Neurocritical Care

Background: The Functional Outcome in Patients with Primary Intracerebral Hemorrhage (FUNC) score was initially validated for prediction of functional independence on the Glasgow Outcome Scale (GOS) 90 days after intracerebral hemorrhage (ICH), but recovery often extends beyond three months. Aims: Our objective was to extend the FUNC score for prediction of 12-month functional independence to strengthen its utility for family counseling and research methodology. Methods: We conducted a single-center prospective cohort study enrolling adult patients with primary ICH between February 2009 and January 2018. We calculated FUNC scores at admission and assessed GOS 12 months after ICH. The primary outcome was 12-month functional independence, defined as a GOS score [≥]4. We calculated the area under the receiver operating characteristic curve (AUC) of the FUNC score using logistic regression, handling missing GOS with multiple imputation by chained equations. We evaluated score calibration using a calibration curve and the Brier score, and we assessed clinical utility using decision curve analysis. We explored the statistical efficiency gains of using FUNC-based sliding dichotomy thresholds for favorable outcome definitions by running simulations of a clinical trial with 1:1 randomization. We ran 5000 simulations for each sample size (100 to 1000, in increments of 10) and treatment effect (odds ratio of 1.5, 2.0 and 2.5) combination and calculated efficiency gains for each respective treatment effect as the percentage reduction in sample size required to have 80% power using sliding versus fixed dichotomy thresholds. Results: A total of 535 patients were included (median [IQR] age 68 [54-79], 237 [44%] female, median [IQR] NIHSS 16 [6-25], median [IQR] FUNC 8 [6-9]). Overall, 99 of 445 (22%) patients with known 12-month GOS achieved functional independence. The FUNC score had an AUC of 0.79 (95%-CI: 0.75-0.84) for 12-month functional independence. The calibration plot was reasonable, with modest evidence of overestimation at low predicted probabilities, and the Brier score was 0.15. A net benefit was observed across 5-50% threshold probabilities. Sliding dichotomy had an efficiency gain of 27% for a treatment effect of OR=2.0, and a gain of 22% for a treatment effect of OR=2.5. The efficiency gain for a treatment effect of OR=1.5 could not be calculated because the fixed dichotomy did not reach 80% power despite a sample size of 1000 patients. Conclusions: The FUNC score's predictive performance for 12-month functional independence was comparable to its originally validated 3-month discrimination. Following external validation across centers, the FUNC score may be leveraged to counsel families on global measures of long-term functional independence and to implement sliding dichotomy methodology in ICH research.

BackgroundNeonatal cerebral venous sinus thrombosis (CVST) is associated with intracranial hemorrhage (ICH) and ischemic lesions. There is no scale to characterize the spectrum of brain injury secondary to neonatal CVST. ObjectiveTo develop the Neonatal CVST Hemorrhage Score (NeoCVST Score) to characterize ICH and brain injury in neonates with CVST. MethodsThis was a retrospective cohort study of neonates with CVST diagnosed using brain MRI/MRV. The NeoCVST Score was developed using the study cohort, integrating elements from previous hemorrhage classification systems and expert consensus. Logistic regression examined associations between NeoCVST score and neurodevelopmental outcomes (Pediatric Stroke Outcome Measure). Interrater reliability was assessed with intraclass correlation coefficient. ResultsThe study included 100 neonates (77% term and 23% preterm) with CVST. Thrombosis of multiple venous sinuses was present in 62%. ICH was present in 63%. Supratentorial hemorrhage was present in 57% and included germinal matrix hemorrhage and intraventricular hemorrhage (GMH-IVH) grades 1-2 (22%), GMH-IVH grade 3 (15%), parenchymal (43%) and thalamic (18%) hemorrhage. Infratentorial hemorrhage was present in 19% and included cerebellar (18%) and brainstem (4%) hemorrhage. Extra-axial hemorrhage was present in 32% and included epidural (2%), subdural (26%) and subarachnoid hemorrhage (6%). Ischemic brain injury was present in 67% and included lesions in the medullary vein distribution (13%), white matter (54%), basal ganglia (17%) and thalamus (25%). Neurodevelopmental outcomes included 40% with normal outcomes and 60% with neurodevelopmental impairments. NeoCVST total score (OR=1.1, P=0.02) and subscores for thalamic hemorrhage (OR=1.9, P=0.04), thalamic ischemia (OR=2.2, P=0.005) and bilateral thalamic ischemia (OR=2.8, P=0.01) were predictors of adverse neurodevelopmental outcome. Inter-rater reliability showed moderate-good agreement between reviewers with an intraclass correlation coefficient of 0.71. ConclusionsThe NeoCVST Score is a simple clinical tool to characterize ICH and brain injury secondary to neonatal CVST. Increasing NeoCVST total score and subscores for thalamic hemorrhage and ischemia were associated with worse neurodevelopmental outcomes.

