correction for multiple testing. The two leading signals were a rising CD4/NK lymphocyte trajectory associated with lower mortality (pooled odds ratio 0.53, 95% confidence interval 0.31 to 0.90) and a rising emergency-granulopoiesis trajectory associated with higher mortality (1.60, 0.92 to 2.79), both per one standard deviation. We then tested both in an independent transcriptomic cohort with serial sampling (63 patients, 15 deaths), scored by the identical frozen method, and against their cell-count analogues in an intensive-care database of 12,607 adults meeting Sepsis-3 criteria, of whom 744 to 4,206 had the serial measurements each analogue required. Independent testing separated the two signals, in the order opposite to the one discovery had suggested. The emergency-granulopoiesis association was reproduced in direction and effect size without reaching conventional significance on its own (validation odds ratio 1.72, 0.92 to 3.20, p=0.088; pooled 1.65, 1.09 to 2.50), was positive in all nine sensitivity analyses, each fixed before the estimates were examined, and was supported by two of its three analogues, including the neutrophil-to-lymphocyte ratio (1.31, 1.20 to 1.42). The CD4/NK association did not reproduce (1.06, 0.59 to 1.89), was null in the window most favourable to it, and received no support from an analogue well powered to detect the discovery effect. The discovery signal that looked most consistent failed independent testing.

Background: The 2026 American Heart Association/American College of Cardiology (AHA/ACC) guidelines replaced the 2019 European Society of Cardiology (ESC) four-tier pulmonary embolism (PE) risk scheme with five clinical categories (A-E) and subcategories. These categories were set by expert consensus and have not been validated against outcomes. How patients are reclassified relative to ESC, or how the two systems compare prognostically, is unknown. Methods: We utilized three cohorts of patients with confirmed PE using structured electronic health record data, laboratory biomarkers, and large-language-model abstraction of radiology reports: Duke University Health System (n=12,992, drawn from 95,760 consecutive inpatient CT pulmonary angiography studies, 2014-2025, with no referral or registry enrollment step between imaging and cohort entry), INSPECT (Stanford; n=3,870), and MIMIC-IV (Beth Israel Deaconess; n=361). Patients were assigned AHA/ACC categories B through E, subcategorized where data allowed, and mapped to 2019 ESC risk strata. The primary outcome was 30-day mortality; discrimination was assessed with Harrell C-index. Results: Among 17,223 patients with confirmed PE, pooled 30-day mortality rose monotonically across categories: 1.5% (B), 8.9% (C), 15.5% (D), and 31.9% (E), with the ordering preserved in all three cohorts despite differing baseline mortality. Subcategory-level discrimination was reliable only at the high-acuity extreme (D2-E2); across subcategories C1 through D1, mortality did not order monotonically (9.2%, 10.8%, 8.1%, 10.9%), and adding subcategories to category C did not improve discrimination at Duke (C-index 0.699 vs 0.699). Category C patients lacking both echocardiography and biomarker testing (12.7% of category C) had mortality (10.4%) equal to or exceeding classified peers. Relative to ESC, the frameworks were concordant at the extremes, but 5.7%of ESC intermediate-risk patients were reclassified to category D, with modestly higher but non-significant 30-day mortality than those remaining in category C (10.8% versus 8.9%). Conclusions: Across a three-health-system cohort, the 2026 AHA/ACC framework produced a reproducible mortality gradient at the category level, with added subcategory granularity refining risk chiefly at the highest-acuity tiers. Discrimination across the broad intermediate band was limited, and reclassification from ESC fell almost entirely within this range.

