bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 106: Safety and Efficacy of Sonothrombolysis in Acute Ischemic Stroke Patients With Large Vessel Occlusion: International Collaborative Individual Patient Data Meta-Analysis
Authors: Tsivgoulis Georgios , Katsanos Aristeidis H , Eggers Jürgen , Larrue Vincent , Thomassen Lars , Grotta James C , Mavridis Dimitris , Schellinger Peter D , Seitidis Georgios , Demchuk Andrew , Novotny Vojtech , Molina Carlos , Veroniki Areti-Angeliki , Köhrmann Martin , Soinne Lauri , Khanevski Andrej Netland , Barreto Andrew D , Saqqur Maher , Psaltopoulou Theodora , Muir Keith W , Fiebach Jochen B , Rothlisberger Travis , Kent Thomas , Mandava Pitchaiah , Alexandrov Anne W , Alexandrov Andrei V
Published: June 2021

Introduction:
Conflicting evidence has been published regarding the safety and efficacy of ultrasound-enhanced thrombolysis (sonothrombolysis) in acute ischemic stroke (AIS) patients with large vessel occlusion (LVO).

Methods:
We conducted an individual participant data meta-analysis of available randomized controlled trials (RCTs) comparing sonothrombolysis with or without addition of microspheres (treatment group) to intravenous thrombolysis alone (control group) in AIS patients with LVO.

Results:
We included 6 in total RCTs that enrolled 1077 AIS patients. A total of 138 and 134 confirmed LVO patients were randomized to treatment and control groups respectively (median age 68 years, 58% men, median baseline NIHSS score 16). Patients randomized to sonothrombolysis had increased odds of complete recanalization compared to patients receiving intravenous thrombolysis alone (40.3% vs. 22.4%; OR=2.30, 95%CI: 1.05-5.02; adjusted OR=2.33, 95%CI: 1.02-5.34). They also tended to have increased odds of any (complete or partial recanalization (66.4% vs. 53.0%; OR=1.78, 95%CI: 0.95-3.33; adjusted OR=1.85, 95%CI: 0.97-3.53). The likelihood of symptomatic intracranial hemorrhage did not differ between the two groups (7.3% vs. 3.7%, OR=2.52, 95%CI: 0.77-8.29; adjusted OR=2.55, 95%CI: 0.76-8.52). No differences in the likelihood of asymptomatic intracranial hemorrhage (adjusted OR: 1.30, 95%CI: 0.38-4.39), three-month mortality (adjusted OR: 1.23, 95%CI: 0.25-6.05), three-month favorable functional outcome (mRS-scores of 0-1; adjusted OR: 1.43, 95%CI: 0.64-3.19) and three-month functional independence (mRS-scores of 0-2; adjusted OR: 1.43, 95%CI: 0.77-2.64) were documented.

Conclusion:
Sonothrombolysis was associated with a two-fold increase in the odds of complete recanalization compared to intravenous thrombolysis alone in AIS patients with LVOs. Further study of the safety and efficacy of sonothrombolysis is warranted.
Abstract 123: Age-Related Diminishment of the Subventricular Zone Cytogenic Response and Its Contributions to Motor Recovery After Cortical Infarcts
Authors: Williamson Michael R , Le Stephanie , Franzen Ronald L , Drew Michael R , Jones Theresa A
Published: June 2021

Stroke increases proliferation within the subventricular zone (SVZ) cytogenic niche and causes subsequent migration of newborn cells towards the site of injury. We investigated the functional consequences of age-related blunting of the SVZ cytogenic response to ischemia. We found that there was a marked reduction in proliferation and neural stem cell markers within the SVZ of middle aged (aged 12-16 months) versus young adult (aged 3-5 months) mice in the intact brain and after photothrombotic infarcts in motor cortex. Using an inducible, heritable lineage tracing system (Nestin-CreER
T2
:: Ai14 mice) to quantify SVZ-derived neural precursor cells (NPCs) that migrated towards the infarct, we found that there was a considerable age-related reduction in the number of NPCs in peri-infarct cortex. These findings indicate a marked diminishment of SVZ NPC proliferation and migration after focal ischemia by middle age. Next, we assessed the contributions of the SVZ cytogenic response to recovery of skilled motor function. We used glial fibrillary acidic protein-thymidine kinase mice to conditionally ablate NPCs with ganciclovir administration. In young adult mice, NPC ablation significantly impaired recovery of motor performance on the single seed reaching task after motor cortical infarcts. By contrast, NPC ablation did not affect motor recovery in middle aged mice. Importantly, the magnitude of recovery was less in middle aged mice—regardless of NPC ablation—than in control young adult mice. Middle aged mice recovered similarly to young adult mice lacking NPCs. These results indicate that SVZ cytogenesis contributes to functional improvements after cortical infarcts and that the diminishment of the cytogenic response with age may be implicated in age-related worsening of outcome after stroke. Restoration of SVZ cytogenesis in aged animals might improve behavioral recovery.
Abstract 126: The Influence of Physical Activity on Cavernous Malformation Hemorrhage
Authors: Joseph Nycole K , Flemming Kelly D
Published: June 2021

Background:
Cavernous malformations (CM) are low flow vascular malformations of the central nervous system. Brainstem location and prior hemorrhage increase the risk for future hemorrhage. Little is known about the influence of physical activity on increasing the risk of hemorrhage.

Methods:
Consecutive patients with radiologically confirmed CM were recruited to participate in a prospective registry beginning in 2015. A structured interview, survey, and examination were performed at baseline. Patients were asked if anything unusual occurred in the days leading to initial clinical presentation. Medical records and magnetic resonance imaging (MRI) studies were reviewed. Patients were surveyed about their involvement in select physical activity after the diagnosis of CM was made. Follow up surveys were sent annually to patients to ascertain new clinical hemorrhages. Follow up was censored at last follow up, hemorrhage, surgery, or death. Univariate analysis was performed to assess whether involvement in select physical activities increased the risk of prospective hemorrhage.