Background: Thalamic low-intensity transcranial focused ultrasound (tFUS) has shown promise for increasing behavioral responsiveness in disorders of consciousness (DOC), but no study has examined whether it can causally modulate the well-validated behavioral, electrophysiological, and metabolic biomarkers of DOC impairment. Methods: Sixteen adult patients (44% Female; Age, M=37.81, SD=15.97) with a chronic DOC (Time Since Injury, M=3.39, SD=1.94 years) secondary to severe brain injury (TBI 44%, non-TBI 56%) underwent a 10-day inpatient, longitudinal, single-arm, open-label protocol. tFUS was delivered in a single session targeting the left central thalamus. Well-known behavioral (CRS-R), electrophysiological (EEG {delta}/{beta} ratio), metabolic (18F-FDG PET), and polysomnographic outcomes were assessed at baseline and after sonication. Results: The maximum CRS-R total score increased significantly following tFUS compared to baseline (M=13.27 vs. M=10.33; t(14)=7.407, p<0.001, d=1.913), as did the global EEG {delta}/{beta} ratio (N=14; W=17, p=0.025, r=0.68), with the degree of frontal slowing positively predicting behavioral gains ({tau}b=0.51, p=0.016). Glucose metabolism decreased bilaterally in thalamus and frontal, temporal, and parietal cortices at both post-tFUS timepoints compared to baseline. Finally, N2 sleep increased by 33% following tFUS (N=11; t(10)=2.386, p=0.038, d=0.72), though this did not survive correction. No severe adverse events were observed. Conclusion: Thalamic tFUS can causally modulate well-validated behavioral, electrophysiological, and metabolic biomarkers of DOC. The convergent inhibitory signature across these measures suggests a thalamocortical reset mechanism, complementing existing excitatory neuromodulation approaches and providing the mechanistic foundation for a large, randomized sham-controlled trial.

Fv-HSP72 is a rapid cell-penetrating human heat shock protein for the treatment of traumatic organ injuries. We have shown this re-engineered protein (HSP72) is capable of crossing the blood brain barrier (BBB) of rats suffering a controlled cortical impact (CCI) and remains in brain tissue for up to 12 hours; long after clearance from the cortex of uninjured rats. Peptide sequences unique to Fv-HSP72 allow for its differential detection from endogenous HSP72. Male Sprague-Dawley rats were divided into 10 groups of n=10 with those animals receiving a CCI subjected to a unilateral cortical contusion simulating a moderate to severe brain injury using an electronically controlled pneumatic impact device. Control groups were either uninjured (Sham), injured (TBI Only), or injured and given buffer (TBI+Vehicle). Rats treated with one of three Fv-HSP72 variants were dosed at 10 or 30mg/kg 15m post-impact, then sacrificed 48 hours later. Cortical tissues were extracted from the ipsilateral and contralateral hemispheres for biomarker analysis. Here we report results of our drug inhibiting neurodegeneration based on five biomarkers (NF-L, pNF-H, pTau [T181, T231, S396]). These results were statistically significant, especially for one of the Fv-HSP72 variants, when comparing differences both between treatment groups and within groups (i.e. when comparing ipsi-vs. contralateral hemispheres). Significant inhibition of oxidative stress (3-NT) and inflammatory (IL-6) biomarkers were also observed (both p<0.0001). With similar results obtained for a blast injury model being published elsewhere, the analyses suggest Fv-HSP72 is neuroprotective following a direct impact brain injury. One sentence summaryThis study describes the effectiveness of a biologic agent, Fv-HSP72, in significantly inhibiting neuronal tissue damage in the brain when administered after a direct cortical impact.