Introduction Postoperative analgesic management after minimally invasive cardiac surgery (MICS) should facilitate early recovery while providing adequate pain control. However, direct evidence comparing postoperative remifentanil- and fentanyl-based analgesic strategies after MICS remains limited. We compared these strategies and explored their associations with postoperative recovery, postoperative nausea and vomiting (PONV), and pain management. Methods This retrospective single-center observational cohort study included patients who underwent MICS via a right mini-thoracotomy between January 2023 and June 2026. Patients were categorized according to postoperative remifentanil- or fentanyl-based analgesia in the intensive care unit. Outcomes included time to extubation, PONV, postoperative pain assessed using the numerical rating scale (NRS), additional analgesic use, and intensive care unit length of stay. Multivariable logistic regression examined the association between postoperative opioid strategy and PONV, adjusting for age, sex, and smoking history. Results PONV occurred less frequently in the remifentanil group than in the fentanyl group (20.6% vs 45.0%, P = 0.004), and this association remained significant after adjustment (adjusted odds ratio, 0.23; 95% confidence interval, 0.10-0.56; P = 0.001). Time to extubation was shorter with remifentanil (median, 179 [interquartile range, 134-240.5] vs 247 [190.2-276.5] min; P < 0.001). In contrast, NRS pain scores on postoperative day 0 were higher with remifentanil (3 [1-6] vs 1 [0-2]; P < 0.001), and additional analgesics were used more frequently (80.6% vs 33.3%; P < 0.001). Pain scores on postoperative day 1 did not differ significantly between groups. Conclusion Postoperative remifentanil-based analgesia after MICS was associated with less PONV and earlier extubation but also with greater early postoperative pain and more frequent additional analgesic use than fentanyl-based analgesia. Appropriate transition to longer-acting analgesics with multimodal analgesia may help preserve the potential benefits of remifentanil while maintaining adequate postoperative pain control.

Background and Objectives: Preterm infants are commonly transfused, yet direct cardiorespiratory effects of red blood cell (RBC) transfusions remain poorly understood. We explored the feasibility of using multicentre electronic health data (EHD) to study such cardiorespiratory responses. Methods: Highly granular routine EHD were collected from preterm infants born <32 weeks gestational age at three European centres. Heart rate, oxygen saturation, and respiratory rate were evaluated 12 hours before and after the RBC transfusion. Results: A total of 321 transfusions in 164 infants were analysed. Overall, there was no significant change in the rate of bradycardia and apnoea following transfusion. Cardiorespiratory parameters varied substantially between infants; e.g. 20% of transfusions were associated with an unexpected, significant increase in heart rate. Respiratory rate and oxygen saturation exhibited similarly heterogenous patterns following transfusion. In sub-group analysis, the proportion of transfusions with increased heart rate was significantly higher within the first two weeks than later (32% vs 13%, p=0.0019). Conclusions: Multicentre EHD extraction allows to identify otherwise masked short-term effects of RBC transfusions on cardiorespiratory parameters, possibly indicating cardiac or pulmonary overload. Such effects may vary with adaptation to anaemia. Analysing EHD may ultimately enable personalized transfusion practice.

Background: Serial glial fibrillary acidic protein (GFAP) trajectories have become an important framework for contextualizing evolving secondary-injury pathophysiology after moderate-to-severe traumatic brain injury (msTBI). However, total GFAP pools release and clearance signals that may be less useful for longitudinal bedside decisions than a proteoform-resolved assay. We compared total GFAP with neoGFAP, defined here as calpain-generated GFAP proteoforms intended to index active astroglial proteolysis during the subacute phase. Methods: We analyzed 651 serial serum samples from 95 msTBI patients from a previously described single-site cohort. Total GFAP and neoGFAP were measured on the same MSD platform from 6 to 240 hours after injury. Early (6 to 72 h) and late (96 to 240 h) windows, data-derived tertiles, and serial trajectory summaries were calculated directly from serial samples. Models were benchmarked against age plus admission post-resuscitation Glasgow Coma Scale (GCS) and the admission IMPACT extended risk score using five-fold stratified cross-validation. Outcomes were unfavorable outcome (GOSE 1 to 4), less-than-good recovery (GOSE 1 to 6), Disability Rating Scale (DRS) [&ge;]15, mortality, and neuroimaging worsening at 6 months. Results: The cohort contributed 95 serial biomarker profiles, with 90 participants evaluable for 6-month GOSE and 89 for DRS. Unfavorable outcome occurred in 57/90 (63.3%), and less-than-good recovery in 79/90 (87.8%). For unfavorable outcome, IMPACT plus early neoGFAP reached AUROC 0.85 versus 0.84 for IMPACT plus early total GFAP and 0.81 for IMPACT alone. For less-than-good recovery, IMPACT plus late neoGFAP achieved AUROC 0.90 versus 0.84 for late total GFAP and 0.82 for IMPACT alone. Secondary analyses for DRS, mortality, and neuroimaging worsening showed smaller differences. Conclusions: In this retrospective analysis, neoGFAP provided clearer incremental value than total GFAP for recovery-oriented monitoring, especially when late-window reassessment of patients who remained at risk for less-than-good recovery was required. Results support prospective testing of neoGFAP as a pathophysiology-informed adjunct to serial bedside decision making, repeat-assessment thresholds, and recovery stratification.

