Mediation Analysis of Acute Carotid Stenting in Tandem Lesions: Effect on Functional Outcome in a Multicenter Registry.

BACKGROUND AND OBJECTIVES: Current evidence suggests that acute carotid artery stenting (CAS) for cervical lesions is associated with better functional outcomes in patients with acute stroke with tandem lesions (TLs) treated with endovascular therapy (EVT). However, the underlying causal pathophysiologic mechanism of this relationship compared with a non-CAS strategy remains unclear. We aimed to determine whether, and to what degree, reperfusion mediates the relationship between acute CAS and functional outcome in patients with TLs. METHODS: This subanalysis stems from a multicenter retrospective cohort study across 16 stroke centers from January 2015 to December 2020. Patients with anterior circulation TLs who underwent EVT were included. Successful reperfusion was defined as a modified Thrombolysis in Cerebral Infarction scale ≥2B by the local team at each participating center. Mediation analysis was conducted to examine the potential causal pathway in which the relationship between acute CAS and functional outcome (90-day modified Rankin Scale) is mediated by successful reperfusion. RESULTS: A total of 570 patients were included, with a median age (interquartile range) of 68 (59-76), among whom 180 (31.6%) were female. Among these patients, 354 (62.1%) underwent acute CAS and 244 (47.4%) had a favorable functional outcome. The remaining 216 (37.9%) patients were in the non-CAS group. The CAS group had significantly higher rates of successful reperfusion (91.2% vs 85.1%; p = 0.025) and favorable functional outcomes (52% vs 29%; p = 0.003) compared with the non-CAS group. Successful reperfusion was a strong predictor of functional outcome (adjusted common odds ratio [acOR] 4.88; 95% CI 2.91-8.17; p < 0.001). Successful reperfusion partially mediated the relationship between acute CAS and functional outcome, as acute CAS remained significantly associated with functional outcome after adjustment for successful reperfusion (acOR 1.89; 95% CI 1.27-2.83; p = 0.002). Successful reperfusion explained 25% (95% CI 3%-67%) of the relationship between acute CAS and functional outcome. DISCUSSION: In patients with TL undergoing EVT, successful reperfusion predicted favorable functional outcomes when CAS was performed compared with non-CAS. A considerable proportion (25%) of the treatment effect of acute CAS on functional outcome was found to be mediated by improvement of successful reperfusion rates.

Cervical Dissection in Patients With Tandem Lesions Is Associated With Distal Embolism and Lower Recanalization Success.

BACKGROUND: Tandem lesions consist of cervical internal carotid artery (ICA) stenosis or occlusion, most commonly of atherosclerosis or dissection etiology, plus a large vessel occlusion. In this study, we compare outcomes in patients with atherosclerosis versus dissection of the cervical ICA. METHODS: This multicenter retrospective cohort study includes data from tandem lesion patients who underwent endovascular treatment from 2015 to 2020. Atherosclerosis was defined as ICA stenosis/occlusion associated with a calcified lesion and dissection by the presence of a tapered or flame-shaped lesion and intramural hematoma. Primary outcome: 90-day functional independence (modified Rankin Scale score, 0-2); secondary outcomes: 90-day favorable shift in the modified Rankin Scale score, modified Thrombolysis in Cerebral Infarction score 2b-3, modified Thrombolysis in Cerebral Infarction score 2c-3, symptomatic intracranial hemorrhage, parenchymal hematoma type 2, petechial hemorrhage, distal embolization, early neurological improvement, and mortality. Analysis was performed with matching by inverse probability of treatment weighting. RESULTS: We included 526 patients (68 [59-76] years; 31% females); 11.2% presented dissection and 88.8%, atherosclerosis. Patients with dissection were younger, had lower rates of hypertension, hyperlipidemia, diabetes, and smoking history. They also exhibited higher rates of ICA occlusion, multiple stents (>1), and lower rates of carotid self-expanding stents. After matching and adjusting for covariates, there were no differences in 90-day functional independence. The rate of successful recanalization was significantly lower in the dissection group (adjusted odds ratio, 0.38 [95% CI, 0.16-0.91]; P=0.031), which also had significantly higher rates of distal emboli (adjusted odds ratio, 2.53 [95% CI, 1.15-5.55]; P=0.021). There were no differences in other outcomes. Acute ICA stenting seemed to increase the effect of atherosclerosis in successful recanalization. CONCLUSIONS: This study reveals that among patients with acute stroke with tandem lesions, cervical ICA dissection is associated with higher rates of distal embolism and lower rates of successful recanalization than atherosclerotic lesions. Using techniques to minimize the risk of distal embolism may mitigate this contrast. Further prospective randomized trials are warranted to fully understand these associations.

Automated detection of early signs of irreversible ischemic change on CTA source images in patients with large vessel occlusion.