ObjectiveThe JAK2 V617F mutation increases the risk of thrombosis in patients with myeloproliferative neoplasms (MPNs). However, it remains unclear whether individuals who carry the JAK2 V617F mutation without MPN also have an increased risk of stroke. MethodsWe prospectively tested for the JAK2 617F mutation in consecutive patients with acute ischemic stroke or transient ischemic attack (TIA) admitted between January 2020 and September 2024. Patients with overt MPN or abnormal blood counts were excluded. We used allele-specific PCR to detect the mutations. ResultsIn total, 921 patients (median age, 77 years; 557 men (62%); TIA, 32 patients) were enrolled in this study. Among them, 11 patients (1.2%; median age, 72 years; 8 male) tested positive for the JAK2 V617F mutation. There were no significant differences in clinical background, including age, sex, BMI, comorbidities, or history of thrombosis, between the positive and negative groups. The blood count and coagulation parameters did not differ significantly between the two groups. Among the 11 patients in the positive group, 9 had embolic stroke and 2 had thrombotic stroke. Embolic stroke of undetermined source (ESUS) was more frequently observed in the positive group than in the negative group (45 vs. 13%; p=0.002). Stroke severity and outcomes did not differ between the two groups. DiscussionApproximately 1% of patients with acute ischemic stroke or TIA carry the JAK2 V617F mutation despite normal blood counts. Of the 11 mutation-positive patients, nine (82%) exhibited embolic imaging features and five (45%) met the ESUS criteria, whereas other clinical characteristics did not differ significantly from the mutation-negative group.

ObjectivesTo determine whether heterogeneous treatment effects (HTE) explain the inconclusive results of targeted temperature management (TTM) trials after cardiac arrest, using causal machine learning across four datasets. DesignSecondary analysis of one multicenter RCT and three observational ICU cohorts using S-learner and forest-based R-learner models to estimate conditional average treatment effects (CATE). SettingTwenty-six French ICUs (HYPERION), approximately 200 U.S. ICUs (eICU-CRD), Johns Hopkins Hospital (PMAP), and Beth Israel Deaconess Medical Center (MIMIC-IV). PatientsAdults ([&ge;]18 years) with cardiac arrest; 4,507 patients across the four datasets, of whom 1,814 (40.2%) received TTM. InterventionsTTM as administered clinically or per HYPERION protocol. Ascertainment: randomization (HYPERION), treatment documentation (eICU-CRD), sustained hypothermia <36{degrees}C for >12 hours (PMAP), or documented cooling device use [&ge;]12 hours (MIMIC-IV). Measurements and Main ResultsThe primary outcome was hospital mortality; the secondary outcome was favorable neurologic function (Cerebral Performance Category 1-2 at 90 days for HYPERION; last motor Glasgow Coma Scale = 6 for observational cohorts). Three S-learner models (XGBoost, neural network, Bayesian Additive Regression Trees) and one forest-based R-learner (CausalForestDML) estimated CATE. HTE was assessed by likelihood-ratio tests for CATExtreatment interaction, CausalForestDML 95% confidence intervals, Group Average Treatment Effects (GATES) across CATE quintiles, and SHAP feature importance. S-learner discrimination was adequate (AUROC 0.72-0.82). No model showed a significant CATExTTM interaction in any dataset (all p > 0.05). Individual CATE confidence intervals uniformly crossed zero, and GATES showed no monotonic gradient of benefit across quintiles in any dataset. ConclusionsAcross four diverse datasets and multiple causal machine-learning approaches, we found no evidence of heterogeneous treatment effects for TTM after cardiac arrest. The inconclusive findings of TTM trials are unlikely explained by differential effects in identifiable subgroups defined by routinely available clinical features. KEY POINTSQuestion: Do identifiable patient subgroups derive differential benefit from targeted temperature management (TTM) after cardiac arrest? Findings: In a causal machine-learning analysis of 4,507 patients across one randomized trial and three observational ICU cohorts, no model detected significant heterogeneous TTM effects on mortality or neurologic outcome. Meaning: Conflicting TTM trial results are unlikely explained by differential effects in identifiable subgroups, weakening the rationale for personalized TTM strategies based on routinely available clinical features.

Background and Purpose Prognostication after acute ischemic stroke often relies on limited variables and simple risk scores, despite richer information being available at admission. We developed a multimodal AI model using admission data to predict modified Rankin Scale (mRS) outcomes and compared it to established tools. Methods In a retrospective study of ischemic stroke/TIA patients, we trained three modality-specific models on admission non-contrast head CT, history and physical notes, and structured clinical variables, and combined them in a weighted-average ensemble. We predicted binary (mRS 0-2 versus 3-6) and ordinal mRS (0-6) outcomes at discharge and 90 days. Performance on an external test cohort was compared with THRIVE and SPAN-100 scores using AUROC, AUPRC, Brier score, mean absolute error (MAE), and quadratic weighted kappa (QWK). Results A total of 6,915 patients were split into training, validation and testing cohorts in a 3:1:1 ratio. For discharge binary mRS (n=1596), the multimodal ensemble achieved significantly better discrimination (AUROC 0.859, AUPRC 0.858) with 25-61% lower Brier scores than THRIVE or SPAN?100 (all p<0.001). For 90?day binary mRS (n=207), the model also outperformed both THRIVE and SPAN-100 (AUROC 0.838, AUPRC 0.805, with 3-38% lower Brier scores). Ordinal mRS prediction showed similarly strong performance with significantly better QWK at discharge and numerically lower MAE. The multimodal ensemble model reassigned about one?third of patients to different risk categories versus THRIVE and was closer to the true discharge outcome in ~74% of discordant cases. Conclusions We developed a well-calibrated multimodal AI model for prediction of discharge and 90-day post-stroke functional outcomes using only data present at the time of admission. This model outperforms existing prognostic tools and can support early clinical decision-making.