Results:
Of 195 patients, 117 (60 %) were female and the average age at diagnosis was 41 years (31-56 years). One hundred and three (52.8%) patients returned the survey about physical activity
after
diagnosis (cerebral n=100; spine n=3). Twenty-three patients had a prospective hemorrhage over 539.4 patient years. Five of these patients were removed from the analysis because they had less than 6 weeks of physical activity exposure before censor. Of 98 remaining patients, there was no difference in prospective hemorrhage risk in those patients participating 3 or more times monthly in walking, running, lifting more than 20 pound weights, lifting less than 20 pound weights, or participating in non-contact sports. Very few patients reported participation in contact sports (n=5), scuba diving (n=2) or high altitude climbing (n=1) more than 3 times monthly.

Conclusion:
Aerobic activity and non-contact sports do not increase the risk of hemorrhage in patients with cerebral CM and patients should not be restricted. Less information is known about contact sports, high altitude climbing or scuba diving and those with spinal cord CM.
Abstract 13: Corticospinal Tract Injury Estimated From Acute Stroke Imaging Predicts Upper Extremity Motor Recovery After Stroke
Authors: Lin David J , Cloutier Alison M , Erler Kimberly S , Cassidy Jessica M , Snider Samuel B , Ranford Jessica , Parlman Kristin , Giatsidis Fabio , Burke James F , Schwamm Lee , Finklestein Seth P , Hochberg Leigh , CRAMER Steven C
Published: June 2021

Introduction:
Injury to the corticospinal tract (CST) has been shown to have a major effect on upper extremity motor recovery after stroke. This study aimed to examine how well CST injury, measured from neuroimaging acquired during the acute stroke workup, predicts upper extremity motor recovery.

Methods:
Patients (N = 48) with upper extremity weakness after ischemic stroke were assessed using the upper extremity Fugl-Meyer (FM) during the acute stroke hospitalization and again at 3-month follow-up. CST injury was quantified and compared, using four different methods, from images obtained as part of the stroke standard-of-care workup. Logistic and linear regression were performed using CST injury to predict delta FM. Injury to primary motor and premotor cortices were included as potential modifiers of the effect of CST injury on recovery.

Results:
48 patients were enrolled 4.2 ± 2.7 days post-stroke and completed this study. CST injury distinguished patients who reached their recovery potential (as predicted from initial impairment) from those who did not, with AUC values ranging from 0.75 to 0.8. In addition, CST injury explained ~20% of the variance in the magnitude of upper extremity recovery, even after controlling for the severity of initial impairment. Results were consistent when comparing four different methods of measuring CST injury. Extent of injury to primary motor and premotor cortices did not significantly influence the predictive value that CST injury had for recovery.

Conclusions:
Structural injury to the CST, as estimated from standard-of-care imaging available during the acute stroke hospitalization, is a robust way to distinguish patients who achieve their predicted recovery potential and explains a significant amount of the variance in post-stroke upper extremity motor recovery.
Abstract 135: Examining the Information Loss Between Neuroimages and Neuroimaging Reports for Detection of Silent Brain Infarcts and White Matter Disease Using Artificial Intelligence Technologies
Authors: Leung Lester Y , Fu Sunyang , Nelson Jason , Kallmes David F , Luetmer Patrick H , Liu Hongfang , Kent David M
Published: June 2021

Background:
Real world studies of silent brain infarction (SBI) and white matter disease (WMD) are impeded by challenges in cohort identification. Natural language processing (NLP) from imaging reports may facilitate future studies. However, electronic health records can be heterogeneous and the process of interpreting neuroimages and generating reports can vary. Understanding knowledge representation and relationships between neuroimages and imaging reports is crucial for using NLP to facilitate disease management and cohort identification.

Methods:
A balanced sample of head neuroimages (CT, MRI) of patients >50 years without clinical histories of symptomatic stroke, TIA, or dementia were obtained at Mayo Clinic and Tufts Medical Center. A team of 4 radiology residents performed report interpretation (RI) on 1000 reports according to a standardized protocol for the presence of SBIs, the presence of WMD, and WMD grade. A random subsample of 400 was doubly read for interrater reliability. For benchmarking, a team of 4 neuroradiologists directly reviewed and described findings on a subsample of 182 images, each doubly read. We assessed interrater reliability for direct review (DR) and RI, and agreement between these 2 information sources. An NLP algorithm was developed to review and extract findings from 1000 imaging reports.

Results:
For DR, interrater reliability was moderate for SBIs and WMD (k = 0.53, 95% CI 0.43-0.64 and k = 0.47, 95% CI 0.33-0.61) and good for WMD grade (Spearman 0.71, p<0.001). For RI, interrater reliability for SBIs, WMD and WMD grade was good (k = 0.88, 95% CI 0.80-0.97; k = 0.98, 95% CI 0.97-1.00; and Spearman = 0.985, p<0.001, respectively). Agreement between DR and RI was good for SBIs (k = 0.77, 95% CI 0.67-0.86) and WMD (k = 0.65, 95% CI 0.54-0.77). Spearman rank correlations comparing WMD grade interpretation DR to RI was 0.60 (p<0.001). In identifying the presence of SBIs and WMDs, the accuracy of the NLP algorithm was 0.991 and 0.994, respectively.