Background: The condition of a patient with acute stroke often changes within hours of ICU admission. Prognostic work here targets fixed endpoints predicted from admission data, and trajectory phenotyping assigns one label per patient. We used longitudinal ICU data to identify interpretable dynamic clinical states, characterize transitions between them, and relate the current state to later events. Methods: Retrospective cohort study of 6368 adults with acute stroke in MIMIC IV v3.1. The first 72 h were divided into twelve 6-hour windows, and a hidden Markov model was fitted to 21 neurological, physiological and organ support variables. State number was chosen against criteria fixed before fitting: statistical fit, restart stability, state occupancy and clinical interpretability. Generalized estimating equations related the current state to new mechanical ventilation and vasopressor use within 12 h, and to ICU death within 72 h. Eleven sensitivity analyses assessed the robustness of the state solution. Results: Four states were selected: neurologically preserved-low support, neurological impairment low support, impairment renal dysfunction and impairment-respiratory support (63.3%, 7.8%, 11.8% and 17.1% of windows). Within 72 h, 40.3% of patients changed state at least once, and transitions ran in both directions rather than along a single severity gradient. States were identified without outcome data, yet ICU mortality by last state ranged from 2.9% to 43.9%. Adjusted for age, sex, subtype and Charlson index, the current state remained associated with organ-support escalation and death. State prevalence differed by at most 1.1 percentage points between training and test sets, and 10 of 11 sensitivity analyses gave a stable four-state solution (ARI 0.754 0.955). Conclusions: The early ICU course of acute stroke can be represented as movement among a small number of clinically interpretable states. The representation was reproducible in a held out set and across admission eras, but requires validation in an independent database before any clinical use.

Introduction: Anesthesia is known to modulate glymphatic clearance and cerebrospinal fluid (CSF) transport in rodents, but how these effects translate to a larger, gyrencephalic brain is unknown. With its anatomical similarity to the human brain, the pig offers a valuable translational model for examining anesthesia-dependent CSF-to-brain transport. Methods: We used dynamic in vivo SPECT/CT imaging for six hours following cisterna magna injection of [99mTc]-DTPA to quantify CSF-to-brain tracer transport in pigs under two anesthesia regimens: ketamine/dexmedetomidine (K/D, n=5) which previously has been shown in rodents to enhance glymphatic influx relative to GABAergic anesthesia, and propofol (PRO, n=5). Brain and CSF spaces were delineated using a data-driven non-negative matrix factorization approach, and tracer kinetics were quantified using a one-tissue compartment model. Results: Brain influx could be stably estimated from 2 hours post-injection. Hierarchical sub-division of the brain parenchyma identified two kinetically distinct components with different anatomical distributions: a surface component, located ventrally and within the interhemispheric fissure, showed faster kinetics than the anatomically deeper and lateral-dorsal component. Consistent with rodent findings, K/D-anesthetized pigs showed 62% (p=0.002) greater brain tracer accumulation than PRO-anesthetized pigs. However, while the brain influx rates did not differ substantially (p=0.047), a 52% higher cumulative CSF tracer concentration (p=0.047) could account for most of the difference by providing greater tracer availability for brain entry. Conclusions: In the larger gyrencephalic pig brain, we found higher brain tracer accumulation under K/D anesthesia compared to PRO anesthesia. A significant portion of this difference is readily explained by higher CSF retention, likely driven by a slower CSF turnover. This underscores the necessity of dynamic CSF tracer concentration measurements when assessing CSF-brain influx, a factor we suggest that future glymphatic studies should take into account.

