bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 45: Vwf Inhibitor Lyses Middle Cerebral Artery Occlusion After 6 Hours Of Large Vessel Occlusion Stroke
Authors: Wheeler Debra , Joseph Matthew , Milks Michael W , Zakeri Amanda , Huttinger Allyson , Kini Aarushi , Carfora Arianna , Stork Taggart , Anderson Cole , Shujaat Mohammad T , Nimjee Shahid M
Published: February 2022

Introduction:
Acute ischemic stroke (AIS) is the leading cause of combined morbidity and mortality worldwide. Recombinant tissue plasminogen activator (rtPA) is the only FDA-approved drug to treat AIS, however, it is limited to treating patients within 4.5 hours of stroke onset because of the risk of intracranial hemorrhage. This limits rtPA administration to ~6% of patients. Moreover, it poorly lyses large vessel occlusion (LVO) stroke. Endovascular mechanical thrombectomy (MT) effectively recanalizes LVO but is limited to highly specialized hospitals, leaving the majority without acute therapy.

Hypothesis:
We hypothesize that targeted von Willebrand Factor (VWF) inhibition by DTRI-031 will recanalize arterial thrombosis in a canine model of LVO stroke, and DTRI-031 activity will be rapidly reversed by DTRI-025, which is specifically designed to inhibit DTRI-031.

Methods:
Utilizing a canine embolic middle cerebral artery occlusion (eMCAO) model of LVO stroke, we assessed DTRI-031 on vessel recanalization after 6 hours of LVO stroke by digital subtraction angiography (DSA). We also measured the effect of recanalization on infarct volume (efficacy) and hemorrhage (safety) using magnetic resonance imaging (MRI). Finally, we assessed the ability of DTRI-025, an oligonucleotide that binds DTRI-031 to reverse DTRI-031 activity.

Results:
DTRI-031 administration after 6 hours of LVO stroke resulted in ≥TICI 2A in 62.5% and ≥TICI 2B in 50% of canines (n=8). The negative control group demonstrated no revascularization (n=7). Recanalization resulted in reduced infarct volume compared to the negative control (p<0.05, unpaired t-test). None of the animals that received DTRI-031 had an intracranial hemorrhage on MRI. Finally, DTRI-025 completely reversed the activity of DTRI-031 within 5 minutes of administration in both whole blood impedance aggregometry (WBA) and PFA-100. There was no difference in heart rate, blood pressure, or temperature among the 3 groups studied.

Conclusion:
DTRI-031 effectively recanalizes LVO after 6 hours of stroke onset with reduced infarct volume and no incidence of hemorrhage. DTRI-025 rapidly reverses DTRI-031. This drug/reversal agent combination represents a robust yet safe approach to treat AIS.
Abstract 48: Hospital Door To Rapid Follow Up, A Nurse Practitioner Led Model
Authors: Taylor Kathryn L , Brouillette Leslyn Q , Naylor Margaret E , Lindholm Daniel M
Published: February 2022

Introduction:
The Neuroscience Institute is comprised of a Comprehensive Stroke Center and three Primary Centers. The healthcare team manages 1,800 hospital admissions yearly with expertise in acute treatment. However, door to rapid follow-up was not well defined. Literature review indicates expeditious post-stroke visits, a structured path to clinic, standardized ambulatory management and clear communication across the continuum ensures best practice.

Hypothesis:
A defined post-acute stroke management model could be implemented with Nurse Practitioners (NPs). A principal objective was to facilitate a rapid ambulatory visit less than two weeks post-hospitalization.

Methodology:
NPs were hired in 2019, then trained in acute and outpatient clinical rotations with Vascular Neurologists and inpatient Neurology NPs. Ambulatory NPs created a comprehensive guideline for sub acute visits. Content included: review of hospitalization, appropriate referrals, secondary prevention, functional assessments, medication adherence and stroke health literacy. Formal visit templates were imbedded in the electronic medical record, affording a consistent approach by NPs. Education templates were developed, with content personalized and provided to patients. Interval summary are completed by inpatient NPs; this includes a synopsis of stroke mechanism and acute intervention, neurological deficits, comorbid diagnosis and management plan at discharge. The summary incorporates a thorough review of core measures. A consistent process for scheduling rapid appointments was defined.

Results:
Data January to June 2021 demonstrated > 50% of patients completed rapid clinic appointments. Communication across the continuum was improved by electronic documentation and enhanced collaboration. There is a standardized approach to ambulatory management with individuation to patients. Expeditious outpatient visits are consistently occurring with an optimized process.