PURPOSE: To create and validate an automated pipeline for detection of early signs of irreversible ischemic change from admission CTA in patients with large vessel occlusion (LVO) stroke. METHODS: We retrospectively included 368 patients for training and 143 for external validation. All patients had anterior circulation LVO stroke, endovascular therapy with successful reperfusion, and follow-up diffusion-weighted imaging (DWI). We devised a pipeline to automatically segment Alberta Stroke Program Early CT Score (ASPECTS) regions and extracted their relative Hounsfield unit (rHU) values. We determined the optimal rHU cut points for prediction of final infarction in each ASPECT region, performed 10-fold cross-validation in the training set, and measured the performance via external validation in patients from another institute. We compared the model with an expert neuroradiologist for prediction of final infarct volume and poor functional outcome. RESULTS: We achieved a mean area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity of 0.69±0.13, 0.69±0.09, 0.61±0.23, and 0.72±0.11 across all regions and folds in cross-validation. In the external validation cohort, we achieved a median [interquartile] AUC, accuracy, sensitivity, and specificity of 0.71 [0.68-0.72], 0.70 [0.68-0.73], 0.55 [0.50-0.63], and 0.74 [0.73-0.77], respectively. The rHU-based ASPECTS showed significant correlation with DWI-based ASPECTS (rS = 0.39, p<0.001) and final infarct volume (rS = -0.36, p<0.001). The AUC for predicting poor functional outcome was 0.66 (95%CI: 0.57-0.75). The predictive capabilities of rHU-based ASPECTS were not significantly different from the neuroradiologist's visual ASPECTS for either final infarct volume or functional outcome. CONCLUSIONS: Our study demonstrates the feasibility of an automated pipeline and predictive model based on relative HU attenuation of ASPECTS regions on baseline CTA and its non-inferior performance in predicting final infarction on post-stroke DWI compared to an expert human reader.

Use of a dedicated open transcarotid access system for neurovascular disease.

BACKGROUND: Transcarotid artery revascularization (TCAR) is an increasingly popular technique for the management of extracranial carotid stenosis. Its off-label use in the treatment of intracranial neurovascular disease is poorly described. Our objective is to describe the use of a dedicated open transcarotid access system for the treatment of neurovascular pathologies other than extracranial carotid stenosis. METHODS: We conducted a retrospective review of a prospectively maintained database of consecutive patients who underwent treatment of neurovascular disease at a single academic center using the ENROUTE Transcarotid Arterial Sheath. Demographics, procedural characteristics, and patient outcomes were reported. RESULTS: Twenty patients were included in the study between September 2017 and March 2023. The following pathologies were treated: intracranial atherosclerotic disease (ICAD, nine patients), complex cervico-petrous carotid disease (five patients), intracranial aneurysms (three patients), and large vessel occlusion-acute ischemic stroke (three patients). Eighteen of the 20 cases were performed with active carotid flow reversal. All cases were successfully completed. There were no access-related complications. One periprocedural complication was incurred: a microguidewire perforation during an exchange maneuver for the treatment of ICAD. CONCLUSION: An open transcarotid approach using a dedicated transcarotid system may offer a safe alternative access strategy for the endovascular treatment of complex neurovascular pathologies when a traditional transfemoral or transradial approach is contraindicated or failed.

Impact of sleep quality and physical activity on blood pressure variability.

Increased blood pressure variability (BPV) is linked to cardiovascular disease and mortality, yet few modifiable BPV risk factors are known. We aimed to assess the relationship between sleep quality and activity level on longitudinal BPV in a cohort of community-dwelling adults (age ≥18) from 17 countries. Using Withings home measurement devices, we examined sleep quality and physical activity over one year, operationalized as mean daily step count and number of sleep interruptions, both transformed into tertiles. The primary study outcome was high BPV, defined as the top tertile of systolic blood pressure standard deviation. Our cohort comprised 29,375 individuals (mean age = 58.6 years) with 127.8±90.1 mean days of measurements. After adjusting for age, gender, country, body mass index, measurement days, mean blood pressure, and total time in bed, the odds ratio of having high BPV for those in the top tertile of sleep interruptions (poor sleep) was 1.37 (95% CI, 1.28-1.47) and 1.44 (95% CI, 1.35-1.54) for those in the lowest tertile of step count (physically inactive). Combining these exposures revealed a significant excess relative risk of 0.20 (95% CI, 0.04-0.35, p = 0.012), confirming their super-additive effect. Comparing individuals with the worst exposure status (lowest step count and highest sleep interruptions, n = 2,690) to those with the most optimal status (highest step count and lowest sleep interruptions, n = 3,531) yielded an odds ratio of 2.01 (95% CI, 1.80-2.25) for high BPV. Our findings demonstrate that poor sleep quality and physical inactivity are associated with increased BPV both independently and super-additively.

Anesthetic management for large vessel occlusion acute ischemic stroke with tandem lesions.