Background: Patients in socioeconomically disadvantaged neighborhoods face barriers to care. Missing BP documentation may signal gaps in risk-factor management, a crucial component of primary and secondary prevention of intracerebral hemorrhage (ICH). We tested whether neighborhood deprivation was associated with absent electronic health record (EHR) blood pressure (BP) documentation surrounding ICH and whether absent documentation predicted subsequent uncontrolled BP. Methods: We conducted a case-only study within the NIH All of Us Research Program. We included ICH survivors (ICD-10 I61.x, surviving >=1 year) with available ZIP3-based Deprivation Index. Deprivation was categorized as Privileged, Intermediate, or Deprived using cohort-based tertiles. We excluded BP measurements collected by All of Us. Outcomes were (1) absent EHR-derived BP documentation and (2) uncontrolled BP (mean systolic BP >=140 mmHg) during three windows: 1-365 days before ICH; 30-365 days and 1-5 years after ICH. Multivariable logistic regression tested associations adjusting for age, sex, and race/ethnicity. Results: 1,474 ICH survivors were included (mean age 60.1, 50.4% female). Compared to privileged neighborhoods, those living in deprived neighborhoods had higher odds of absent EHR BP documentation in the year prior to ICH (OR 2.10, 95% CI 1.60-2.76; p<0.001), 30-365 days post-ICH (OR 2.82, 95% CI 2.14-3.73; p<0.001) and 1-5 years post-ICH (OR 2.81, 95% CI 2.13-3.71; p<0.001). Absence of EHR BP documentation in the year before ICH predicted uncontrolled BP 30-365 days (OR 1.97, 95% CI 1.36-2.85; p<0.001; N=888) and 1-5 years (OR 1.83, 95% CI 1.24-2.69; p=0.002; N=814) after ICH. Absence of BP documentation 30-365 days post-ICH also predicted uncontrolled BP 1-5 years post-ICH (OR 1.66, 95% CI 1.10-2.50; p=0.017; N=814). Conclusions: Neighborhood deprivation is associated with persistent gaps in EHR BP documentation surrounding ICH, and absent documentation before or soon after ICH predicts subsequent uncontrolled BP. These findings highlight the need for community-level strategies that ensure equitable BP monitoring for socioeconomically disadvantaged populations.

Background and PurposeDespite high rates of macrovascular recanalization, approximately half of patients with large vessel occlusion stroke fail to achieve functional independence after endovascular thrombectomy (EVT). Residual tissue-level perfusion abnormalities on post-procedural CT perfusion (CTP) may indicate futile recanalization and inform selection for adjuvant therapy. We synthesized post-EVT CTP thresholds, summarized acquisition timing, and discussed implications for patient selection in trials of intra-arterial thrombolysis, antithrombotics, and neuroprotection, limited to studies performing perfusion imaging after EVT. MethodsWe searched MEDLINE, EMBASE, and the Cochrane Library (January 2018-April 2026) for studies performing perfusion imaging after EVT, reporting [&ge;]1 quantitative CTP parameter with functional or neurological outcome, and enrolling [&ge;]10 patients; pre-EVT CTP studies were excluded. Functional independence with versus without post-EVT hypoperfusion was pooled using DerSimonian-Laird random-effects. Individual patient data from our prospective Cerebrolysin proof-of-concept cohort (N=18) were integrated. ResultsNine post-EVT perfusion imaging studies (497 patients) met inclusion criteria. Residual hypoperfusion occurred in 21-53% of angiographically successful reperfusions and was associated with lower odds of functional independence (pooled OR 0.23, 95% CI 0.17-0.33; I{superscript 2}=29%). A Tmax >6 s volume <3.5 mL at 30-90 minutes post-EVT was the most consistently validated threshold (OR 3.5, 95% CI 1.6-7.8). In our cohort, an ischemic core (rCBF <30%) of 0 mL versus any detectable residual core was associated with markedly higher odds of independence (OR 27.5, 95% CI 1.0-746 with continuity correction; {rho}=0.77, p=0.003). The optimal CTP acquisition window is 30-120 minutes post-EVT. ConclusionsPost-EVT CTP outperforms modified TICI grading for predicting functional outcome and identifies biologically distinct subgroups for adjuvant therapy selection. Standardized post-EVT CTP at 30-120 minutes, applied with the proposed threshold framework, should be used for eligibility and stratification in future trials of intra-arterial thrombolysis, antithrombotics, and neuroprotection.