Conclusion:
NPs are essential stroke providers, closing gaps in the system of care in the acute and post-acute settings. A future goal is to increase the percentage of patients managed expeditiously, reducing incidence of cerebrovascular events thru a comprehensive ambulatory care model.
Abstract 51: Age Stratified Risk Of Cerebral Venous Sinus Thrombosis After Sars-Cov-2 Vaccination
Authors: Krzywicka Katarzyna , van de Munckhof Anita , Sanchez van Kammen Mayte , Heldner Mirjam R , Jood Katarina , Lindgren Erik , Tatlisumak Turgut , Putaala Jukka , Kremer Hovinga Johanna A. , Middeldorp Saskia , Levi Marcel M , Cordonnier Charlotte , Arnold Marcel , Zwinderman Aeilko H , Ferro Jose M , Coutinho Jonathan M , Aguiar de Sousa Diana
Published: February 2022

Introduction:
Cerebral Venous Sinus Thrombosis (CVST) as a part of the thrombosis and thrombocytopenia syndrome is a rare adverse drug reaction of SARS-CoV-2 vaccination. The estimated background rate of CVST in adults is around 1 case per million per month, and CVST with thrombocytopenia accounts for 8% of all CVST. We assessed the age-stratified risk of CVST with and without thrombocytopenia after SARS-CoV-2 vaccination.

Methods:
We estimated the absolute risk of any CVST, CVST with thrombocytopenia, and CVST without thrombocytopenia, within 28 days of first dose SARS-CoV-2 vaccination, using data from the European Medicines Agency’s EudraVigilance database (until 13 June 2021). As a denominator, we used data on vaccine delivery from 31 European countries. For 22.8 million adults from 25 countries we estimated the absolute risk of CVST after the first dose of ChAdOx1 nCov-19 per age category.

Results:
The absolute risk of CVST within 28 days of first dose vaccination was 7.5 (95%CI 6.9-8.3), 0.7 (95%CI 0.2-2.4), 0.6 (95%CI 0.5-0.7) and 0.6 (95%CI 0.3-1.1) per million of first doses of ChAdOx1 nCov-19, Ad26.COV2.S, BNT162b2 and mRNA-1273, respectively. The absolute risk of CVST with thrombocytopenia within 28 days of first dose vaccination was 4.4 (95%CI 3.9-4.9), 0.7 (95%CI 0.2-2.4), 0.0 (95%CI 0.0-0.1) and 0.0 (95%CI 0.0-0.2) per million of first doses of ChAdOx1 nCov-19, Ad26.COV2.S, BNT162b2 and mRNA-1273, respectively. In recipients of ChAdOx1 nCov-19, the risk of CVST, both with and without thrombocytopenia, was the highest in the 18-24 years age group (7.3 per million, 95%CI 2.8-18.8 and 3.7, 95%CI 1.0-13.3, respectively). The risk of CVST with thrombocytopenia was the lowest in ChAdOx1 nCov-19 recipients ≥70 years (0.2, 95%CI 0.0-1.3). Age <60 compared to ≥60 was a predictor for CVST with thrombocytopenia (incidence rate ratio 5.79; 95%CI 2.98-11.24, p<0.001).

Discussion:
The risk of CVST with thrombocytopenia within 28 days of first dose vaccination with ChAdOx1 nCov-19 was higher in younger age groups. The risk of CVST with thrombocytopenia was slightly increased in patients receiving Ad26.COV2.S, comparing with the estimated background risk. The risk of CVST with thrombocytopenia was not increased in recipients of mRNA vaccines for SARS-CoV-2.
Abstract 54: Significantly Higher Odds Of Mortality In Stroke-Related Admissions During COVID-19 Pandemic Versus Pre-COVID/Pandemic: A Meta-Analysis Of 455,073 Stroke Admissions
Authors: Desai Rupak , Singh Sandeep , Srikanth Sashwath , Went Terry R , Wiltshire Dwayne , Sultan Waleed , Sasidharan Nayana , Mohammad Aamer , Kumar Jaish , Asfeen Ummul Z , Rizvi Bisharah , Jain Akhil
Published: February 2022

Background:
COVID-19, being a prothrombotic state, has been linked to ischemic infarcts. Pooled data on impact of COVID-related stroke on mortality are sparse. We conducted a meta-analysis to assess the risk of stroke-related inpatient mortality (SRIM) during the COVID pandemic vs. pre-pandemic.

Methods:
Pubmed/Medline, SCOPUS & EMBASE were searched for articles till August 2021 reporting stroke and SRIM during COVID-19 pandemic vs. pre-pandemic. Random-effects model for odds ratio (OR), I
2
statistics for heterogeneity assessment and leave-one-out method for sensitivity analysis were employed.