Seasonal influenza remains a major cause of morbidity and mortality worldwide. Although neuraminidase inhibitors improve outcomes, influenza-related deaths persist. We evaluated the impact of early aspirin (ASA) and non-aspirin nonsteroidal anti-inflammatory drug (NSAID) use on outcomes in adults hospitalized with influenza. This retrospective study included adults admitted to the University of Minnesota Medical Center from 2016 to 2018. Continuous variables were summarized as medians with interquartile ranges (IQRs) and categorical variables as counts and percentages. Group comparisons used Wilcoxon rank-sum, Chi-square, or Fishers exact tests. Analyses included case-control comparisons, assessments by vaccination status, and subgroup analyses by early ASA or NSAID use. Among 2,816 patients, 320 had laboratory-confirmed influenza, with vaccination less common among cases. Unvaccinated patients had higher rates of intensive care unit (ICU) admission (23.6% vs. 11.1%; P = 0.003) and ventilatory support (15.0% vs. 6.1%; P = 0.009). In vaccinated patients, early ASA use was associated with older age and higher in-hospital mortality, whereas early NSAID use was associated with no in-hospital deaths, better one- and three-year survival (P < 0.001), and fewer, though not statistically significant, cardiovascular complications. In unvaccinated patients, ASA use was associated with lower three-year survival (59.1% vs. 79.2%; P = 0.013), while NSAID use was associated with fewer ICU admissions and no cardiovascular or renal complications. In both vaccinated and unvaccinated adults hospitalized with influenza, early NSAID use was associated with improved survival and fewer complications, whereas ASA use was associated with worse outcomes.

Background: ERAS protocols reduce hospital stay by 1.88 days and complications by 29% globally, but their one-size-fits-all paradigm, validated at sea level, may fail at high altitude where chronic hypoxia and population-specific genetic adaptations remodel baseline physiology. No study has quantified ERAS effect weight shifts at high altitude or proposed a theoretical model to explain the gap. Objectives: To evaluate three dimensions of plateau ERAS remodeling: (i) risk factor weight shift, (ii) traditional marker failure, (iii) genetic background modification, and propose the PAERS (Plateau Adaptation-ERAS Remodeling Syndrome) risk stratification model tailored to altitude. Methods: Retrospective cohort of 612 adults undergoing elective laparoscopic cholecystectomy (2018-2023) at Qinghai Red Cross Hospital (2260 m). Three analytical tiers: (1) multivariable regression comparing risk factor coefficients against plain-altitude benchmarks; (2) restricted cubic spline and interaction modeling for Hb, SpO2, and LOS; (3) inferential genetic modifier analysis using population-level EPAS1 carrier rates. Primary outcomes: LOS and complication rate. Results: Three-dimensional shift was observed: (1) Weight Remodeling: BMI replaced sex as primary risk factor (OR = 1.86, P < .001), surgeon variability amplified (F = 6.33 vs plain benchmark 2-4, an ~58% increase in F-statistic ratio, P < .001); (2) Marker Failure: Hb showed J-type relationship with LOS (Hb x SpO2 interaction beta = -0.0095, P = .009), with effect reversal across SpO2 strata (Plateau Hemoglobin Paradox); (3) Genetic Modification (population-level inference): ~70% EPAS1 carrier rate (range 57-85% across studies) suggests HIF-2alpha pathway is a baseline modifier that must be accounted for. Three falsifiable predictions were proposed. Conclusions: High-altitude ERAS faces three challenges: effect weight remodeling, biomarker failure, and genetic background calibration. The PAERS hypothesis proposes an integrated risk stratification model, shifting from one-size-fits-all to altitude-aware, patient-specific protocols.