Conclusion:
For the presence of SBI and WMD, and WMD grade, agreement between RI and DR was similar to agreement between 2 neuroradiologists directly reviewing neuroimages. It is highly feasible to use NLP to identify patients with SBIs and WMDs for clinical studies.
Abstract 14: A Randomized Study to Determine Efficacy of Sovateltide (PMZ-2010) in Patients With Acute Cerebral Ischemic Stroke
Authors: Gulati Anil , Agrawal Nilesh , Vibha Deepti , Misra U.K. , Paul Birinder , Pandian Jeyaraj , Borgohain Rupam , Lavhale Manish
Published: June 2021

Sovateltide (IRL-1620, PMZ-1620), an endothelin-B receptor agonist, administered intravenously following acute cerebral ischemic stroke increased cerebral blood flow, had anti-apoptotic activity and produced neurovascular remodeling. Its safety and tolerability were confirmed in healthy human volunteers (CTRI/2016/11/007509). A prospective, multi-centric, randomized, double-blind, parallel, controlled clinical study to compare efficacy of sovateltide with standard treatment in patients with acute cerebral ischemic stroke (CTRI/2017/11/010654; NCT04046484) was conducted in 40 patients, of which 36 completed 90-day follow-up. Patients received saline (n=18; 11 male and 7 female) or sovateltide (n=18; 15 male and 3 female) within 24 hours of onset of stroke. Standard treatment in both cohorts was similar. Mean age in saline and sovateltide cohorts was 58.34±1.73 and 49.83±2.79 years, respectively. Number of patients receiving investigational drug within 20 hours of onset of stroke were 14/18 in saline and 10/18 in sovateltide cohorts. National Institute of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS) and Barthel Index (BI) on day 6 when compared to day 1 showed P values of 0.0495, 0.0859 and 0.3948, respectively in saline cohort, whereas the P value in sovateltide cohort was less than 0.0001 of all three indices in sovateltide cohort. An improvement of 6 or more in NIHSS at 90 day of treatment was 57% in sovateltide and 43% patients in saline cohort (P=0.2714; Odds ratio 2.275). mRS improvement of 2 or more was observed in 60% and 40% patients in sovateltide and saline cohorts, respectively (P=0.0519; Odds ratio 5.25). BI improvement of 40 or more was 64% and 36% in sovateltide and saline cohorts, respectively (P=0.0112; Odds ratio 12.44). Number of patients with full recovery achieving NIHSS score of 0 and BI of 100 were significantly (P<0.05) more in sovateltide cohort compared to saline. Hemodynamic, biochemical or hematological parameters were not affected and no incidence of drug related adverse event with sovateltide was reported. Sovateltide (PMZ-1620) has the potential to an effective first-in-class drug that promotes quicker recovery and improves neurological outcome in acute ischemic stroke patients.
Abstract 144: Roles of Aging and Cellular Senescence in Intracranial Aneurysm Rupture
Authors: Sato Hiroki , Ikedo Taichi , Kimura Tetsuro , Purcell James , Merrow Samantha , Sato Hitomi , Lawton Michael , Hashimoto Tomoki
Published: June 2021

Background:
Aging is an independent risk factor for the rupture of intracranial aneurysm. One of the hallmarks of aging is chronic tissue inflammation. Sirtuin-1 keeps inflammation in check through the deacetylation of various proteins. It is well known that the levels of Sirtuin-1 in vascular tissues decrease with aging, resulting in chronic vascular inflammation. Age-dependent decrease in Sirtuin-1 may explain the link between aging and increased risk for aneurysmal rupture.

Hypothesis:
Reduction of Sirtuin-1 promotes aneurysmal rupture by inducing sustained aneurysmal wall inflammation.

Methods:
First, we assessed the levels of Sirtuin-1 expression in intracranial aneurysm tissues from patients older than 70 y.o. and compared with those from the younger patients (40 to 50 y.o.). Second, using a mouse model, we tested effects of Sirtuin-1 specific activator SRT1720 (15mg/kg/day) and specific inhibitor EX-527 (2.5mg/kg/day) on the development of aneurysmal rupture. In addition, we assessed the mRNA expression of inflammatory cytokines (IL-6, IL-1beta, MCP-1, and MMP-9) in cerebral arteries and aneurysms in mice treated with vehicle, SRT1720, or EX-527.

Results:
Sirtuin-1 expression levels in intracranial aneurysm tissues from the older patients were lower than those from the younger patients. The pharmacological inhibition of Sirtuin-1 increased rupture rate in mice (vehicle vs. EX-527: 58% vs. 88%,
P
<0.05). Moreover, the pharmacological activation of Sirtuin-1 reduced rupture rate in mice (vehicle vs. SRT1720: 80% vs. 50%,
P
<0.05). Levels of IL-6, MMP-9 mRNAs in cerebral arteries were significantly higher in the inhibitor group than in the vehicle group. On the other hand, both mRNA levels were lower in the activator group than in the vehicle group.

Conclusions:
Our findings suggest that the reduction of Sirtuin-1 promotes aneurysmal rupture via the induction of inflammation. This may explain the increased risk for aneurysmal subarachnoid hemorrhage in the older population. Our findings may become a basis for future studies to develop new therapies that target Sirtuin-1 for the prevention of aneurysmal rupture, especially in older patients.
Abstract 151: Early Neurologic Decline in Acute Ischemic Stroke Patients Receiving Thrombolysis With Large Vessel Occlusion and Initial Mild Deficits
Authors: Thakur Gaurav , Powers Ciaran J , Nimjee Shahid M , Youssef Patrick , Lakhani Sushil , Heaton Sharon , Lee Vivien H
Published: June 2021

Introduction:
A quarter of ischemic stroke patients with initial mild deficits have a poor outcome. We sought to determine the rate of early neurological decline in acute ischemic stroke patients with large vessel occlusion (LVO) who presented with mild deficits.