High-density electrophysiological recording using Neuropixels probes enables single-unit resolution of human neural activity. However, integrating these systems into clinical environments remains challenging. Reported human recordings have been limited to a few centres in the United States utilising variable regulatory, sterilisation and operative techniques. Here, we present human Neuropixels recordings under a nationally managed ethical and regulatory framework in the United Kingdom. We provide a reproducible roadmap to overcome regulatory and equipment constraints. Guided by the IDEAL Stage 2a (Development) framework, we established a frameless intraoperative workflow utilising manufacturer-sterilised probes and a commercially available, clinical-grade setup for Neuropixels insertion including micromanipulator and endoscope holder. We prospectively evaluated this workflow across six participants (mean age 62.5 years) undergoing elective ventriculoperitoneal shunt surgery. Iterative failure-mitigation cycles successfully resolved key technical barriers, including neuronavigation interference and hardware instability. Assessed across three predefined endpoints (clinical safety, procedural timing, and neural data yield), the workflow achieved zero research-related adverse events and maintained a strict 30-minute procedural extension. Progressive technical refinements increased single-unit yield from 25 units during early development to 146 manually curated units. This approach provides a scalable, clinically integrated workflow to safely perform high-density electrophysiology in routine neurosurgical environments.

Traumatic brain injury (TBI) is a condition of high incidence worldwide, but remains mostly undertreated. Previous observations in preclinical studies pointed to a beneficial effect of insulin-like growth factor 1 (IGF-1) in TBI. As brain injury is associated to loss of IGF-1 sensitivity, we tested the therapeutic potential of AIK3a305 (AIK3), a novel IGF-1 sensitizer. Twenty-four hours after mild TBI induced by controlled impact, mice received daily intraperitoneal injections of AIK3 during 4 weeks. We found that TBI-associated sensorimotor disturbances measured with the adhesive-removal test were reverted by AIK3 treatment. In addition, neurological and cognitive disturbances measured by the neurological severity score and Y maze respectively, were also ameliorated by treatment with the IGF-1 sensitizer, whereas increased anxiety after mild TBI was also normalized by AIK3. Circulating levels of IGF-1 were increased after AIK3 treatment in TBI mice, while serum IL-6 levels, a biomarker of inflammation associated to TBI were similar to control mice treated with AIK3. Transcriptomic analysis determined that treatment with AIK3 widely affected gene expression in TBI brains, showing a general reduction in both up- and down-regulated genes. Collectively, these data support the use of IGF-1 sensitizers such as AIK3 for treatment of TBI.

BackgroundHemorrhagic transformation (HT) is a frequent and serious complication, occurring in up to 40% of cases after endovascular treatment (EVT) for acute ischemic stroke (AIS). Inflammation has been increasingly recognized as a key factor influencing both stroke pathophysiology and post-treatment complications (such as HT) interacting with endothelial dysfunction to exacerbate vascular injury after EVT. The objective of this study is to evaluate whether systemic inflammatory status predicts HT in AIS patients, and its relationship with endothelial biomarkers in the setting of this complication. MethodsWe retrospectively reviewed a prospective cohort of 229 AIS patients treated with EVT. Demographic, clinical, imaging, and laboratory data were collected. Inflammatory markers included white blood cell subsets and indices such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-neutrophil ratio (PNR), systemic immune-inflammation index (SII), and systemic inflammation response index (SIRI). Endothelial function was assessed by flow-mediated dilation (FMD) and circulating homoarginine (HArg), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA). The main outcome was radiological or symptomatic HT, classified according to ECASS criteria. ResultsHT was observed in 92 patients (40.2%), of whom 35 (36.1% of HT and 15.3% of the total) were symptomatic. In multivariate analysis, independent predictors of HT included higher NIHSS at admission, higher plasma glucose at admission, the use of non-aspiration devices, lower pre-recanalization lymphocyte count, higher pre-recanalization SII and higher NLR levels. Among endothelial function markers, HArg correlated with inflammatory markers, ANC (r = -0.2) and WBC (r = -0.19), and was associated to PH and symptomatic HT, but not with any radiologic HT after AIS. ConclusionsAn altered inflammatory status prior to EVT in AIS patients is associated with an increased risk of developing HT after EVT. Additionally, endothelial dysfunction could participate in the more aggressive forms of this complication.