Results:
A total of 31 studies with 455,073 stroke hospitalizations; 365253 pre-pandemic and 89820 pandemics (mean age 72 vs 70 yrs) were analyzed. With a comparable distribution of males, AF, and thrombolysis, the meta-analysis showed a nearly 40% higher risk of mortality during pandemic vs. pre-pandemic admissions (OR 1.42, 95%CI:1.06-1.92, p=0.018, I
2
=98.59). Further subgroup analysis showed a slightly higher risk of mortality in cohorts with mean age <70 years of age vs. ≥70 yrs [mean <70 years (n=11): OR:1.48, p=0.020 vs. ≥70 years (n=17): OR:1.27, p<0.001]. Cross-continental subgroup analysis revealed significantly higher mortality in Europe (n=14, OR:1.31, p<0.001) during pandemic vs. pre-pandemic, and non-significantly higher association in Asia (OR 1.13, p=0.57), USA (OR 1.59, p=0.23), Africa (OR 1.20, p=0.46)
(Fig. 1).
Subgroup analysis of 16 studies with n=100-1000 showed significantly higher OR (1.31) for SRIM during the pandemic vs. pre-pandemic, whereas studies with n<100 or >1000 did not show any significant difference. Sensitivity analysis showed overall and subgroup stability in OR.

Conclusions:
This largest meta-analysis to date on the subject found that hospitalized stroke patients, elderly or non-elderly, had nearly 40% higher risk of mortality during the COVID pandemic vs. pre-COVID era across the globe, more significantly in Europe.
Abstract 62: The Need For Speed- Treating Stroke In Thegolden Hour Ina Large Community Cohort
Authors: Klingman Jeff , Alexander Janet , Vinson David R , Nguyen-huynh Mai N
Published: February 2022

Background:
Acute stroke treatment with IV thrombolysis is time dependent and most effective within the first hour of symptom onset, the “golden hour”. We evaluated the rate of treatment within the golden hour in our system.

Methods:
We included all potential strokes arriving by ambulance who were treated with intravenous thrombolysis at 21 Kaiser Permanente Northern California stroke centers from 1/1/19 to 8/31/20. All patients were evaluated by teleneurologists on arrival. Assessment included demographics, mode of arrival, initial NIHSS, door-to-needle (DTN) and door-in-door-out times, large vessel occlusion (LVO), discharge outcomes. Bivariate analysis and multivariate models were used to assess percent with Modified Rankin Scale (mRS) 0 to 2, and 90-day mortality for patients treated within the golden hour compared to outside that window.

Results:
Among 1056 patients in the study cohort, 148 (14%) were treated in the golden hour. Rate of treatment within the golden hour varied greatly by facility (5-21%). These patients had higher initial NIHSS, lower DTN times, more LVO, and a trend for better 90-day mRS 0-2 (Table). Multivariate model revealed lower 90-day mortality among those treated during the golden hour (OR=0.44, 95% CI 0.25-0.77, p= 0.004). The success rate of being able to treat within 60 minutes of symptom onset was primarily dependent on the percentage of patients arriving at the hospital within 40 minutes of symptom onset rather than any differences in speed of treatment after arrival.

Conclusions:
Patients treated within the golden hour had higher NIHSS, faster treatment, lower mortality, and a trend toward better favorable mRS. Given that the main determinant of golden hour treatment was how quickly patients arrived at the emergency department, further public education to call 911 is needed and EMS agencies should optimize prehospital stroke evaluation in favor of rapid transport.
Abstract 65: Assessment Of MR Blood-Oxygen-Level-Dependent Cerebrovascular Reactivity Under General Anaesthesia In Children With Moyamoya
Authors: Choi Eun Jung , Logan William , Kirkham Fenella J , Robertson Amanda , Muthusami Prakash , Shroff Manohar , Moharir Mahendranath D , Dirks Peter , MacGregor Daune , Slim Mahmoud , Pulcine Elizabeth , Bhathal Ishvinder , Kaseka Matsanga Leyila , Levin David , Kassner Andrea , Deveber Gabrielle A , Dlamini Nomazulu
Published: February 2022

Background:
Moyamoya is a progressive arteriopathy condition characterized by steno-occlusion of the arteries of the circle of Willis. MRI performed with hypercapnic challenge can image blood-oxygen-level-dependent cerebrovascular reactivity (BOLD-CVR) thereby assessing cerebrovascular reserve. MRI studies of children <7 years of age, or with significant behavioural challenges require anesthesia. The purpose of this study was to validate the use of ventilator-induced hypercapnic challenge under general anaesthesia (GA).

Methods:
Children with moyamoya underwent two BOLD-CVR imaging in the same session under GA (GA-CVR). Differences in CVR estimates and intraclass correlation coefficient (ICC) between repeated scans were examined to determine repeatability across grey and white matter tissue and vascular territories. Bland-Altman plots were used to visulaize the overall variation between the scans. The associations with age, moyamoya types, and stroke presentation were also examined. Qualitative scoring by visual inspection was also conducted by trained neurologists.