Methods:
Among 1022 acute ischemic stroke patients who received intravenous tissue plasminogen activator (IVtPA) admitted to our institution from January 1, 2014 to March 31, 2019, we identified 313 (30.6%) with LVO. We defined anterior circulation LVO as M1, M2, or carotid artery terminus (ICAT). Mild deficits were defined as National Institute of Health Stroke Scale (NIHSS) ≤ 7. Data was abstracted on demographics, neuroimaging, last known well (LKW), time to IVtPA, intra-arterial therapy (IAT) revascularization, Thrombolysis in Cerebral Infarction score (TICI), clinical presentation, and outcome. Early neurologic decline was defined as NIHSS worsening of ≥ 4 points within 24 hours.

Results:
Among 313 patients with LVO, we identified 94 (30%) who presented with initial low NIHSS (≤ 7) due to anterior circulation LVO. We excluded 13 patients who did not have natural history data (underwent IAT with mild deficits), leaving 81 patient for analysis. The mean age was 65.8 years (range 25 to 93) and 41% were female. IVtPA time from LKW was a mean 2.5 hours (range, 0.8 to 7). LVO sites were as follows: 5 (6%) ICAT, 23 (28%) M1, and 53 (65%) M2 occlusions. Among the 81 patients, 27 (33.3%) had early neurological decline. Patients with decline were significantly older (71.2 vs 63.1 years, p=0.03). Among the 27 patients with decline, the mean change in NIHSS was 10.5 (range, 4 to 22) and 12 patients (44%) underwent rescue IAT resulting in TICI 2B (6) and TICI 3 (6) revascularization. On hospital discharge, patients with decline were less likely to be discharged home (26% vs 65%, p=0.006).

Conclusions:
Among LVO patients who received IVtPA, 30% present with initial mild deficits. Early neurological decline occurred in one-third of LVO patients with initial mild deficits despite receiving IVtPA, and patients with decline were less likely to be discharged home. Clinicians need to be aware of the natural history of LVO with initial mid deficits, as patients who decline would be eligible for rescue IAT in the expanded 24 hour window.
Abstract 152: Genome-wide Association Study of Early-Onset Ischemic Stroke Identifies Novel Locus on Chromosome 12 Near
BCL7A/MLXIP
Authors: Jaworek Thomas , Kittner Steven J , Jern Christina , de Leeuw Frank Erik , Dichgans Martin , Malik Rainer , Fernandez Israel , Slowik Agnieszka , Boncoraglio Giorgio Boncoraglio , Lindgren Arne , Jimenez-Conde Jordi , Schmidt Reinhold , Sharma Pankah , Lemmens Robin , Melander Olle , Rothwell Peter , Levi Christopher , Sudlow Catherine , Debette Stephanie , Howson Joanna , Pare Guillaume , Markus Hugh , Salaheen Danish , Zand Ramin , Worrall Brad , Meschia James , Rundek Tatjana , Woo Dan , Lee Jin-Moo , Irvin Ryan , Rexrode Kathyn , Smoller Sylvia , Rosand Jonathan , Mueller Martina , Salomaa Veikko
Published: June 2021

Introduction:
Genetic studies of early-onset disease have been an effective strategy to identify novel pathways and drug targets relevant to later-onset disease. Few studies have investigated the role of common genetic variation in the etiology of early-onset ischemic stroke (IS).

Methods:
We performed a GWAS meta-analysis of 38 studies from 10 countries, comprised of 5,847 IS cases of European ancestry under age 60 and 32,533 controls.

Results:
We identified two genome-wide significant (p< 5 x 10
-8
) loci (see Figure). The
ABO
locus has previously been associated with venous thrombosis and ischemic stroke in predominantly older adults, but the effect size of our top SNP (OR 1.18; p = 9.1 x 10
-12
) is larger than the effect size for this same SNP in MEGASTROKE (OR: 1.05; p = 6.5 x 10
-5
). The lead SNP at the
BCL7A/MLXIP
locus is a novel GWAS finding for stroke (OR 1.14, 95% CI 1.08-1.19; p = 1.7 x 10
-8
) and is noteworthy because of prior reports linking SNPs in these genes to BMI and blood pressure.

Conclusions:
We identified a novel locus that is near variants associated with BMI and blood pressure. Further studies are needed to confirm this locus, examine subtype specificity, and determine its function. The larger effect size observed at the ABO in this early-onset IS sample compared to older-onset IS samples is consistent with a larger role for prothrombotic mechanisms in early-onset IS.
Abstract 166: Mechanical Thrombectomy in Ischemic Stroke Patients With Pre-Stroke Disability
Authors: Mistry Eva , Salwi Sanjana , Cutting Shawna , Salgado Alan , Espaillat Kiersten , Fusco Matthew , Froehler Michael , Kirshner Howard , Chitale Rohan , Schrag Matthew , Jasne Adam , Burton Tina , MacGrory Brian , Saad Ali , Jayaraman Mahesh , Madsen Tracy , Dakay Katarina , McTaggart Ryan , Yaghi Shadi , Mistry Akshitkumar , Khatri Pooja
Published: June 2021

Background:
The current AHA/ASA guidelines recommend only offering mechanical thrombectomy (MT) to patients without pre-stroke disability. We aimed to compare outcomes of acute ischemic stroke patients with none-to-minimal (modified Rankin score, mRS, 0-1) and moderate (mRS 2-3) pre-stroke disability treated with MT.

Methods:
Consecutive adult patients undergoing MT for an anterior circulation stroke were prospectively identified at two comprehensive stroke centers from 2012-2018. Procedural and 90-day functional outcomes were compared among patients with pre-stroke mRS 0-1 and 2-3 using Chi-squared, logistic, and linear regression tests and were adjusted for prespecified covariates.