BackgroundEndovascular thrombectomy (EVT) is the standard of care for acute ischemic stroke caused by large-vessel occlusion. However, the additional benefit of intravenous thrombolysis (IVT) before EVT remains controversial. This systematic review and meta-analysis evaluated the efficacy and safety of bridging therapy (EVT plus IVT) compared with EVT alone. MethodsThis systematic review and meta-analysis was conducted according to PRISMA 2020 and Cochrane Handbook recommendations and prospectively registered in PROSPERO. PubMed, EMbase, Scopus, and the Cochrane Library were searched for randomized controlled trials published between 1st January 2015 and 30th April 2026 comparing EVT plus IVT versus EVT alone in acute ischemic stroke. Random-effects meta-analysis was performed to estimate pooled odds ratios (ORs) with 95% confidence intervals (CIs). Primary outcomes included functional independence at 90 days and successful recanalization. Secondary outcomes included symptomatic intracranial hemorrhage (sICH) and all-cause mortality. ResultsEleven randomized controlled trials involving 4,419 patients were included in the meta-analysis. Compared with EVT alone, bridging therapy was associated with significantly better functional independence at 90 days (OR=1.25; 95% CI: 1.02-1.53). Patients receiving EVT plus IVT also demonstrated a trend toward higher rates of successful recanalization (OR=1.25; 95% CI: 0.95-1.64) and lower 90-day mortality (OR=0.84; 95% CI: 0.67-1.04). The risk of sICH was comparable between the two treatment strategies (OR=1.07; 95% CI: 0.81-1.40). Overall, the certainty of evidence was rated as moderate. ConclusionsBridging therapy before EVT may improve functional outcomes and recanalization without increasing sICH, supporting its use as a reasonable treatment strategy in eligible patients with acute ischemic stroke.

BackgroundPostoperative delirium is a common complication in older adults and is associated with neuroinflammation and cognitive decline. Previous studies have shown that the number of surgical procedures is associated with hippocampal volume loss in older adults in a large-scale UK Biobank study. However, it remains unclear whether hippocampal volume loss within one year after surgery is associated with postoperative delirium. MethodsLongitudinal structural MRI data and blood biomarkers were collected before surgery and one year postoperatively from 62 participants (>65 years, 27 females) undergoing major non-intracranial surgery. Hippocampal and other subcortical volumes were quantified using FreeSurfer. Cortical thickness was measured for cortical regions defined by the Desikan-Killiany (DK) atlas. One-year structural changes were examined in relation to peak Delirium Rating Scale (DRS) scores and one-year changes in plasma interleukin (IL)-6 levels. ResultsOne-year volume loss in the right hippocampus was significantly correlated with postoperative peak DRS scores and the one-year change in IL-6. Additional gray matter reductions were observed in the right putamen and the right superior parietal cortex. Right putamen volume loss was also associated with the one-year change in IL-6, while cortical thinning in the right superior parietal cortex was associated with peak DRS scores. ConclusionsPostoperative delirium is associated with longitudinal gray matter loss following surgery. Delayed resolution of inflammation may also contribute to postoperative brain structural changes. Clinical trial registrationNCT01980511 and NCT03124303.

BackgroundHypertension is the most potent modifiable risk factor for recurrent intracerebral hemorrhage (ICH), yet blood pressure (BP) control after ICH remains suboptimal, particularly among disadvantaged racial and socioeconomic groups. To what extent post-ICH BP disparities reflect pre-existing hypertension inequities versus differences in post-ICH management is unknown. We examined disparities in BP control before and after ICH, assessed whether post-ICH care differentially improves BP across groups and whether post-ICH disparities persist after accounting for pre-existing BP differences. MethodsWe performed a case-only study in the All of Us Research Program, identifying ICH survivors using electronic health record diagnosis codes. Mean systolic BP was calculated for pre-ICH (1-365 days before) and post-ICH (30-365 days after) windows. Neighborhood deprivation tertiles were calculated using 3-digit ZIP codes. The primary outcome was uncontrolled BP ([&ge;]140 mmHg). Logistic regression estimated odds of uncontrolled BP, and mediation analysis estimated the proportion of post-ICH disparities explained by pre-ICH BP. ResultsAmong 2,226 ICH survivors (mean age 60; 50.6% female), 1,760 had pre-ICH and 1,852 had post-ICH BP data. Uncontrolled BP was more common in Black than White survivors both pre-ICH (38.9% vs 21.4%; p<0.001) and post-ICH (34.3% vs 16.3%; p<0.001), and in Deprived versus Privileged neighborhoods post-ICH (23.7% vs 15.8%; p<0.001). In adjusted models, Black race (OR 3.51; 95% CI 2.55-4.83; p<0.001) and Deprived neighborhoods (OR 1.38; 95% CI 1.00-1.91; p=0.048) were associated with uncontrolled post-ICH BP. Among survivors uncontrolled before ICH, 67% of White but only 45% of Black survivors achieved control afterward (p=0.001). Adjusting for pre-ICH BP control status only modestly attenuated the Black-White disparity (OR 4.05 to 2.95; P<0.001). In mediation analyses, pre-ICH BP explained only 27% of the racial (P<0.001) and 26% of the deprivation (P=0.014) disparity. ConclusionsRacial and socioeconomic disparities in BP control persist after ICH, but most post-ICH disparities are not explained by pre-existing inequalities. More advantaged populations achieve greater BP improvement, suggesting effective post-ICH management exists but does not reach all patients equitably. Targeted interventions addressing barriers to post-ICH BP control in disadvantaged populations may substantially reduce persistent disparities.

