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Inflammation plays an important role in the pathogenesis of stroke. The differential expression of inflammatory and angiogenic factors in thrombi and plasma remain undefined. In this observational cohort study, we evaluated angiogenic factors and inflammatory cytokines, in cerebral thrombi, local cerebral plasma (CP), and peripheral plasma (PP) in patients with acute ischemic stroke. Protein analysis of thrombi, CP and PP were used to measure angiogenic and inflammatory proteins using electrochemiluminescence. Our data indicate that VEGF-A, VEGF-C, bFGF, IL-4, IL-13, IL-1β, IL-2, IL-8, IL-16, IL-6 and IL-12p70 were higher in the thrombi of acute ischemic stroke patients than in the CP and PP of stroke patients. Moreover, the protein levels of GM-CSF were lower in the PP than in the CP and the clot. Moreover, VEGF-D, Flt-1, PIGF, TIE-2, IL-5, TNF-β, IL-15, IL-12/IL-23p40, IFN-γ and IL-17A were higher in PP and CP than in thrombi. Our results show that cytokines mediating the inflammatory response and proteins involved in angiogenesis are differentially expressed in thrombi within the cerebral and peripheral circulations. These data highlight the importance of identifying new biomarkers in different compartments of the circulatory system and in thrombi that may be used for the diagnosis and treatment of stroke patients.

Introduction: Mechanical thrombectomy (MT) is a highly safe and effective standard of care for acute ischemic strokes with large vessel occlusion. However, timely access to MT is extremely limited on a global scale, with vast disparities in access between countries. MT2020+, a global non-profit initiative of SVIN, aimed to create a semi-quantitative global MT access barrier score (MTABS) to objectively measure the barriers impeding the implementation of treatment worldwide. Methods: Four independent investigators performed an in-depth systematic literature review using the peer review of electronic search strategies. Barriers to access were identified and categorized into 3 groups: information and diagnostic, physical, and financial. An international expert panel was created and scored each attribute using a modified Delphi process with the assistance of consultants from the University of Calgary W21C. A 1-9-point scale was used, with 1 being not at all important and 9 being extremely important. A meeting was held for the attributes that require deliberation. After an agreement, a list of attributes for access was elaborated. Next, a ranking of importance and individual weighting was done. We assigned a presence of or lack of an attribute a numerical value (1 for yes, 0 for no) and multiply by its weight to determine a final score. Results: After an initial screening of 2864 abstracts, 121 studies were included in the final systematic review. A total of 34 possible attributes that are barriers to access were identified. After the modified Delphi process, 26 individual attributes were selected. The MTABS was made with possible results from 0-62 points, with higher scores meaning higher barriers to access to MT. Conclusions: The global MTABS represents the first tool to quantify barriers to MT access worldwide. Its implementation will objectively measure the magnitude and identify key barriers to guide regional public health interventions to improve MT workflow and access.

Background: Stroke education of emergency medical service (EMS) personnel improves stroke recognition, prenotification, and thrombolytic delivery. Prehospital identification of large vessel occlusion (LVO) stroke may facilitate the creation of a regional bypass protocol and improvement of intrahospital and interhospital workflows. However, the current status of EMS personnel’s knowledge of LVO, their stroke severity assessment training, and preferences in educational methods have not been studied. We conducted an EMS survey across the United States. Methods: The Society of Vascular and Interventional Neurology (SVIN) in collaboration with EMS-World created an online questionnaire distributed to all subscribers of EMS-World involved in pre-hospital work. It included 12 multiple-choice questions to test participants on LVO knowledge, stroke center certification levels, prior LVO education, and preferences on educational content delivery. Results: The survey email was opened by 1830 subscribers out of whom 1107 (60%) completed the survey across 50 states in the United States. Respondents identified themselves as paramedics/EMTs (91.4%), ground critical care (5.7%) and flight crew (2.9%). The number of stroke patients that survey participants transported in the past year was 25 (14.2%). Two hundred eighty-five (25.8%) participants answered both LVO knowledge questions correctly and 379 (34.2%) answered one correctly. Only 128 (11.6%) correctly identified all types of centers with thrombectomy capability. Although 877 (79.2%) were familiar with at least one stroke severity scale, 376 (34%) denied receiving training to perform them. Five sixty-seven (51.2%) respondents preferred in-person training for LVO training and 429 (38.8%) an online training program. About half of all respondents (535,48%) picked 'lack of standardized LVO training' as the greatest hurdle to pre-hospital LVO management. Conclusion: EMS providers in the United States reported inadequate LVO training and demonstrated gaps in knowledge of LVO, stroke severity scales, and stroke center levels. Systematic efforts to enhance and standardize the educational content and delivery of LVO education are urgently needed.