Results:
A total of 881 patients were included (mean age 70±16 years; 45% female) and 259 (29.4%) had moderate pre-stroke disability. Primary outcome of no accumulation of additional disability at 90 days was observed in 22.4% and 26.7% of patients with no-to-minimal and moderate pre-stroke disability, respectively (OR 1.27[0.88-1.81], p=0.2; adjusted OR 1.90[1.24, 2.94], p=0.004, Figure). Rate of symptomatic intracerebral hemorrhage (7.3% vs 6.2%, p=0.65), successful recanalization (86.7% vs 83.8%, p=0.33), and median length of hospital stay (5 vs 5 days, p=0.06) were not significantly different. Mean change in utility weighted mRS from baseline to 90 days was 0.35±0.35 in pre-stroke mRS 0-1 vs -0.38 ±0.32 in pre-stroke mRS 2-3, p=0.17. Death by 90-days was higher in patients with moderate pre-stroke disability (14.3% vs 40.3%, OR 4.06[2.82-5.86], p<0.001; adjusted OR 2.83[1.84, 4.37], p<0.001).

Interpretation:
One-third of patients undergoing MT had a moderate pre-stroke disability. The odds of maintaining pre-stroke functional status at 90-days and procedural success rates were not different between patients with no-to-minimal and moderate pre-stroke disability. However, patients with pre-stroke disability were more likely to die by 90 days.
Abstract 179: Significant Efficacy of Adenosine A3 Receptor Agonist AST-004 in Rat and Non-human Primate Models of Transient Middle Cerebral Artery Occlusion
Authors: Liston Theodore , Ren JingMei , Poe Russell B , Hayashi Ikuo , Takamatsu Hiroyuki , Korinek William S , Davenport Matthew , Lechleiter James D
Published: June 2021

Acute Ischemic Stroke (AIS) is the second-leading cause of global mortality with an estimated 6.7 million victims dying each year. Our research has focused on a non-neuronal cell type, the astrocyte, and has demonstrated that GPCR receptor-mediated maintenance of astrocyte function enhances critical homeostatic mechanisms in the brain including protection against AIS-associated edema, glutamate excitotoxicity and oxidative stress. AST-004 is a small-molecule agonist of the GPCR Adenosine A3 receptor (ADORA3), demonstrating excellent pharmacokinetics and blood-brain barrier permeability in preclinical species. The efficacy and dose-response of AST-004 was assessed in rat and non-human primate stroke models of transient occlusion of the middle cerebral artery (tMCAO). In rats, a 1.5-hour tMCAO was conducted with a 24-hour steady-state intravenous infusion of vehicle or AST-004 initiated at time of reperfusion (vehicle or three AST-004 dose levels, n=12/group); neurological deficit and stroke lesion volume (TTC staining/image analysis) were assessed 24 hours post-reperfusion. Compared to vehicle, AST-004 reduced brain lesion volume by 50% (p=0.04) and improved neurological function by 36% (p=0.03). In non-human primates (cynomolgus macaque), a 4-hour tMCAO was conducted with a 22-hour steady-state intravenous infusion initiated 2 hours prior to reperfusion (vehicle or three AST-004 dose levels, n=4/group). Stroke lesion, perfusion deficits and penumbral endpoints were assessed by FLAIR, T2, MRA, DWI and ASL at multiple timepoints out to 5 days post-occlusion. Neurological deficit was assessed at 5-days post-occlusion. AST-004 treatment resulted in statistically significant improvements in outcome relative to vehicle, up to a 44% decrease in lesion volume (p=0.02) and a 72% decrease in percentage of lesion growth (p=0.0006) over the 5-day study period. AST-004 treatment during occlusion also reduced the slope of lesion evolution prior to reperfusion by 72% (p=0.05) relative to vehicle. Together, these studies indicate the potential of a non-neuronal approach to reducing stroke lesion damage via the ADORA3 receptor. AST-004 is a first-in-class candidate that warrants further evaluation in human clinical stroke trials.
Abstract 186: Telestroke Networks Provide a Halo Effect for Non-Stroke Service Lines
Authors: Majersik Jennifer J , Knavel Jason , Sanders James , de Havenon Adam , Smith Jaleen , Chung Lee S , Reddy Vivek , Hannon Peter M , Pulst Stefan , Lasson Grant
Published: June 2021

Introduction:
Hub-and-spoke TS networks link tertiary and community hospitals, typically resulting in increased stroke transfer rates between them. We hypothesized that such linkages may create a “halo effect” of downstream benefits to non-stroke service lines. The hub-and-spoke University of Utah (UU) TS Network includes 29 hospitals in 6 states and provides an excellent testbed for our hypothesis.

Methods:
We used business analytics to study all patients transferred to UU from a TS spoke, regardless of diagnosis. Using each spoke as its own control, we compared transfers 24 mo pre-TS initiation to 24 mo post. TS initiation was part of a coordinated UU outreach program which included initiation of ICU or Burn teleprograms during the study period for 5 sites. We excluded spokes with <5 average transfers / mo or if data was unavailable. Case severity was determined by Medicare Severity Diagnosis Related Groups (MSDRG). Contribution margin (CM) included downstream value to UU for 12 mo post transfer (data available 2013-19).

Results:
Data analysis included 20,353 transfers from 13 spokes in 5 states (initiation dates 2011-15). The mean number of monthly transfers pre-TS initiation was 13.9±5.0 vs 21.0±17.7 post (p<0.001) resulting in a 30% mean compounded annual growth rate (p<0.001,
Fig 1A
). High growth service lines included acute / intensive medicine (155%), behavioral health (110%), neurosciences (89%), and oncology (71%). There was no change in transferred case severity (
Fig 1B)
and thus no change in mean CM nor wRVU. However increased transfer volumes led to an increased number of high value (>96% CM) cases, creating an inflection point in the linear trend of number of transferred high value episodes (R
2
= 0.66
, Fig 1C
).