Results:
Thirty-two paired GA-CVR studies (sixty-four scans in total) were analyzed (mean age: 7.07 (2.74 -17.95) years, 13 females). Forty-one percent (41%) were under 7 and 77%, under 10. No significant differences between repeated scans were found for any of the CVR estimates, when summarized by tissue and vascular territory. Of the paired studies, repeatability (ICC) for the whole-brain CVR estimates was excellent (≥0.74) in 14 (43.8%), good (≤0.59, >0.74) in 7 (21.9%), fair (≤0.41, >0.59) in 6 (18.8%) and poor (<0.41) in 5 (15.6%). Bland-Altman plots illustrated the overall variation of whole-brain CVR within 95% confidence interval level. Repeatability indices were not affected by children’s age and other clinical factors. On qualitative scoring, the Cohen weighted kappa showed substantial agreement in both right (0.75) and left (0.81) hemispheres.

Conclusion:
Our study support the clinical use of GA-CVR across all ages and disease conditions. The GA-CVR provides a feasible, repeatable, and reliably interpretable tool for the assessment of cerebrovascular reserve of very young and behaviourally challenged children with moyamoya.
Abstract 69: Extent Of Tau And Its Cognitive Implications In Cerebral Amyloid Angiopathy
Authors: Gokcal Elif , Becker John , Horn Mitchell J , Das Alvin S , DiPucchio Zora , Schwab Kristin , Goldstein Joshua N , Viswanathan Anand , Biffi Alessandro , Rosand Jonathan , Sperling Reisa A , Johnson Keith A , Greenberg Steven M , Gurol Edip
Published: February 2022

Background:
Tau pathology is an important component of Alzheimer’s Disease but its extent and impact in cognitively healthy patients with cerebral amyloid angiopathy (CAA) are not clear. We compared in vivo tau stages estimated from the patterns of tau PET tracer uptake in patients with CAA and healthy controls (HC) and explored its relationship with amyloid burden and cognitive function in CAA.

Methods:
The study included 50 cognitively healthy probable CAA patients (mean age 70±7.6) and 50 age-, sex-matched HCs (mean age 70±7.5) who underwent MRI, Pittsburgh compound B (PiB, for amyloid) and
18
F-flortaucipir (FTP, for tau) PET imaging. Mean global cortical PiB uptake was calculated. Tau stages were estimated based on the distribution pattern of cortical FTP uptake and grouped into three categories (PET Braak Staging, Figure). Within the CAA cohort, standardized z-scores of memory, processing speed and executive function testing were obtained.

Results:
In the whole group, tau stages significantly correlated with age (rho=0.407, p<0.001) and global cortical PiB uptake (rho=0.554, p<0.001). Patients with CAA were more likely to exhibit more extensive tau (Stage III-VI) compared to HCs in univariate analyses (Figure, p=0.003). In a logistic regression model, more extensive tau independently associated with age (p=0.001) and PiB uptake (p<0.001) but not with the CAA diagnosis (p=0.264). Within the CAA cohort, tau stage was again independently associated with PiB uptake (p=0.002), but it did not show any association with scores of cognitive domains in univariate or multivariate models (p>0.2 for all comparisons).

Conclusion:
Our results show that patients with CAA have higher PET Braak tau stages when compared to similarly aged HCs but this difference disappeared after controlling for amyloid load. Extent of tau did not correlate with cognitive scores in CAA. Overall, tau stages appear to be driven by amyloid without clinical impact in cognitively healthy CAA patients.
Abstract 70: Racial Differences In Small Vessel Disease Measured In MRI Of Stroke/ TIA Patients
Authors: Martin Chylee , Kabetso Amanda , Logue Makenzie , Kodumuri Nishanth , Mascari Rachel , LaValley Elizabeth , Vezzetti Alexandra , Patel Shraddha , Hogan Nicole , Sen Souvik
Published: February 2022

Introduction:
White matter hyperintensities (WMH) and cerebral microbleeds (CMB) are manifestations of small vessel disease (SVD), a surrogate for vascular cognitive impairment. Few studies have systematically investigated the racial differences in SVD among African American (AA) and white stroke/TIA patients.

Methods:
MRI scans of consecutive ischemic stroke and TIA patients admitted to our tertiary stroke center were assessed as a part of a stroke study. Deep and periventricular WMHs (DWMHs and PVWMHs, respectively) were rated visually on axial FLAIR images using the 4-point Fazekas scale and categorized into none/mild (grades 0 and 1) or moderate/severe (grades 2 and 3). Subsequently T2*-weighted MRI scans for the number, location, and topography of CMBs, as well as patients’ demographic, clinical information, and periodontal disease (PD) were evaluated. Student t-tests were performed to test continuous variables. X
2
tests were used to compare categorical variables. Multivariable analysis using multiple logistic regression was used to test the association between AA and SVD.