BACKGROUND: Endovascular therapy (EVT) stands as an established and effective intervention for acute ischemic stroke in patients harboring tandem lesions (TLs). However, the optimal anesthetic strategy for EVT in TL patients remains unclear. This study aims to evaluate the impact of distinct anesthetic techniques on outcomes in acute ischemic stroke patients presenting with TLs. METHODS: Patient-level data, encompassing cases from 16 diverse centers, were aggregated for individuals with anterior circulation TLs treated between January 2015 and December 2020. A stratification based on anesthetic technique was conducted to distinguish between general anesthesia (GA) and procedural sedation (PS). Multivariable logistic regression models were built to discern the association between anesthetic approach and outcomes, including the favorable functional outcome defined as 90-day modified Rankin Score (mRS) of 0-2, ordinal shift in mRS, symptomatic intracranial hemorrhage (sICH), any hemorrhage, successful recanalization (modified Thrombolysis In Cerebral Infarction (mTICI) score ≥2b), excellent recanalization (mTICI 3), first pass effect (FPE), early neurological improvement (ENI), door-to-groin and recanalization times, intrahospital mortality, and 90-day mortality. RESULTS: Among 691 patients from 16 centers, 595 patients (GA 38.7%, PS 61.3%) were included in the final analysis. There were no significant differences noted in the door-to-groin time (80 (46-117.5) mins vs 54 (21-100), P=0.607) and groin to recanalization time (59 (39.5-85.5) mins vs 54 (38-81), P=0.836) among the groups. The odds of a favorable functional outcome (36.6% vs 52.6%; adjusted OR (aOR) 0.56, 95% CI 0.38 to 0.84, P=0.005) and a favorable shift in the 90-day mRS (aOR 0.71, 95% CI 0.51 to 0.99, P=0.041) were lower in the GA group. No differences were noted for sICH (3.9% vs 4.7%, P=0.38), successful recanalization (89.1% vs 86.5%, P=0.13), excellent recanalization (48.5% vs 50.3%, P=0.462), FPE (53.6% vs 63.4%, P=0.05), ENI (38.9% vs 38.8%, P=0.138), and 90-day mortality (20.3% vs 16.3%, P=0.525). An interaction was noted for favorable functional outcome between the type of anesthesia and the baseline Alberta Stroke Program Early CT Score (ASPECTS) (P=0.033), degree of internal carotid artery (ICA) stenosis (P<0.001), and ICA stenting (P<0.001), and intraparenchymal hematoma between the type of anesthesia and intravenous thrombolysis (P=0.019). In a subgroup analysis, PS showed better functional outcomes in patients with age ≤70 years, National Institutes of Health Stroke Scale (NIHSS) score <15, and acute ICA stenting. CONCLUSIONS: Our findings suggest that the preference for PS not only aligns with comparable procedural safety but is also associated with superior functional outcomes. These results prompt a re-evaluation of current anesthesia practices in EVT, urging clinicians to consider patient-specific characteristics when determining the optimal anesthetic strategy for this patient population.

Radiomics-Based Prediction of Collateral Status from CT Angiography of Patients Following a Large Vessel Occlusion Stroke.

BACKGROUND: A major driver of individual variation in long-term outcomes following a large vessel occlusion (LVO) stroke is the degree of collateral arterial circulation. We aimed to develop and evaluate machine-learning models that quantify LVO collateral status using admission computed tomography angiography (CTA) radiomics. METHODS: We extracted 1116 radiomic features from the anterior circulation territories from admission CTAs of 600 patients experiencing an acute LVO stroke. We trained and validated multiple machine-learning models for the prediction of collateral status based on consensus from two neuroradiologists as ground truth. Models were first trained to predict (1) good vs. intermediate or poor, or (2) good vs. intermediate or poor collateral status. Then, model predictions were combined to determine a three-tier collateral score (good, intermediate, or poor). We used the receiver operating characteristics area under the curve (AUC) to evaluate prediction accuracy. RESULTS: We included 499 patients in training and 101 in an independent test cohort. The best-performing models achieved an averaged cross-validation AUC of 0.80 ± 0.05 for poor vs. intermediate/good collateral and 0.69 ± 0.05 for good vs. intermediate/poor, and AUC = 0.77 (0.67-0.87) and AUC = 0.78 (0.70-0.90) in the independent test cohort, respectively. The collateral scores predicted by the radiomics model were correlated with (rho = 0.45, p = 0.002) and were independent predictors of 3-month clinical outcome (p = 0.018) in the independent test cohort. CONCLUSIONS: Automated tools for the assessment of collateral status from admission CTA-such as the radiomics models described here-can generate clinically relevant and reproducible collateral scores to facilitate a timely treatment triage in patients experiencing an acute LVO stroke.

Deviation From Personalized Blood Pressure Targets Correlates With Worse Outcome After Successful Recanalization.