Conclusion:
This data suggests that when part of a larger outreach strategy, TS networks can create a halo effect for non-stroke hub service lines by increasing overall transfer volumes. The impact of such volume growth on commercial payer CM is exponential.
Abstract 20: Deep Learning-Based Automated Intracranial Hemorrhage Detection and Notification
Authors: Zahneisen Benjamin , Straka Matus , Bammer Shalini , Albers Greg , Bammer Roland
Published: June 2021

Introduction:
Ruling out hemorrhage (stroke or traumatic) prior to administration of thrombolytics is critical for Code Strokes. A triage software that identifies hemorrhages on head CTs and alerts radiologists would help to streamline patient care and increase diagnostic confidence and patient safety.

ML approach:
We trained a deep convolutional network with a hybrid 3D/2D architecture on unenhanced head CTs of 805 patients. Our training dataset comprised 348 positive hemorrhage cases (IPH=245, SAH=67, Sub/Epi-dural=70, IVH=83) (128 female) and 457 normal controls (217 female). Lesion outlines were drawn by experts and stored as binary masks that were used as ground truth data during the training phase (random 80/20 train/test split). Diagnostic sensitivity and specificity were defined on a per patient study level, i.e. a single, binary decision for presence/absence of a hemorrhage on a patient’s CT scan. Final validation was performed in 380 patients (167 positive). Tool: The hemorrhage detection module was prototyped in Python/Keras. It runs on a local LINUX server (4 CPUs, no GPUs) and is embedded in a larger image processing platform dedicated to stroke.

Results:
Processing time for a standard whole brain CT study (3-5mm slices) was around 2min. Upon completion, an instant notification (by email and/or mobile app) was sent to users to alert them about the suspected presence of a hemorrhage. Relative to neuroradiologist gold standard reads the algorithm’s sensitivity and specificity is 90.4% and 92.5% (95% CI: 85%-94% for both). Detection of acute intracranial hemorrhage can be automatized by deploying deep learning. It yielded very high sensitivity/specificity when compared to gold standard reads by a neuroradiologist. Volumes as small as 0.5mL could be detected reliably in the test dataset. The software can be deployed in busy practices to prioritize worklists and alert health care professionals to speed up therapeutic decision processes and interventions.
Abstract 30: Prediction Scale Thresholds Selected to Rule Out Large Vessel Occlusion Stroke Result in Very Low Positive Predictive Values and Many False Positives
Authors: Keenan Kevin J , Smith Wade S , Cole Sara , Martin Christine , Hemphill J Claude , Madhok Debbie Y
Published: June 2021

Introduction:
Many prior large vessel occlusion (LVO) prevalence and prediction scale accuracy studies have not had samples representative of a prehospital suspected stroke population. To address this, we studied emergency medical systems (EMS) identified prehospital suspected stroke patients brought to the Emergency Department (ED) at Zuckerberg San Francisco General Hospital from July 2017 to July 2018.

Methods:
Patients were eligible for the prevalence study if the EMS prehospital alert call included suspected stroke with a last known well time within 6 hours and a positive Cincinnati Prehospital Stroke Scale. LVO prediction scale scores were retrospectively calculated from arrival NIHSS subitems. We excluded patients missing NIHSS scores and scales requiring non-NIHSS data. LVO stroke included internal carotid, M1, M2, or basilar arteries. Diagnoses were determined by chart review. Prevalences, scale scores, and accuracy statistics were then calculated. We prespecified that negative results of scale thresholds must reduce the post-test probability to ≤5% to rule out LVO stroke and positive results must increase the post-test probability to ≥80% to rule in LVO stroke.

Results:
Of 220 EMS transported patients there were 30 LVO strokes (13.6%), 35 ICHs (15.9%), 45 non-LVO strokes (20.5%), and 110 mimics (50%). There were 184 patients eligible for the LVO prediction study. Table 1 shows the accuracy statistics of qualifying scale thresholds.

False positive rates ranged from 58% to 80%. Only FAST-ED ≥7 resulted in a positive predictive value (PPV) of ≥80% but this missed 83% of LVO strokes.

Conclusions:
The prevalence of LVO stroke among EMS suspected acute stroke patients brought to our ED over one year was 13.6%. Prediction scale thresholds selected to rule out LVO stroke result in very low PPVs and many false positives. No scale achieved a PPV above 50% while maintaining a sensitivity above 50% suggesting limitations in the ability of scales to rule in LVO stroke.
Abstract 57: Deployment of Portable, Bedside, Low-Field Magnetic Resonance Imaging for Evaluation of Stroke Patients
Authors: Cahn Bradley A , Shah Jill T , Dyvorne Hadrien , O'Halloran Rafael , Poole Michael , Yuen Matthew M , Mazurek Mercy H , Ward Adrienne , Payabvash Sam , Beekman Rachel , Brown Stacy C , Falcone Guido , Gobeske Kevin , Petersen Nils , Jasne Adam , Sharma Richa , Schindler Joseph , Sansing Lauren , Gilmore Emily , Wira Charles , Matouk Charles , Sze Gordon , Rosen Matthew , Kimberly W. T , Sheth Kevin N
Published: June 2021

Background:
Magnetic resonance imaging (MRI) is a powerful modality for diagnosing stroke. Conventionally, patients must travel to the location of a high-field MRI device. Advances in low-field MRI have enabled acquisition of clinically useful images using a portable device at the bedside. The feasibility of using point of care (POC) MRI in a clinical stroke setting is unknown.

Objective:
To determine the safety and feasibility of portable, bedside, low-field MRI in a clinical setting.

Design/Methods:
POC MRI exams were performed in Yale’s Neuroscience Intensive Care Unit (NICU) from July 2018 to August 2019. Images were acquired at the bedside using a standard 110V, 15A power outlet. The environment included the bedside vitals monitor, ventilators and intravenous infusion pumps. Exams were performed by research staff trained to operate the POC scanner in the absence of a trained MRI technician. No special precautions were necessary to remove ferrous metals from the room. Scan parameters were controlled using a tablet computer interface, and images were available immediately after acquisition.