Results:
Among a total of 861 consecutive patients (741 stroke, 120 TIA), 469 AA patients were compared with 360 white for moderate/severe PVWMH (38%), DWMH (32%) and CMB≥5 (3%). Those with moderate/severe PVWMH were older (age 68±11 vs. 61±12, p<0.001), more likely to be male (42% vs. 35%, p=0.02), hypertensive (40% vs. 26%, p=0.02), diabetic (43% vs. 34%, p=0.007), and have severe PD (41% vs. 35%, p=0.07). AA race was associated with PVWMH (Adj. OR 1.9, 95% 1.4-2.7) when adjusted for age, gender, hypertension, diabetes, and PD. Those with moderate/severe DWMH were older (age 68±10 vs. 62±13, p<0.001), and more likely to be hypertensive (33% vs. 24%, p=0.09), diabetic (37% vs. 27%, p=0.003), and have severe PD (36% vs. 28%, p=0.01). AA race was associated with DWMH (Adj. OR 1.5, 95% 1.1-2.2) when adjusted for age, hypertension, diabetes, and PD. Those with CMB≥5 were more likely to be hypertensive (5% vs. 1%, p=0.008). AA race was associated with CMB≥5 (Adj. OR 4.1, 95% 1.3-12.6) when adjusted for age and hypertension.

Conclusion:
We report significant independent association between AA race and various manifestations of SVD including moderate/severe DWMH, PVWMH, and CMB≥5.
Abstract 79: Direct Bypass To Endovascular Capable Stroke Center Compared To Secondary Transfer From Primary Stroke Centers
Authors: Hong Jae Beom , Diprose William , Wang Michael , Meyer Juliette , Kilfoyle Dean , Barber P A
Published: February 2022

Introduction:
All stroke care in our metropolitan region is provided by three primary stroke centers (PSCs) and a central endovascular thrombectomy capable stroke center (EVT-SC). There is a hybrid organizational structure with all potential large vessel occlusion (LVO) patients taken to the nearest stroke center during office-hours, and directly bypassed to the EVT-SC after-hours.

Aim:
To compare process times and EVT outcomes in PSC locality patients who were transferred to the EVT-SC by these two methods.

Methods:
Between August 2017 and February 2021, consecutive anterior LVO patients transferred via road with EVT initiation within 6 hours were included. Patients were grouped into method of presentation: 1) PSC locality patients directly bypassed to EVT-SC (‘EVT-SC direct’); 2) PSC locality patients taken to local PSC with subsequent transfer to EVT-SC (‘PSC-transfer’); 3) patients normally resident in the EVT-SC locality (‘EVT-SC local’). The primary outcome was 3-month functional independence (modified Rankin Scale score 0-2). Secondary outcomes included symptomatic intracranial hemorrhage, and mortality at 7-days and at 3-months.

Results:
343 patients (142 women; mean±SD age 66.5±16.0 years) were included. There were 91 (26.5%) EVT-SC direct, 168 (49.0%) PSC-transfer, and 84 (24.5%) EVT-SC local patients. For EVT-SC direct patients, the median (interquartile range) distance travelled was 13 (10-18) miles. EVT-SC direct patients were younger (mean±SD age 63.8±15.1 years versus 68.5±15.0 years;
P
=0.02), had shorter LKN-to-thrombolysis (120 vs 147 minutes,
P
=0.004) and LKN-to-puncture times (190 vs 230 minutes,
P<
0.001), compared to the PSC-transfer patients. With multivariable logistic regression analysis, at 3-months EVT-SC direct patients were more likely to be functionally independent (OR=2.04, [95% CI, 1.12-3.73];
P
=0.02), and less likely to be dead (OR=0.33, [95% CI, 0.12-0.91];
P
=0.03). For every 100 patients directly bypassed to EVT-SC, there were 14 additional patients functionally independent and 9 less deaths at 3-months.

Conclusion:
The results of this study suggest where the distance is less than 20 miles, direct bypass to EVT-SC is associated with better process times and outcomes.
Abstract 82: The Second X Chromosome Contributes to Stroke Sensitivity in the Absence of Activational Hormonal Effects
Authors: Qi Shaohua , Ngwa Conelius , Sharmeen Romana , McCullough Louise , Liu Fudong
Published: February 2022

Introduction:
Stroke is a sexually dimorphic disease. Stroke sensitivity in the elderly is altered by the decline of estrogen levels in females. Our previous studies suggested a X chromosomal effect on stroke sensitivity in aged mice; however, these mice were gonadal intact and the activational effect of hormones cannot be ruled out. In this study, we utilized the XY* mice model in which mice of four genotypes were produced (XX, XO, XY, and XXY) to dissociate the effect of X chromosome from that of Y. To rule out the activational effect of hormones, we gonadectomized all mice at 3 weeks old, and let them survive for 6-8 weeks to achieve “surgical post-menopause”. We hypothesized that the second X chromosome mediates the stroke sensitivity in the absence of activational sex hormones. Two X escapee genes (
Kdm6A
and
Kdm5C
) that escape from the X chromosome inactivation and involved in microglial activation, were also examined to explore the potential mechanisms.