BACKGROUND: Personalized blood pressure (BP) management for patients with acute ischemic stroke after successful endovascular thrombectomy lacks evidence. We aimed to investigate whether the deviation of BP from cerebral autoregulation limits is associated with worse outcomes. METHODS AND RESULTS: We determined autoregulation by measuring mean velocity index and calculated the percentage of time and the burden (defined as the time-BP area) with BP outside the autoregulatory limits of each subject within 48 hours after endovascular thrombectomy. In total, 91 patients with large vessel occlusion stroke who had achieved successful recanalization were prospectively enrolled between May 2020 and February 2022. The burden with BP outside the autoregulatory limits was associated with poor outcome (modified Rankin Scale score 3-6) at 90 days (adjusted odds ratio, 1.28 [95% CI, 1.03-1.59]). The percentage of time with BP out of the autoregulatory limits was correlated with early neurological deterioration (National Institute of Health Stroke Scale scores increased ≥2 at 7 days) (adjusted odds ratio, 1.38 [95% CI, 1.04-1.83]). The burden of BP that decreased below the autoregulatory lower limit was associated with significant infarct growth (volume of infarct growth >11.6 mL) at 7 days (adjusted odds ratio, 1.21 [95% CI, 1.01-1.44]). The percentage of time that BP exceeded the autoregulatory upper limit was associated with symptomatic intracranial hemorrhage within 48 hours (adjusted odds ratio, 1.55 [95% CI, 1.02-2.34]). CONCLUSIONS: Both the percentage of time and the burden of BP that deviates from the autoregulation-preserved range are associated with unfavorable clinical outcomes. This study highlights the potential benefits of autoregulation-guided BP management strategy after successful recanalization.

Primary and Secondary Intracerebral Hemorrhage in Pregnant and Nonpregnant Young Adults by SMASH-UP Criteria.

BACKGROUND: Intracerebral hemorrhage (ICH) is a major cause of maternal morbidity, but its pathophysiology is poorly characterized. We investigated characteristics of pregnancy-associated ICH (P-ICH), compared with ICH in similar aged nonpregnant adults of both sexes. METHODS AND RESULTS: We performed a retrospective analysis of 134 adults aged 18 to 44 years admitted to our center with nontraumatic ICH from January 1, 2012, to December 31, 2021. We compared ICH characteristics among 3 groups: those with P-ICH (pregnant or within 12 months of end of pregnancy); nonpregnant women; and men. We categorized ICH pathogenesis according to a modified scheme, SMASH-UP (structural, medications, amyloid angiopathy, systemic, hypertension, undetermined, posterior reversible encephalopathy syndrome/reversible cerebral vasoconstriction syndrome), and calculated odds ratios and 95% CIs for primary (spontaneous small-vessel) ICH versus secondary ICH (structural lesions or coagulopathy related), using nonpregnant women as the reference. We also compared specific ICH pathogenesis by SMASH-UP criteria and functional outcomes between groups. Of 134 young adults with nontraumatic ICH, 25 (19%) had P-ICH, of which 60% occurred postpartum. Those with P-ICH had higher odds of primary ICH compared with nonpregnant women (adjusted odds ratio, 4.5 [95% CI, 1.4-14.7]). The odds of primary ICH did not differ between men and nonpregnant women. SMASH-UP pathogenesis for ICH differed significantly between groups (P<0.001). While the in-hospital mortality rate was lowest in the P-ICH group (4%) compared with nonpregnant women (13%) and men (24%), 1 in 4 patients with P-ICH were bedbound and dependent at the time of discharge. CONCLUSIONS: In our cohort of young adults with ICH, 1 in 5 was pregnancy related. P-ICH differed in pathogenesis compared with non-pregnancy-related ICH in young adults, suggesting unique pathophysiology.

Uncertainty-aware deep-learning model for prediction of supratentorial hematoma expansion from admission non-contrast head computed tomography scan.

Hematoma expansion (HE) is a modifiable risk factor and a potential treatment target in patients with intracerebral hemorrhage (ICH). We aimed to train and validate deep-learning models for high-confidence prediction of supratentorial ICH expansion, based on admission non-contrast head Computed Tomography (CT). Applying Monte Carlo dropout and entropy of deep-learning model predictions, we estimated the model uncertainty and identified patients at high risk of HE with high confidence. Using the receiver operating characteristics area under the curve (AUC), we compared the deep-learning model prediction performance with multivariable models based on visual markers of HE determined by expert reviewers. We randomly split a multicentric dataset of patients (4-to-1) into training/cross-validation (n = 634) versus test (n = 159) cohorts. We trained and tested separate models for prediction of ≥6 mL and ≥3 mL ICH expansion. The deep-learning models achieved an AUC = 0.81 for high-confidence prediction of HE≥6 mL and AUC = 0.80 for prediction of HE≥3 mL, which were higher than visual maker models AUC = 0.69 for HE≥6 mL (p = 0.036) and AUC = 0.68 for HE≥3 mL (p = 0.043). Our results show that fully automated deep-learning models can identify patients at risk of supratentorial ICH expansion based on admission non-contrast head CT, with high confidence, and more accurately than benchmark visual markers.

Discovery of a Biotin Synthase That Utilizes an Auxiliary 4Fe-5S Cluster for Sulfur Insertion.