Results:
POC MRI was obtained in 85 stroke cases (46% female, ages 18-96 years, 46% ischemic stroke, 34% intracerebral hemorrhage, 20% subarachnoid hemorrhage). Scans were obtained within 7 days of symptom onset. NIHSS scores ranged from 1 to 29 (median of 7). Of the 85 patients analyzed, 68 underwent T2-weighted imaging, 72 underwent FLAIR imaging, and 39 underwent diffusion weighted imaging (DWI). DWI was only tested in ischemic stroke cases. Patients’ BMI ranged from 20.0 to 46.5 with a median of 26.7. The majority 74 (87%) of patients completed the entire exam. Five patients (6%) were unable to fit in the scanner’s 30 cm opening, while 6 patients (7%) experienced claustrophobia resulting in early termination of the exam. Mean exam time was 28.9 ± 8.4 minutes. The 64 mT static magnetic field, gradient and RF pulses of the POC MRI scanner did not interfere with NICU equipment, and no significant adverse events occurred.

Conclusions:
We report the first use of a portable, low-field MRI system to image stroke patients at the bedside. This early work suggests our approach is safe and viable in a complex clinical care environment.
Abstract 70: Age and Outcomes After Carotid Stenting and Endarterectomy: A Pooled Analysis of the Crest and Act I Trials
Authors: Voeks Jenifer , Hanlon Bret , Howard George , Matsumura Jon , Rosenfield Ken , Roubin Gary , Brott Thomas
Published: June 2021

Introduction:
Using pooled data from randomized trials of symptomatic patients assigned to carotid artery stenting (CAS) versus carotid endarterectomy (CEA), we have previously shown age to be an effect modifier, with increasing risk at older ages for CAS but not for CEA. To extend assessment of age as an effect modifier to the asymptomatic population, we combined the asymptomatic patients from CREST with the patients from ACT I.

Methods:
We analyzed data from 2544 subjects with >= 70% carotid stenosis randomized to CAS or CEA in addition to standard management of cardiovascular risk factors. CREST enrolled 1091 (548 CAS, 543 CEA) and ACT I enrolled 1453 (1089 CAS, 364 CEA) asymptomatic patients less than 80 years old (upper age eligibility in ACT I). We examined the impact of age on risk within CAS-treated and CEA-treated patients using Kaplan-Meier methods. Age was considered in three strata (< 65, 65 to 74, and 75+). The pre-specified, primary composite endpoint was stroke, myocardial infarction, or death during the periprocedural period or any ipsilateral stroke within 4 years after randomization.

Results:
For patients assigned to CAS, risk differed between the age strata (p <0.0001) where relative to those under age 65, there was no difference in risk for those aged 65 to 74 (HR = 1.3 ; 95% CI: 0.7, 2.3, p=0.38), but those aged 75+ were at substantially higher risk (HR = 2.9; 95% CI: 1.5, 5.5, p=0.001). In contrast, risk did not differ by age strata (p = 0.80) for those assigned to CEA.

Conclusions:
Age-related risk factors, e.g. carotid anatomy and underlying cerebral pathology, should be considered before selecting patients aged 75+ for CAS.
Abstract 78: Fully Automated Segmentation Algorithm for Hematoma Volumetric Analysis in Spontaneous Intracerebral Hemorrhage
Authors: Ironside Natasha , Chen Ching-Jen , Mutasa Simukayi , Sim Justin , Roh David , Ding Dale , Mayer Stephan , Lignelli Angela , Connolly Edward
Published: June 2021

Background and Purpose:
Hematoma volume measurements influence prognosis and treatment decisions in patients with spontaneous intracerebral hemorrhage (ICH). The aims of this study are to derive and validate a fully automated segmentation algorithm for ICH volumetric analysis using deep learning methods.

Methods:
Inpatient computed tomography scans of 300 consecutive adults (age ≥18 years) with spontaneous, supratentorial ICH who were enrolled in the Intracerebral Hemorrhage Outcomes Project (2009-2018) were separated into training (n=260) and test (n=40) datasets. A fully automated segmentation algorithm was derived using convolutional neural networks (CNN), and it was trained on manual segmentations from the training dataset. The algorithm’s performance was assessed against manual and semi-automated segmentation methods in the test dataset.

Results:
The mean volumetric Dice similarity coefficients for the fully automated segmentation algorithm when tested against manual and semi-automated segmentation methods were 0.894±0.264 and 0.905±0.254, respectively. ICH volumes derived from fully automated vs. manual (R
2
=0.981;p<0.0001), fully automated vs. semi-automated (R
2
=0.978;p<0.0001), and semi-automated vs. manual (R
2
=0.990;p<0001) segmentation methods had strong between-group correlations. The fully automated segmentation algorithm (mean 12.0±2.7 seconds/scan) was significantly faster than both of the manual (mean 201.5±92.2 seconds/scan; p<0.001) and semi-automated (mean 288.58±160.3 seconds/scan; p<0.001) segmentation methods.

Conclusions:
The fully automated segmentation algorithm quantified hematoma volumes from CT scans of supratentorial ICH patients with similar accuracy and substantially greater efficiency compared with manual and semi-automated segmentation methods.
Abstract 83: Encephaloduroarteriosynangiosis Surgery Averts Stroke in Atherosclerotic Patients With Border-Zone Stroke
Authors: Quintero-Consuegra Miguel D , Toscano Juan F , Babadjouni Robin , Chang Daniel , Nisson Peyton , Saver Jeffrey , Gonzalez Nestor R
Published: June 2021

Introduction:
Intracranial atherosclerotic disease (ICAD) is one of the most common causes of stroke around the world. Among patients with ICAD being treated with Intensive Medical Management (IMM), those who initially present with ischemia in border-zone areas have the highest recurrence rates (37% at one year) due to association with poor collaterals.