The impact of social parameters on brain health among people with traumatic brain injury (TBI) has been extensively documented. However, translation of this evidence into policy and clinical practice remains limited. This may reflect a lack of coordinated and equity-driven approaches to brain health that integrate diverse stakeholder perspectives, limiting progress toward equity-oriented research and service delivery models. We conducted a convergent parallel mixed-methods study guided by the REporting guideline for PRIority SEtting of health research (REPRISE). We utilized the PROGRESS-Plus framework (Place of residence, Race/ethnicity, Occupation, Gender/sex, Religion, Education, Socioeconomic status, Social capital, and context-specific parameters) to ensure systematic consideration of social parameters in the study. For Objective 1, we synthesized existing evidence on social parameters and brain health outcomes. For Objective 2, we surveyed people with lived experience of TBI, family members/friends, clinicians, researchers, and community leaders across the globe to assess their prioritization of social parameters relevant to brain health. For Objective 3, we integrated evidence synthesis and stakeholder input through a structured Round Robin consensus activity to prioritize actionable areas for feasibility and impact. The activity culminated in the development of a knowledge mobilization agenda designed to inform equity-centred policy, research, and clinical practice. In Objective 1, we identified 59 publications with evidence on the effect of PROGRESS-Plus parameters on brain health outcomes following TBI. Meta-research highlighted that education, age, and country-level indicators are prognostic for brain health after TBI. In Objective 2, the highest-ranked priorities of 113 stakeholders across four continents (North America, Europe, Africa, and Oceania) were education, access to benefits, and income. These priorities were at the centre of discussion in Objective 3, which comprised idea sharing, refinement and thematic clustering, and a final prioritization poll. The resulting final 15 priorities were organized into two tracks: Track A, actions feasible in the short term, and Track B, longer-term implementation priorities. Building on this priority-setting process, co-created with stakeholders around the globe, the findings provide a roadmap for integration of social parameters in TBI research, knowledge exchange, policy, and practice.

Background: Immune-mediated mechanisms are increasingly implicated in childhood arterial ischemic stroke (AIS), but the associated inflammatory pathways and how they differ by stroke subtype and outcome remain poorly understood. Understanding immune responses to AIS may identify subtype-specific mechanisms and inform targeted strategies to reduce ischemic injury. Methods: We conducted a prospective cohort study with cross-sectional transcriptomic analysis through the Vascular Effects of Infection in Pediatric Stroke Study Part II (VIPS II) at 22 academic centers in the United States, Canada, and Australia between December 2016 and January 2022. Children aged 28 days to 18 years with centrally confirmed AIS were enrolled within 72 hours of stroke onset, in addition to enrollment of stroke-free well children. Peripheral blood RNA sequencing was performed on samples collected within 72 hours of stroke or at enrollment for controls. Differential gene expression (DGE) and pathway analyses were performed comparing all AIS cases to stroke-free well children. Additional cross-sectional analyses stratified by stroke subtype and neurological outcomes were performed. Results: Transcriptomes were available in 190/205 AIS cases (median age 11.7 years) and 91/100 stroke-free children (11.8 years). Stroke subtypes included 67 definite arteriopathic, 74 probable arteriopathic, 23 cardioembolic, and 26 idiopathic, with similar demographics but smaller infarct size for idiopathic cases. 47 genes (false discovery rate (FDR) <0.05 and log2 fold-change (log2FC)>1) were differentially expressed in AIS versus stroke-free well children, with upregulated pathways reflecting innate immune responses. Stratification by subtype revealed these inflammatory responses occurred after arteriopathic and cardioembolic AIS, but not idiopathic AIS; in sensitivity analyses, these findings were not explained by infarct size. Four immune-related genes were differentially expressed in children with good versus poor neurological outcomes at hospital discharge or 12 months; upregulation of one (Joining Chain; JCHAIN) correlated with poor outcomes at both timepoints. Conclusions: Compared with stroke-free children, children with AIS, particularly arteriopathic and cardioembolic subtypes, have upregulated innate immune pathways, including neutrophil activation and interleukin-1 signaling. Differential expression of immune-related genes also correlated with neurological outcomes. These findings support immune dysregulation as a key feature of early pediatric AIS while highlighting differences across subtypes and clinical outcomes, with implications for targeted immunomodulatory therapies and future biomarker development.