Biotin synthase (BioB) is a member of the Radical SAM superfamily of enzymes that catalyzes the terminal step of biotin (vitamin B7) biosynthesis, in which it inserts a sulfur atom in desthiobiotin to form a thiolane ring. How BioB accomplishes this difficult reaction has been the subject of much controversy, mainly around the source of the sulfur atom. However, it is now widely accepted that the sulfur atom inserted to form biotin stems from the sacrifice of the auxiliary 2Fe-2S cluster of BioB. Here, we bioinformatically explore the diversity of BioBs available in sequence databases and find an unexpected variation in the coordination of the auxiliary iron-sulfur cluster. After in vitro characterization, including the determination of biotin formation and representative crystal structures, we report a new type of BioB utilized by virtually all obligate anaerobic organisms. Instead of a 2Fe-2S cluster, this novel type of BioB utilizes an auxiliary 4Fe-5S cluster. Interestingly, this auxiliary 4Fe-5S cluster contains a ligated sulfide that we propose is used for biotin formation. We have termed this novel type of BioB, Type II BioB, with the E. coli 2Fe-2S cluster sacrificial BioB representing Type I. This surprisingly ubiquitous Type II BioB has implications for our understanding of the function and evolution of Fe-S clusters in enzyme catalysis, highlighting the difference in strategies between the anaerobic and aerobic world.

Blood Pressure Trajectories and Outcomes After Endovascular Thrombectomy for Acute Ischemic Stroke.

BACKGROUND: Data on systolic blood pressure (SBP) trajectories in the first 24 hours after endovascular thrombectomy (EVT) in acute ischemic stroke are limited. We sought to identify these trajectories and their relationship to outcomes. METHODS: We combined individual-level data from 5 studies of patients with acute ischemic stroke who underwent EVT and had individual blood pressure values after the end of the procedure. We used group-based trajectory analysis to identify the number and shape of SBP trajectories post-EVT. We used mixed effects regression models to identify associations between trajectory groups and outcomes adjusting for potential confounders and reported the respective adjusted odds ratios (aORs) and common odds ratios. RESULTS: There were 2640 total patients with acute ischemic stroke included in the analysis. The most parsimonious model identified 4 distinct SBP trajectories, that is, general directional patterns after repeated SBP measurements: high, moderate-high, moderate, and low. Patients in the higher blood pressure trajectory groups were older, had a higher prevalence of vascular risk factors, presented with more severe stroke syndromes, and were less likely to achieve successful recanalization after the EVT. In the adjusted analyses, only patients in the high-SBP trajectory were found to have significantly higher odds of early neurological deterioration (aOR, 1.84 [95% CI, 1.20-2.82]), intracranial hemorrhage (aOR, 1.84 [95% CI, 1.31-2.59]), mortality (aOR, 1.75 [95% CI, 1.21-2.53), death or disability (aOR, 1.63 [95% CI, 1.15-2.31]), and worse functional outcomes (adjusted common odds ratio,1.92 [95% CI, 1.47-2.50]). CONCLUSIONS: Patients follow distinct SBP trajectories in the first 24 hours after an EVT. Persistently elevated SBP after the procedure is associated with unfavorable short-term and long-term outcomes.

Association between blood pressure variability and outcomes after endovascular thrombectomy for acute ischemic stroke: An individual patient data meta-analysis.

INTRODUCTION: Data on the association between blood pressure variability (BPV) after endovascular thrombectomy (EVT) for acute ischemic stroke (AIS) and outcomes are limited. We sought to identify whether BPV within the first 24 hours post EVT was associated with key stroke outcomes. METHODS: We combined individual patient-data from five studies among AIS-patients who underwent EVT, that provided individual BP measurements after the end of the procedure. BPV was estimated as either systolic-BP (SBP) standard deviation (SD) or coefficient of variation (CV) over 24 h post-EVT. We used a logistic mixed-effects model to estimate the association [expressed as adjusted odds ratios (aOR)] between tertiles of BPV and outcomes of 90-day mortality, 90-day death or disability [modified Rankin Scale-score (mRS) > 2], 90-day functional impairment (⩾1-point increase across all mRS-scores), and symptomatic intracranial hemorrhage (sICH), adjusting for age, sex, stroke severity, co-morbidities, pretreatment with intravenous thrombolysis, successful recanalization, and mean SBP and diastolic-BP levels within the first 24 hours post EVT. RESULTS: There were 2640 AIS-patients included in the analysis. The highest tertile of SBP-SD was associated with higher 90-day mortality (aOR:1.44;95% CI:1.08-1.92), 90-day death or disability (aOR:1.49;95% CI:1.18-1.89), and 90-day functional impairment (adjusted common OR:1.42;95% CI:1.18-1.72), but not with sICH (aOR:1.22;95% CI:0.76-1.98). Similarly, the highest tertile of SBP-CV was associated with higher 90-day mortality (aOR:1.33;95% CI:1.01-1.74), 90-day death or disability (aOR:1.50;95% CI:1.19-1.89), and 90-day functional impairment (adjusted common OR:1.38;95% CI:1.15-1.65), but not with sICH (aOR:1.33;95% CI:0.83-2.14). CONCLUSIONS: BPV after EVT appears to be associated with higher mortality and disability, independently of mean BP levels within the first 24 h post EVT. BPV in the first 24 h may be a novel target to improve outcomes after EVT for AIS.