Methods:
“Surgical postmenopausal” XY* mice were subjected to a 60-min middle cerebral artery occlusion (MCAO) (n=6-8/gp for stroke and = 4-5/gp for sham). Infarct volumes and behavior deficits were quantified 3 days after MCAO. Plasma inflammatory cytokine (TNFα, IL-1β, IL-4, iNOS, TGF-β1 and IL-10) levels were determined by ELISA. KDM6A and KDM5C expression in microglia was examined by IHC.

Results:
XX mice had significantly larger infarct size than XO mice in striatum (55.02±12.38% vs. 36.06±9.25%, P=0.0387) and the ipsilateral hemisphere (45.33±10.77% vs. 26.55±6.92%, p=0.0413); the same pattern was seen in XXY vs. XY group in striatum (58.47±14.26% vs. 34.22±15.24%, P=0.0027). Neurological deficit scores were higher in XX vs. XO mice. Mice with two copies of the X chromosome had significantly higher plasma levels of pro-inflammatory cytokines (TNFα, IL-1β) than the mice with one X. Significantly higher levels of KDM6A or KDM5C in Iba-1 positive microglial cells were also found in mice with two vs. one copy of X.

Conclusion:
The second X chromosome contributes to stroke sensitivity in the absence of activational sex hormones. Our future goal is to use
Kdm6A
and
Kdm5C
microglial conditional knockout mice to explore the molecular mechanisms underlying chromosomal factors in stroke sensitivity.
Abstract 86: Dicer Ablation In Oligodendrocytes Impairs Oligodendrogenesis And Functional Recovery After Stroke
Authors: Liu Xianshuang , Fan Baoyan , Wang Xinli , Wei Min , Golembieski William , Chopp Michael , Zhang Zheng Gang
Published: February 2022

Introduction:
Stroke-induced oligodendrogenesis contributes to ischemic brain remodeling and spontaneous functional recovery. Genes that regulate microRNA biogenesis in stroke-induced oligodendrogenesis remain little known.

Methods:
We employed a transgenic mouse line with conditional and inducible ablation of Dicer, a key gene of miRNA biogenesis, in myelin proteolipid protein (PLP) lineage oligodendrocytes (Dicer-KO). A PLP reporter mouse line was used as a control. Mice were subjected to transient (60min) middle cerebral artery occlusion (MCAO, n=8/group). An array of behavioral and cognitive tests were performed. All mice were sacrificed at 28 days after MCAO. Fluorescence-activated cell sorting (FACS) in combination with miRNA sequencing were used to profile the miRNA alteration.

Results:
Compared to ischemic reporter mice, ischemic Dicer-KO mice exhibited significantly increased infarct volumes and significantly impaired neurological outcomes and cognitive deficits post stroke as assayed by social recognition memory, novel object recognition, and Morris water-maze tests. Immunochemistry analysis revealed that ischemic Dicer-KO mice showed a significant reduction of the number of PLP-lineage NG2
+
oligodendrocyte precursor cells (OPCs) and APC
+
myelinating oligodendrocytes compared to ischemic reporter mice. Moreover, Dicer-KO mice exhibited a robust reduction of myelinated axons measured by myelin binding protein (MBP) and Bielschowsky/Luxol Fast Blue assay. FACS analysis of PLP-lineage cells in peri-infarct regions showed that ablation of Dicer significantly decreased many miRNAs including the miR-200 family that are known to regulate oligodendrogenesis.

Conclusion:
Our data indicate that Dicer in PLP lineage oligodendrocytes is required for stroke-induced oligodendrogenesis and myelination, and that Dicer is involved in spontaneous functional recovery after stroke.
Abstract 88: Workflow Delays And Outcome Of Endovascular Thrombectomy In The Late Stroke Window:results From A Pooled Multicenter Analysis
Authors: Ademola Ayoola , Menon Bijoy K , GOYAL MAYANK , Thornton John M , Casetta Ilaria , Nannoni Stefania , Herlihy Darragh , Fainardi Enrico , Power Sarah , Saia Valentina , Hegarty Aidan , Pracucci GIOVANNI , Demchuk Andrew M , Mangiafico Salvatore , Boyle Karl , Michel Patrik , Bala Fouzi , Hildebrand Kevin A , Sajobi Tolulope , Hill Michael D , Toni Danilo , Murphy Sean , Kim Beom J , Almekhlafi Mohammed A
Published: February 2022

Background:
Efficient healthcare workflow leads to faster reperfusion and better functional outcomes of stroke in the early-time window. We investigated the impact of care delays on the outcomes of stroke patients treated with endovascular thrombectomy (EVT) in the late window.