Background: Ischemic stroke has no approved treatments to enhance recovery. ALD-401 is an enriched population of aldehyde dehydrogenase-bright stem cells, capable of reducing neurological deficits in animal models. The primary objective of this trial was to determine the safety of internal carotid artery, intra-arterially delivered autologous bone marrow–derived ALD-401 in patients with disabling middle cerebral artery stroke in comparison with sham harvest with sham infusion. Secondary objectives were to determine feasibility and efficacy. Methods: This was a prospective phase 2, industry-funded, randomized, sham-controlled, parallel-group, multicenter study with blinded assessments. One hundred subjects were planned, aged 30 to 83 years, with confirmed first-time middle cerebral artery ischemic stroke with modified Rankin scale ≥3. Study patients were randomly assigned 3:2 to bone marrow harvest at 11 to 17 days after stroke followed 2 days later by intracarotid infusion of ALD-401 versus sham harvest and then sham infusion in the same timeframe. The primary study outcome was safety based on the incidence of a 4-point National Institutes of Health Stroke Scale worsening and the proportion of serious adverse events. Efficacy was based on modified Rankin scale change at 90 days. Other secondary outcomes were the proportions of patients experiencing adverse events, disability by Barthel Index, quality of life using EQ-5D, rehabilitation utilization, disability at 1 year, and MRI evidence of complications. Results: There were no infusional or allergic reactions and no difference in treatment emergent adverse events. Four patients had small areas of asymptomatic restricted diffusion on MRI in the treatment group. There was no significant difference between the ALD-401 and placebo groups on the modified Rankin scale for the intent-to-treat population at day 90 (mean difference, 0.3; 95% CI, –0.3 to 0.8; P =0.330). There were no significant differences between the groups on any of the secondary efficacy measures. Conclusions: Intracarotid infusion of ALD-401 does not lead to clinical adverse events in patients with subacute ischemic stroke, although there was a higher incidence of small lesions on MRI in the treatment group. There was no difference in the primary efficacy end point between the groups. The study provides a framework for the design and conduct of future intra-arterial cell therapy trials in stroke. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01273337.

Nearly all data on mechanical thrombectomy for acute ischemic stroke is based on procedures performed on biplane angiography systems. However, thrombectomy may be performed on single-plane systems in situations of triage or limited resources. We present the first US study comparing the safety and effectiveness of mechanical thrombectomy performed on single-plane vs. biplane systems.A retrospective review of a prospectively maintained database identified all patients treated with thrombectomy between July 2020 and July 2021 by a high-volume practice. Patients were dichotomized into those treated on single plane and biplane systems. Demographic, procedural, clinical and follow-up characteristics were compared.Of the 246 patients treated with mechanical thrombectomy, 70 (33%) and 141 (66%) patients were treated on SP and BP systems, respectively. No significant differences were detected in follow-up 'good functional outcome' (mRS ≤ 2; SP 51% vs BP 43%, p = 0.14), successful recanalization (SP 87% vs BP 88%, p = 0.72), intra-procedural vascular injury (SP 3% vs BP 2%, p = 0.96), or time from groin puncture to reperfusion (SP 24 min vs BP 26 min, p = 0.58). Additionally, no significant differences were detected in peri-procedural complications, fluoroscopy times or total radiation. Patients treated on single plane systems required significantly more contrast.Mechanical thrombectomy for acute ischemic stroke performed on single plane angiography systems is as safe and efficacious as when performed on biplane systems. Our results may have implications for increasing stroke care access, both domestically in underserved/rural areas and internationally when considering requirements for stroke care in lower-income countries.