Endovascular treatment of acute ischemic stroke patients with tandem lesions: antegrade versus retrograde approach.

OBJECTIVE: The optimal technique for treating tandem lesions (TLs) with endovascular therapy is debatable. The authors evaluated the functional, safety, and procedural outcomes of different approaches in a multicenter study. METHODS: Anterior circulation TL patients treated from January 2015 to December 2020 were divided on the basis of antegrade versus retrograde approach and included. The evaluated outcomes were favorable modified Rankin Scale (mRS) score (mRS score 0-2) at 3 months, ordinal shift in mRS score, successful recanalization, excellent recanalization, first-pass effect (FPE), time from groin puncture to successful recanalization, symptomatic intracranial hemorrhage (sICH), and 90-day mortality. RESULTS: Among 691 patients treated at 16 centers, 286 patients (174 antegrade and 112 retrograde approach patients) with acute stenting were included in the final analysis. There were no significant differences in mRS score 0-2 at 90 days (52.2% vs 50.0%, adjusted odds ratio [aOR] 0.83, 95% CI 0.42-1.56, p = 0.54), favorable shift in 90-day mRS score (aOR 1.03, 95% CI 0.66-1.29, p = 0.11), sICH (4.0% vs 4.5%, aOR 0.64, 95% CI 0.24-1.51, p = 0.45), successful recanalization (89.4% vs 93%, aOR 0.49, 95% CI 0.19-1.28, p = 0.19), excellent recanalization (51.4% vs 58.9%, aOR 0.59, 95% CI 0.40-1.07, p = 0.09), FPE (58.3% vs 69.7%, aOR 0.62, 95% CI 0.44-1.15, p = 0.21), and mortality at 90 days (16.6% vs 14.0%, aOR 0.94, 95% CI 0.35-2.44, p = 0.81) between the groups. The median (interquartile range) groin puncture to recanalization time was significantly longer in the antegrade group (59 [43-90] minutes vs 49 [35-73] minutes, p = 0.036). CONCLUSIONS: The retrograde approach was associated with faster recanalization times with a similar functional and safety profile when compared with the antegrade approach in patients with acute ischemic stroke with TL.

Impact of Therapeutic Interventions on Cerebral Autoregulatory Function Following Severe Traumatic Brain Injury: A Secondary Analysis of the BOOST-II Study.

BACKGROUND: The Brain Oxygen Optimization in Severe Traumatic Brain Injury Phase II randomized controlled trial used a tier-based management protocol based on brain tissue oxygen (PbtO2) and intracranial pressure (ICP) monitoring to reduce brain tissue hypoxia after severe traumatic brain injury. We performed a secondary analysis to explore the relationship between brain tissue hypoxia, blood pressure (BP), and interventions to improve cerebral perfusion pressure (CPP). We hypothesized that BP management below the lower limit of autoregulation would lead to cerebral hypoperfusion and brain tissue hypoxia that could be improved with hemodynamic augmentation. METHODS: Of the 119 patients enrolled in the Brain Oxygen Optimization in Severe Traumatic Brain Injury Phase II trial, 55 patients had simultaneous recordings of arterial BP, ICP, and PbtO2. Autoregulatory function was measured by interrogating changes in ICP and PbtO2 in response to fluctuations in CPP using time-correlation analysis. The resulting autoregulatory indices (pressure reactivity index and oxygen reactivity index) were used to identify the "optimal" CPP and limits of autoregulation for each patient. Autoregulatory function and percent time with CPP outside personalized limits of autoregulation were calculated before, during, and after all interventions directed to optimize CPP. RESULTS: Individualized limits of autoregulation were computed in 55 patients (mean age 38 years, mean monitoring time 92 h). We identified 35 episodes of brain tissue hypoxia (PbtO2 < 20 mm Hg) treated with CPP augmentation. Following each intervention, mean CPP increased from 73 ± 14 mm Hg to 79 ± 17 mm Hg (p = 0.15), and mean PbtO2 improved from 18.4 ± 5.6 mm Hg to 21.9 ± 5.6 mm Hg (p = 0.01), whereas autoregulatory function trended toward improvement (oxygen reactivity index 0.42 vs. 0.37, p = 0.14; pressure reactivity index 0.25 vs. 0.21, p = 0.2). Although optimal CPP and limits remained relatively unchanged, there was a significant decrease in the percent time with CPP below the lower limit of autoregulation in the 60 min after compared with before an intervention (11% vs. 23%, p = 0.05). CONCLUSIONS: Our analysis suggests that brain tissue hypoxia is associated with cerebral hypoperfusion characterized by increased time with CPP below the lower limit of autoregulation. Interventions to increase CPP appear to improve autoregulation. Further studies are needed to validate the importance of autoregulation as a modifiable variable with the potential to improve outcomes.

Characterization of CSF inflammatory markers after hemorrhagic stroke and their relationship to disease severity.