Methods:
Pooled data from seven randomized clinical trials and registries that only included patients who underwent EVT in the late time window (onset/last known well (LKW) time to imaging time of 6 hours or more) were combined for this analysis. The time intervals from stroke onset to successful reperfusion were analyzed. Logistic regression was used to estimate the likelihood of a functionally independent outcome at 90 days (modified Rankin scale 0-2) for each time interval while adjusting for relevant patients’ characteristics. Negative binomial regression was used to evaluate the relationship between each time interval and the predictors.

Results:
584 patients were included in this analysis. The median age was 70 years (IQR: 21), 293 [50.17%] were females, 298 (53.31%) had wake-up strokes, and the median ASPECTS was 8 (IQR: 2). All patients had CT, and CTA imaging, and 360 (61.64%) underwent perfusion imaging. Successful reperfusion was achieved in 469 (80.45%) patients, and 249 (44.54%) had independent outcomes at 90 days. For every 30 minutes delay, the estimated probability of functional independence decreased by 19% for the emergency department (ED) arrival to imaging time interval, by 25% from groin puncture to end of EVT, and by 12% from ED arrival to end of EVT. Older age and higher NIHSS were associated with longer time from imaging to groin puncture. However, only age was associated with a longer estimated times from stroke onset/LKW to arrival in ED and from stroke onset/LKW to the end of EVT.

Conclusion:
Faster in-hospital care is associated with improved functional independence among late-window patients.

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Abstract 98: Brain-Derived Programmed Death-Ligand 1 Induces Post-Stroke Immunosuppression
Authors: Cheng Nuo , Wang Hong , Shi Kaibin
Published: February 2022

Background and purpose:
Post-stroke immunosuppression is associated with increased infection risk and mortality of stroke patients. However, the mechanisms driving post-stroke immunosuppression are not fully elucidated and strategies to prevent this fatal complication are lacking. We investigated the role of programmed death-ligand 1 (PD-L1) on post-stroke lymphocyte deficiency in a murine model of intracerebral hemorrhage (ICH).

Methods:
ICH was induced by intracerebral injection of autologous blood or collagenase IV to male C57BL/6 (B6) mice. Mice were randomly assigned into two groups to received anti-PD-1 antibody and vehicle respectively via intraperitoneal injection operating at 1 hour after ICH. Neurological function assessment, immunofluorescence, Elisa, flow cytometry, lung colony calculated were analyzed.

Results:
In a mice model of ICH, we identified that neuron-derived programmed death ligand 1 (PD-L1) are downregulated and released to the blood post ICH. Increased PD-L1 induced T cell and NK cell deficiency via their expressed PD-1, which are associated with increased lung infection post-ICH. Blocking PD-L1 pathway via an anti-PD-1 monoclonal antibody prevented the spleen atrophy of ICH mice, and improved peripheral T and NK cell numbers and function. Anti PD-1 antibody treated mice showed improved clinical outcome and reduced pulmonary bacterial burden.

Conclusions:
This study identified brain-derived PD-L1 to the periphery as a new pathway that lead to post-stroke immunosuppression, targeting PD-L1 could be a potential treatment strategy to reduce post-stroke infection risk.

Key words:
Programmed death ligand 1,intracerebral hemorrhage, neuron,immunosuppression, inflammation

Short title:
PD-L1 and post-stroke immunosuppression
Abstract TMP10: Patient-specific Analyses Reveal Differences In Hemodynamic And Morphological Parameters Between Growing And Stable Unruptured Intracranial Aneurysms
Authors: Chien Aichi , Yang Hong-Ho , Colby Geoffrey , Szeder Viktor , Sayre James , Duckwiler Gary , Villablanca Juan , Salamon Noriko , Vinuela Fernando
Published: February 2022

Introduction:
Although image-derived parameters such as wall shear stress (WSS), flow rate (FR), aspect ratio (AR), size ratio (SR), and non-sphericity index (NSI) were previously linked to risks of intracranial aneurysm (IA) growth, findings across studies have been inconsistent. Here, we revisit existing hemodynamic and morphological metrics and compare them between stable and growing IAs. We hypothesize that some may differentiate growing and stable trajectories of IAs.

Methods:
Unruptured IA cases between 2018-2020 were identified from UCLA Medical Center electronic medical records, with follow-up data used to determine growth status. From CTA/MRA images, models of 16 stable and 20 growing unruptured IA cases were reconstructed. Aneurysm diameter, height, neck width, surface area, volume, parent artery diameter, AR, SR, NSI, volume ratio, and surface area ratio were calculated. With data from hemodynamic simulations, we also measured FR and WSS. To capture spatial variations in hemodynamics, we calculated location-dependent mean deviation of WSS and FR at 3 locations within an aneurysm: neck, body, and dome. Pearson chi-square tests were used to compare background variables between groups. MANOVA was employed to compare the index values between stable and growing IAs.