Background Racial‐ethnic disparities in acute stroke care can contribute to inequality in stroke outcomes. We examined race‐ethnic disparities in acute stroke performance metrics in a voluntary stroke registry among Florida and Puerto Rico Get With the Guidelines‐Stroke hospitals. Methods and Results Seventy‐five sites in the Florida Puerto Rico Stroke Registry (66 Florida and 9 Puerto Rico) recorded 58 864 ischemic stroke cases (2010–2014). Logistic regression models examined racial‐ethnic differences in acute stroke performance measures and defect‐free care (intravenous tissue plasminogen activator treatment, in‐hospital antithrombotic therapy, deep vein thrombosis prophylaxis, discharge antithrombotic therapy, appropriate anticoagulation therapy, statin use, smoking cessation counseling) and temporal trends. Among ischemic stroke cases, 63% were non‐Hispanic white ( NHW ), 18% were non‐Hispanic black ( NHB ), 14% were Hispanic living in Florida, and 6% were Hispanic living in Puerto Rico. NHW patients were the oldest, followed by Hispanics, and NHB s. Defect‐free care was greatest among NHBs (81%), followed by NHWs (79%) and Florida Hispanics (79%), then Puerto Rico Hispanics (57%) ( P NHWs =63%, NHBs =65%, Florida Hispanics=59%, Puerto Rico Hispanics=31%; 2014: NHWs =93%, NHBs =94%, Florida Hispanics=94%, Puerto Rico Hispanics=63%). Conclusions Racial‐ethnic/geographic disparities were observed for acute stroke care performance metrics. Adoption of a quality improvement program improved stroke care from 2010 to 2014 in Puerto Rico and all Florida racial‐ethnic groups. However, stroke care quality delivered in Puerto Rico is lower than in Florida. Sustained support of evidence‐based acute stroke quality improvement programs is required to improve stroke care and minimize racial‐ethnic disparities, particularly in resource‐strained Puerto Rico.

Background: Endocrine dysfunction, including thyroid function, has been known to affect cerebral vascular dysfunction. Hypothyroidism has been shown to cause mucopolysaccharide deposition which has been associated with the weakening of blood vessel walls and aneurysm formation in some case reports. However, the connection between hypothyroidism and cerebral aneurysm has not been well studied. We hypothesized that hypothyroidism maybe associated with occurrence of cerebral aneurysms. Methods: We performed a retrospective case-control study of consecutive patients receiving cerebral angiography at our tertiary-care academic medical center. Inclusion criteria included undergoing 3-vessel angiography. Exclusion criteria included any ruptured aneurysm or previous intracranial hemorrhage. Medical history of hypothyroidism was noted along with all other risk factors. The control group of patients did not have any intra-cranial abnormality on angiography. Patients with cerebral aneurysm were matched with controls for known risk factors of cerebral aneurysm, including: age, hypertension, and smoking history. Cases were further subdivided base on gender given females are known to have higher incidence of hypothyroidism. Results: From 2008 through 2013, 82 female and 59 male patients with aneurysms were identified for this study and were matched with equal numbers of controls. Among women, hypothyroidism was present in 20.7% (17/82) among patients with cerebral aneurysms vs. in only 6.1% (5/82) among matched controls: odds ratio (OR) 4.03 (95% CI 1.41-11.51, p=0.01). Among men, 8.5% (5/59) cases and 0/59 controls had hypothyroidism, showing no significant association, with an odds ratio of 12.01 (95% CI 0.65-222.3, p=0.095). Conclusion: We found a significant association of history of hypothyroidism with cerebral aneurysm in women in our patient cohort. Given the potential pathophysiologic connection between hypothyroidism and vascular wall dysfunction, this should be explored further.

Background: The majority of patients enrolled in SWIFT PRIME had CT perfusion imaging immediately prior to randomization; 34 patients were randomized following a diffusion and perfusion MRI. Methods: Patients with MCA (M1) and distal carotid occlusions were randomized to treatment with tPA alone vs. tPA + Solitaire stent retriever. The primary outcome was the distribution of the mRS at 90 days. The same automated software (RAPID) was used for both MRI and CTP patients to identify patients with the Target mismatch profile for enrollment. Results: MRI selection was performed in 34 patients; CTP in 139. Mean age was 71 years (MRI) vs. 68 years (CTP), p=0.08; baseline NIHSS was 17 in both groups. Target mismatch profile was present in 95% (MRI) vs. 83% (CTP), p=0.3. Median time from ER arrival to randomization was 69 min (MRI) vs. 67 min (CTP), p=0.61. A higher percentage of the MRI group was transferred from an outside hospital (59% vs. 35%, p=0.02) and therefore the time from stroke onset to randomization was longer in the MRI group (236 minutes vs. 179 minutes, p=0.003.) Baseline median ischemic core volumes were similar in the MRI vs. CTP group (7 ml vs. 5 ml); baseline perfusion lesions were larger in the MRI group (133 ml vs. 97 ml, P=0.01) Reperfusion rates (> 90%/TICI 3) did not differ in the Solitaire treated patients in the MRI (94%) vs. CTP (85%) groups, p=0.7. The primary efficacy analysis (distribution of mRS at 90 days) demonstrated a statistically significant benefit in both the MRI (p=0.02) and CTP subgroups (p=0.01). Among MRI selected patients, mRS 0-2 at 90 days occurred in 63% of the Solitaire group vs. 33% of the tPA alone group (ARR 30%, p=0.17) and infarct growth was reduced (17 ml vs. 50 ml, p=0.089). CTP selected patients had mRS 0-2 rates at 90 days of 60% in the Solitaire group vs. 40% tPA alone (ARR 20%, p=0.025) and a reduction in infarct growth (14 vs. 27 ml, p=0.047). Conclusions: Although MRI selected patients in SWIFT PRIME were slightly older and treated longer after symptom onset, they demonstrated a statistically significant benefit on the primary efficacy endpoint. Reductions in infarct growth and rates of favorable clinical outcomes in the MR subgroup were also comparable to those seen in the CT perfusion subgroup.