Background: The inflammatory response within the central nervous system is a key driver of secondary brain injury after hemorrhagic stroke, both in patients with intracerebral hemorrhage (ICH) and aneurysmal subarachnoid hemorrhage (aSAH). In this study, we aimed to characterize inflammatory molecules in the blood and cerebrospinal fluid (CSF) of patients within 72 hours of hemorrhage to understand how such molecules vary across disease types and disease severity. Methods: Biological samples were collected from patients admitted to a single-center Neurosciences Intensive Care Unit with a diagnosis of ICH or aSAH between 2014 and 2022. Control CSF samples were collected from patients undergoing CSF diversion for normal pressure hydrocephalus. A panel of immune molecules in the plasma and CSF samples was analyzed using Cytometric Bead Array assays. Clinical variables, including demographics, disease severity, and intensive care unit length of stay were collected. Results: Plasma and/or CSF samples were collected from 260 patients (188 ICH patients, 54 aSAH patients, 18 controls). C-C motif chemokine ligand-2 (CCL2), interleukin-6 (IL-6), granulocyte-colony stimulating factor (G-CSF), interleukin-8 (IL-8), and vascular endothelial growth factor (VEGF), were detectable in the CSF within the first 3 days after hemorrhage, and all were elevated compared to plasma. Compared with controls, CCL2, IL-6, IL-8, G-CSF, and VEGF were elevated in the CSF of both ICH and aSAH patients (p<0.01 for all comparisons). VEGF was increased in ICH patients compared to aSAH patients (p<0.01). CCL2, G-CSF, and VEGF in the CSF were associated with more severe disease in aSAH patients only. Conclusions: Within 3 days of hemorrhagic stroke, proinflammatory molecules can be detected in the CSF at higher concentrations than in the plasma. Early concentrations of some pro-inflammatory molecules may be associated with markers of disease severity.

Association between intraprocedural drops in blood pressure and infarct growth rate patterns after acute large-vessel occlusions.

BACKGROUND: Infarct growth rate (IGR) differs among patients with acute ischemic stroke due to large vessel occlusion (LVO-AIS), and this variability has critical clinical repercussions. We explored IGR patterns and their association with blood pressure during endovascular therapy (EVT). METHODS: This is a two-center cohort observational study that included consecutive anterior circulation LVO-AIS patients who underwent EVT and achieved modified Thrombolysis in Cerebral Infarction (mTICI) 2 c-3. Initial and final infarct volumes (FIV) were defined using admission computed tomography perfusion (CTP) defined as relative cerebral blood flow (rCBF) <30%, and diffusion-weighted imaging-magnetic resonance imaging (DWI-MRI) at 24 hours post-EVT. We categorized IGR patterns as exponential (ExpIGR) and Non-exponential (NonExp) based on their growth curves. We then dichotomized ExpIGR clinical significance based on the association of infarct growth with 90-day Modified Rankin Score (mRS) as ExpIGR-A (>13 mL) and ExpIGR-B (<13 mL). Intraprocedural blood pressure (BP) drops were calculated as the difference between median arterial pressure (MAP) at admission and the lowest intraprocedural MAP reading before recanalization, and the area between admission MAP threshold and all lower measurements of intraprocedural MAP. Logistic and linear regression were used to investigate associations between variables of interest. RESULTS: Of 159 modified Thrombolysis in Cerebral Infarction (mTICI) 2 c-3 patients, we found that 36% demonstrated ExpIGR-A, 31% ExpIGR-B, and 32.7% NonExp patterns. The Exp-A and Exp-B groups differed significantly in National Institutes of Health Stroke Scale (NIHSS) score, Alberta Stroke Program Early CT Score (ASPECTS), glucose, and FIV. The Exp-A and NonExp groups differed in rCBF <30% vol, and time of stroke onset (SO) to admission CTP; and the Exp-B and NonExp groups in NIHSS, rCBF <30%, Tmax <6 s volume, collateral flow measured by hypoperfusion intensity ratio (HIR), and FIV. Hypotensive MAP area (HMA) was independently associated with an ExpIGR-A pattern. Infarct volume increased by 1 mL per 100 units of hypotensive area and 4.2 mL per 0.1 units of HIR, with a significant interaction between both variables. CONCLUSION: After an LVO-AIS, the IGR can be differentiated into two distinct exponential and non-exponential patterns. A subgroup of patients with the exponential pattern experienced clinically meaningful infarct growth rates between CTP acquisition and reperfusion and seem to be highly vulnerable to episodes of sustained intraprocedural BP drops during EVT.

Safety Outcomes of Antiplatelet Therapy During Endovascular Treatment of Tandem Lesions in Acute Ischemic Stroke Patients.