Methods:
We recently concluded a phase II clinical trial of EDAS revascularization for patients with symptomatic ICAD failing medical management (ERSIAS). EDAS creates new collaterals from the donor branches of the external carotid artery. We performed an analysis of ERSIAS patients who had stroke as qualifying event and ischemia of a border-zone area on their initial MRI. We compared their outcomes to the subgroup of patients with border-zone ischemia from SAMMPRIS.

Results:
Of 52 patients included in the ERSIAS trial, 35 patients presented with strokes at baseline and 28 had border-zone pattern, including 15 (54%) with exclusive border-zone ischemia and 13 (46%) with mixed patterns including the border-zone. Of these 28 patients with border zone strokes as qualifying event, three (11%) presented recurrent strokes up to one year after EDAS surgery. When compared with the matched population from the medical arm of SAMMPRIS, EDAS patients had significantly lower than expected rate of recurrence (11% vs. 37% p=0.02, OR:0.21, 95%CI= 0.05-0.84), representing an absolute risk reduction of 26%.

Conclusion:
When compared with matched controls on IMM, EDAS reduced the expected rate of recurrent stroke in patients at the highest risk of recurrence. This supports the concept that EDAS might avert strokes due to hypoperfusion by generating new collaterals to ischemic cerebral territories and could supplement IMM in patients with border-zone infarctions due to ICAD.
Abstract 9: Autologous Bone Marrow Cells Might Repair Corticospinal Tracts in Stroke Patients
Authors: Haque Muhammad E , Hasan Khader M , George Sarah D , Sitton Clark W , ArevaloEspejo Octavio D , Boren Seth B , Alderman Susan , Vahidy Farhaan , Gabr Refaat , Parsha Kaushik N , Rosenbaum David P , Zhang Xu , Jaroslaw Aronowski , Grotta Jmaes , Savitz Sean I
Published: June 2021

Introduction:
Many cell-based therapies attenuate secondary degeneration after initial ischemic injury and enhance repair. We serially compared over time the integrity of the corticospinal tract (CST) in ischemic stroke (IS) patients treated with autologous bone marrow cells versus a prospectively collected, comparable stroke patient population not treated with cells (controls).

Methods:
We imaged 37 IS patients (17=treated, 20=control) at 1, 3, and 12 mo after stroke on a 3T MRI. A maximum of 10 million cells/kg were administered IV within 72 hrs of stroke. 3D anatomical and DTI images were obtained. CST integrity was assessed by relative (ipsilesional/contralesional) rFA in the rostral pons (RP). A mixed model was used for statistical analysis.

Results:
Infarct size of controls was 26.4 ±27 mL and the treated group was 64.7 ± 40.3 mL. The rFA in the rostral pons (RP) of controls decreased from 0.91 ± 0.1 to 0.86 ± 0.1 over 12 months. In the cell treated group, rFA in the RP decreased initially from 0.73 ±0.1 to 0.69 ±0.1 between 1 and 3 months but then increased to 0.76 ± 0.1 at 12 months. Qualitative and quantitative results are summarized (fig). The rFA in the RP was significantly correlated (p <0.05) to the mRS in the treated group.

Conclusion:
Despite smaller infarct size in controls, CST integrity continued to degenerate and showed no improvement by 12 months after stroke. In contrast, the cell treated patients with initial larger infarcts showed initial degeneration of the CST but then had improved CST integrity by 12 months after stroke. The temporal decrease in rFA in controls and increase in rFA in treated patients suggest a potential treatment effect from the cells. Although the results are generated from a non-randomized trial, the significant correlation between mRS and rFA suggests rFA could be used as a surrogate marker of treatment effect.
Abstract 91: Sex and Race Differences in Diabetes and Risk of Ischemic Stroke: Role of Fasting Blood Glucose
Authors: Madsen Tracy E , Long D. Leann , Carson April P , Howard George , Kleindorfer Dawn O , Furie Karen L , Manson JoAnn E , Liu Simin , Howard Virginia J
Published: June 2021

Introduction:
There are known sex and race differences in the risk of incident ischemic stroke (IS) associated with diabetes mellitus (DM), but the mechanism is unclear. To explore the role of impaired glucose metabolism in such differences, we aimed to determine if there are differences in the risk of IS across increasing fasting blood glucose (FBG) by race/sex subgroups.

Methods:
We analyzed data from black and white adults age ≥45 years at baseline (2003-2007) without a history of stroke from the Reasons for Geographic And Racial Differences in Stroke Study, a national longitudinal cohort. Data on age, race, sex, FBG, and DM medications was collected at baseline, and IS events were ascertained by phone every 6 months with physician adjudication of suspected events through September 2018. Cox proportional hazards regression was used to assess the association between FBG (<100 (ref), 100-125, 126-150, >150 mg/dL) and IS in sex/race groups (white women (WW), black women (BW), white men (WM), black men (BM)), stratified by DM medication use (DM medication use vs. no DM medication use) after adjustment for demographics, comorbidities, education, and income .

Results:
Of the 20,338 participants, mean age was 64.5(SD 9.3) years, 38.7% were black, 55.4% were women and 16.2% were using DM medications. There were 954 events. Of those on DM medication, the association between FBG and IS varied by race/sex (adjusted hazard ratios for FBG > 150 compared to FBG <100: WW 3.30 (95% CI 1.20, 9.10), BW 2.02 (95%CI 1.06, 3.87), BM 1.24 (95%CI 0.63, 2.46), WM 1.08 (95%CI 0.53, 2.17), p=0.08). Among those not on diabetes medications, IS risk across FBG did not vary by race/sex (p=0.36) (Table).

Conclusions:
Among those using diabetes medications, the magnitude of the association of increasing FBG with incident IS is highest among white women compared with other race/sex subgroups, suggesting possible race and sex differences in the role of impaired glucose metabolism in stroke risk.