Purpose. Prognostic assessments after acute brain injury are largely narrative, and how prognostic language relates to subsequent care has not been measured at scale. We quantified where it is written and its association with a subsequent code-status limitation. Materials and Methods. Multidatabase observational study of adults with acute brain injury or a related neurologic emergency, using MIMIC-IV (2008-2019; discharge summaries and radiology reports) and a timestamped MIMIC-III cohort (notes and code-status orders). The exposure was documented prognostic language; outcomes were its association with a subsequent full-code-to-limitation transition, note-stream location, and completeness of documented command-following relative to structured Glasgow Coma Scale (GCS) motor scores. Results. Among 31,993 admissions (27,054 patients; median age, 69 years; 54.9% male), prognostic language in the timestamped cohort (MIMIC-III) was associated with a subsequent code-status limitation after multivariable adjustment (adjusted hazard ratio, 4.3; 95% CI, 2.9-6.5; unadjusted 14-day cumulative incidence, 40% vs 8.5%), including the comfort-measures component (3.9), a higher-risk subgroup (4.4), and after acute-physiology adjustment (4.1); the association was concentrated in the first 3 days. Non-prognostic severity language showed no comparable association (hazard ratios, 1.1-1.3). Prognostic language localized almost entirely to the narrative (4.9% of discharge summaries vs 0.015% of radiology reports); command-following was undocumented in 55.7% of summaries, and no final-24-hour GCS motor score was charted in 72.8%. Conclusions. Documented prognostic language after acute brain injury was written in the narrative, not structured fields, and was associated with a subsequent code-status limitation after multivariable adjustment. This observational association cannot establish causation but warrants prospective study.

PurposeIt is well established that volatile anesthetics and surgery induce acute and subacute changes in the cellular and molecular landscape of the brain and peripheral circulation and can impair neurological function. However, the chronic neurological sequelae of isoflurane (Iso) anesthesia combined with surgical operation (OP), as well as the underlying mechanisms of postoperative neurological dysfunction, remain poorly understood. MethodsYoung adult male (M) and female (F) C57BL/6 mice underwent 4 h of 2% Iso plus laparotomy or sham treatment. At 12 weeks, olfactory and cognitive function were assessed by odor memory, buried food, Y-maze, and active avoidance tests. Olfactory bulbs (OB) and hippocampi (HI) were collected for RNAseq, while plasma extracellular vesicles (EVs) were isolated, characterized by NanoFCM, and profiled by Olink proteomics. Lastly, EVs were injected into the HI of naive male mice, and cytokine/chemokine responses were measured 24 h later. ResultsBoth sexes showed olfactory impairment after chronic Iso/OP, with greater deficits in females. Iso/OP mice, especially females, exhibited impaired odor recognition in the OM test and longer latencies to locate buried food. Female mice also showed greater hippocampal-dependent spatial working memory deficits in the Y-maze, with more arm returns and fewer alternations than Sham/F mice, whereas Iso/OP/M mice performed similarly to controls. Likewise, female, but not male, Iso/OP mice displayed impaired associative learning in the active avoidance test, evidenced by fewer avoided trials and more escape responses. These long-term behavioral abnormalities were accompanied by sex-divergent transcriptomic remodeling in the OB and HI, including altered synaptic, neurodevelopmental, extracellular matrix, stress-response, and chemotaxis-related pathways. Iso/OP reduced plasma EV particle numbers in both sexes and shifted EV size distributions, with prominent reductions in the 40-100 nm EV fraction. Proteomics revealed distinct sex-and condition-specific EV profiles, with several EV-associated proteins showing opposing sex-dependent expression patterns. Hippocampal injection of Iso/OP-derived EVs induced donor sex-dependent cytokine remodeling, confirming inflammatory bioactivity. ConclusionsFour-hour isoflurane (Iso) exposure combined with laparotomy in young adult mice induces chronic, sex-dependent neurological deficits with distinct transcriptomic remodeling across brain subregions. Persistent alterations in circulating EV abundance and inflammatory cargo may drive chronic neuroinflammation and long-term brain dysfunction.