Risk of hemorrhage remains with antiplatelet medications required with carotid stenting during endovascular therapy (EVT) for tandem lesion (TLs). We evaluated the safety of antiplatelet regimens in EVT of TLs. This multicenter study included anterior circulation TL patients from 2015 to 2020, stratified by periprocedural EVT antiplatelet strategy: (1) no antiplatelets, (2) single oral, (3) dual oral, and (4) intravenous IV (in combination with single or dual oral). Primary outcome was symptomatic intracranial hemorrhage (sICH). Secondary outcomes were any hemorrhage, favorable functional status (mRS 0-2) at 90 days, successful reperfusion (mTICI score ≥ 2b), in-stent thrombosis, and mortality at 90 days. Of the total 691 patients, 595 were included in the final analysis. One hundred and nineteen (20%) received no antiplatelets, 134 (22.5%) received single oral, 152 (25.5%) dual oral, and 196 (31.9%) IV combination. No significant association was found for sICH (ref: no antiplatelet: 5.7%; single:4.2%; aOR 0.64, CI 0.20-2.06, p = 0.45, dual:1.9%; aOR 0.35, CI 0.09-1.43, p = 0.15, IV combination: 6.1%; aOR 1.05, CI 0.39-2.85, p = 0.92). No association was found for parenchymal or petechial hemorrhage. Odds of successful reperfusion were significantly higher with dual oral (aOR 5.85, CI 2.12-16.14, p = 0.001) and IV combination (aOR 2.35, CI 1.07-5.18, p = 0.035) compared with no antiplatelets. Odds of excellent reperfusion (mTICI 2c/3) were significantly higher for cangrelor (aOR 4.41; CI 1.2-16.28; p = 0.026). No differences were noted for mRS 0-2 at 90 days, in-stent thrombosis, and mortality rates. Administration of dual oral and IV (in combination with single or dual oral) antiplatelets during EVT was associated with significantly increased odds of successful reperfusion without an increased rate of symptomatic hemorrhage or mortality in patients with anterior circulation TLs.

Pulmonary Surfactant: A Mighty Thin Film.

Pulmonary surfactant is a critical component of lung function in healthy individuals. It functions in part by lowering surface tension in the alveoli, thereby allowing for breathing with minimal effort. The prevailing thinking is that low surface tension is attained by a compression-driven squeeze-out of unsaturated phospholipids during exhalation, forming a film enriched in saturated phospholipids that achieves surface tensions close to zero. A thorough review of past and recent literature suggests that the compression-driven squeeze-out mechanism may be erroneous. Here, we posit that a surfactant film enriched in saturated lipids is formed shortly after birth by an adsorption-driven sorting process and that its composition does not change during normal breathing. We provide biophysical evidence for the rapid formation of an enriched film at high surfactant concentrations, facilitated by adsorption structures containing hydrophobic surfactant proteins. We examine biophysical evidence for and against the compression-driven squeeze-out mechanism and propose a new model for surfactant function. The proposed model is tested against existing physiological and pathophysiological evidence in neonatal and adult lungs, leading to ideas for biophysical research, that should be addressed to establish the physiological relevance of this new perspective on the function of the mighty thin film that surfactant provides.

Low dose intravenous cangrelor versus glycoprotein IIb/IIIa inhibitors in endovascular treatment of tandem lesions.

OBJECTIVES: Intravenous (IV) periprocedural antiplatelet therapy (APT) for patients undergoing acute carotid stenting during mechanical thrombectomy (MT) is not fully investigated. We aimed to compare the safety profile of IV low dose cangrelor versus IV glycoprotein IIb/IIIa (GP-IIb/IIIa) inhibitors in patients with acute tandem lesions (TLs). MATERIALS AND METHODS: We retrospectively identified all cases of periprocedural administration of IV cangrelor or GP-IIb/IIIa inhibitors during acute TLs intervention from a multicenter collaboration. Patients were divided in two groups according to the IV APT regimen at the time of MT procedure: 1) cangrelor and 2) GP-IIb/IIIa inhibitors (tirofiban and eptifibatide). Safety outcomes included rates of symptomatic intracranial hemorrhage (sICH), parenchymal hematoma type 1 and 2 (PH1-PH2), and hemorrhagic infarction type 1 and 2 (HI1-HI2). RESULTS: Sixty-three patients received IV APT during MT, 30 were in the cangrelor group, and 33 were in the GP-IIb/IIIa inhibitors group. There were no significant differences in the rates of sICH (3.3% vs. 12.1%, aOR=0.21, 95%CI 0.02-2.18, p=0.229), HI1-HI2 (21.4% vs 42.4%, aOR=0.21, 95%CI 0.02-2.18, p=0.229), and PH1-PH2 (17.9% vs. 12.1%, aOR=1.63, 95%CI 0.29-9.83, p=0.577) between both treatment groups. However, there was a trend toward reduced hemorrhage rates with cangrelor. Cangrelor was associated with increased odds of complete reperfusion (aOR=5.86; 95%CI 1.57-26.62;p=0.013). CONCLUSIONS: In this retrospective non-randomized cohort study, our findings suggest that low dose cangrelor has similar safety and increased rate of complete reperfusion compared to IV GP-IIb/IIIa inhibitors. Further prospective studies are warranted to confirm this association.