Background: Meningiomas are the most common primary intracranial tumors in adults, and volumetric assessment increasingly guides surveillance and treatment decisions. Automated segmentation could enable standardized volumetry but requires robust validation. Purpose: To develop a fully automated three-dimensional deep learning model for meningioma segmentation on multiparametric MRI, and to evaluate segmentation accuracy, external generalizability, failure modes, radiologist-rated clinical plausibility, and workflow feasibility. Methods: From 2024 to 2026, this retrospective study trained a custom 3D nnU-Net residual encoder model. Expert segmentations covered enhancing tumor (ET), tumor core (TC), and whole tumor (WT). Dice similarity coefficient (DSC) was the primary metric. External validation used an independent single-institution dataset (n = 310 intracranial cases) with incomplete MRI protocols. Failure modes, model equity, and inference time were assessed. A blinded multi-rater study (10 radiologists; 510 cases) rated TC segmentations using a 0-10 Likert scale, analyzed with linear mixed-effects models. Results: Model training used the BraTS Meningioma 2023 dataset (n = 1000; mean age 60.2 {+/-} 14.5; 705 female). In cross-validation, mean DSC was 0.939 for ET, 0.937 for TC, and 0.921 for WT. In external validation, mean DSC was 0.872 for TC and 0.842 for WT, despite heterogeneous protocols and incomplete sequences. Predicted TC volumes correlated strongly with reference volumes in cross-validation (r = 0.995) and external validation (r = 0.971). Most common failure modes were skull base and intraosseous tumors with performance equitable across demographic subgroups. Mean inference time was 1.2 seconds. In blinded evaluation (1120 ratings), model segmentations received higher scores than reference annotations (+0.32 BraTS; +1.38 external validation). Conclusion: A fully automated deep-learning model achieved high meningioma segmentation accuracy across multi-institutional training data and external clinical imaging. In a blinded study, model segmentation quality exceeded reference annotations, and 1.2-second inference supported workflow integration. Prospective evaluation is warranted before routine deployment.

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.

Background: Post-operative hypotension and vasoplegia are well recognised following cardiac surgery but remain poorly characterised after major non-cardiac surgery, despite associations with acute kidney injury (AKI), cardiovascular complications, and increased mortality. Dysregulation of the renin angiotensin aldosterone system (RAAS) may underpin haemodynamic instability in this setting, yet data in abdominal surgery are limited. Objectives: The POLECAT (Perioperative delta Renin) study aims to determine whether changes in circulating renin concentration (delta renin) from pre-operative baseline to the early post-operative period are associated with post-operative vasoplegia in patients undergoing major abdominal surgery requiring intensive care admission. Methods: POLECAT is a single-centre, prospective observational study conducted at a UK tertiary referral hospital. Adult patients undergoing planned or emergency abdominopelvic surgery with anticipated intensive care admission are enrolled. Blood samples are obtained pre-operatively, within four hours post-operatively, and on post-operative day one to measure renin and a panel of endothelial, renal, and immune biomarkers. The primary outcome is post-operative vasoplegia, defined as the requirement for a vasopressor infusion at 08:00 on post-operative day one. Secondary outcomes include alternative vasoplegia definitions, AKI (KDIGO criteria), vasopressor burden, organ dysfunction, cardiovascular complications, length of stay, and mortality. Multivariable regression, receiver operating characteristic analyses, and predefined subgroup analyses will be performed, with sensitivity analyses addressing missing data. Conclusions: This study will clarify the relationship between peri-operative RAAS dysfunction and vasoplegia following major abdominal surgery. Findings may support biomarker-guided risk stratification and inform future interventional trials targeting haemodynamic instability in this high-risk population.