Introduction: Prior studies based on MR data have shown that large perfusion lesions with long perfusion delays (Tmax>10s) are associated with poor functional and imaging outcomes. It is uncertain if the same associations exist for patients imaged with CT perfusion (CTP). Hypothesis: Patients with large volumes (>100mL) of tissue with a Tmax delay exceeding 10s (malignant Tmax profile) on CTP exhibit more infarct growth and have larger infarct outcomes than patients without this profile. Methods: The CRISP study is a multi-center NIH-sponsored prospective cohort study designed to evaluate if the presence of a CTP mismatch pattern is associated with a favorable response to reperfusion. All patients underwent CTP prior to endovascular therapy, early follow-up MRI (50% resolution of the Tmax>6s lesion between baseline and early follow-up, or TICI 2b or 3 reperfusion by angiography in the absence of an early follow up scan. The volumes were compared using Wilcoxons rank-sum test, we report median, [IQR]. Results: Baseline mismatch profile, reperfusion status and day 5 MRI were available in 109/201 patients, of whom 99 reperfused. Among patients with reperfusion, those with a malignant Tmax profile (n=24) had more infarct growth than patients without a malignant profile (n=75) (90,[49-116] vs 43,[18-81] mL, p=0.006). Patients with malignant profile also had larger final infarct volumes (110,[61-155] vs 48,[21-99] mL, p=0.001). Both the time from stroke onset and from baseline CTP to intravascular therapy were balanced between the two Tmax profile groups (p=0.32 and 0.53). Of the 10 patients without reperfusion, only 1 had malignant Tmax profile and no comparisons we performed in this group. Conclusion: A Tmax>10s lesion of 100 mL or more on CTP is associated with more than doubling of both infarct growth and final infarct volume despite successful reperfusion. While this does not exclude potential benefit from intraarterial thrombectomy, it suggests that the beneficial effect of reperfusion may be attenuated among patients with a malignant CTP profile.

Background: Stroke is a leading cause of major long-term disability worldwide. Despite availability of IV tPA and mechanical thrombectomy, over half of treated patients have significant disability. Cell based therapy is a promising in pre-clinical studies in improving stroke recovery. Brain infarct volume is a major predictor of stroke outcome and may decrease with this treatment. We hypothesized that patients treated with intra-arterial stem cell therapy will have a significant reduction in stroke volume compared to non-treated patients. Methods: The RECOVER-Stroke trial is a randomized, sham-controlled study to determine the safety and efficacy of processed autologous bone marrow cells (ALD-401) injection via intracarotid infusion in ischemic stroke patients. Ischemic stroke patients were double-blind randomized into 2 groups, receiving ALD-401 injection or sham procedure between 9-19 days post anterior circulation ischemic stroke. All enrolled patients at 1 of 8 sites in the trial were included in this analysis. Two blinded physicians used OSIRIX software to analyze stroke volume on DWI/ 24h CT brain and MRI at 90, 180, 365 days post intervention. Volumes were compared between the 2 groups at these timepoints. Results: A total of 11 patients at our center (out of 48 multicenter patients) were included in this study, 6 patients receiving sham procedure and 5 patients receiving ALD-401. The two groups did not show any significant difference in their baseline variables including age, Mean baseline stroke volumes were not significantly different between ALD-401 (103.9±96.2ml) and sham groups (70.2±46ml), p=0.53. The stroke volume reduction in the ALD-401 was 22.9±15.5ml vs. 4.04±12.5ml in the sham group (p=0.046). On day 180 and 365, both groups did not show any further significant stroke volume reduction from day 90. Conclusion: In this exploratory analysis from one center in the multi-center RECOVER-Stroke trial, intra-arterial stem cell injection with ALD-401 was associated with significant reduction in stroke volume at 90 days post therapy compared to sham procedure in subacute ischemic stroke patients.