Results:
Variables including location, diameter, race, history of smoking, and SAH were not significantly different between groups (p>>.05). Gender (p=0.06) and multiplicity (p=0.06) approached significance. Among the size-related and morphological parameters described above, only IA height (3.07±1.94mm vs. 5.49±3.61mm, p=0.03), neck width (4.93±1.42mm vs. 7.14±3.78mm, p=0.04), and size ratio (1.40±0.62 vs. 2.27±1.27, p =0.02) were significantly different (stable vs. growing, respectively). Growing IA had significantly higher FR spatial variation (0.43±0.35 vs. 0.75±0.44; p=0.03) and WSS spatial variations (0.24±0.20 vs. 0.49±0.28; p=0.008).

Conclusions:
Our findings support that location-dependent hemodynamic variations and SR may be potential risk factors of IA growth. Upon validation in larger studies, these parameters may aid in early identification of incidentally found IAs’ trajectories.
Abstract TMP101: Preoperative Atrial Fibrillation And Risk Of Stroke After Noncardiac Surgery
Authors: Gorham Vargas Andrea , Navi Babak , Merkler Alexander E , Liberman Ava L , Parikh Neal S , Kaleem Safa , Cheung Jim W , Okin Peter M , Weinsaft Jonathan W , Safford Monika M , Kamel Hooman
Published: February 2022

Objective:
To assess rates of postoperative stroke after elective noncardiac surgery in patients with atrial fibrillation (AF).

Methods:
We conducted a retrospective cohort study using all-payer administrative claims data on all non-federal hospitalizations and emergency department visits in 11 states between 2016 and 2018. We included patients hospitalized for elective noncardiac surgery, as defined by a surgical diagnosis related group and major diagnostic category codes. The exposure variable was preoperative AF. The outcome variable was ischemic stroke within 30 days of surgery. We performed survival analyses using Kaplan-Meier cumulative rates and Cox proportional hazards models. We stratified AF patients by their CHA
2
DS
2
-VASc score and tested its discrimination using the c-statistic.

Results:
We identified 1,301,709 patients undergoing elective noncardiac surgery, of whom 94,363 (7.3%) had preoperative AF. Patients with AF were older (mean age, 73 versus 62 years) and had higher CHA
2
DS
2
-VASc scores (mean score, 3.2 vs 2.2). We identified 2,893 patients with postoperative stroke. The cumulative rate of postoperative stroke was 0.65% (95% CI, 0.60-0.70%) in patients with AF vs 0.19% (95% CI, 0.18-0.20%) in patients without AF. After adjustment for demographics and vascular risk factors, AF was associated with a higher risk of postoperative stroke (HR, 1.7; 95% CI, 1.5-1.8). Among AF patients, the CHA
2
DS
2
-VASc score was a good predictor of postoperative stroke (AUC, 0.81; 95% CI, 0.79-0.83). Rates of postoperative stroke among AF patients ranged from <0.1% in those with a CHA
2
DS
2
-VASc score of 0-2 to 14% in those with a score of 8 (Figure).

Conclusions:
Patients with AF faced a heightened risk of postoperative stroke and this risk varied in proportion to the CHA
2
DS
2
-VASc score.
Abstract TMP103: The Heavy Burden Of Allostatic Load On Long-term Survival After Stroke And Stroke-related Mortality
Authors: Jones Erica , Ovbiagele Bruce , Markovic Daniela , Towfighi Amytis
Published: February 2022

Background:
Measurement of allostatic load, quantified by the allostatic load index (ALI), is often utilized to evaluate the physiologic response to stress. Our objective was to assess whether allostatic load is associated with mortality after stroke or with stroke-specific mortality in the general population.

Methods:
Using data from the third National Health and Nutritional Examination Survey (NHANES III, 1988-1994) and the 2015 Linked Mortality File (National Death Index), we selected adults aged ≥ 25 years. Stroke was self-reported. We computed the weighted prevalence of each allostatic load index (ALI) category to obtain nationally representative estimates with higher ALI corresponding to higher stress burden. We evaluated the relationship between ALI category and mortality outcomes using the Cox proportional hazard model considering the survey design variables, adjusting for age, sex, education, marital status, and income.

Results:
Of 15,567 individuals included in the study, there were 48.3% ALI ≤ 1, 21.7% ALI = 2, and 30% ALI ≥ 3. Of 414 individuals with reported history of stroke there were 11.8% ALI ≤ 1, 22.1% ALI = 2, and 66.1% ALI ≥3. Higher ALI correlated with male sex, older age, lower education, married or widowed status, and lower income. In the population with history of prior stroke, those with ALI ≥ 3 had 2.7 times higher all-cause mortality and 4.5 times higher cardiovascular mortality compared to those with ALI ≤ 1 (Table). In the general population, the ALI ≥ 3 group had 1.8 times higher adjusted stroke mortality.

Discussion:
Baseline higher allostatic load predicts greater all-cause and cardiovascular mortality risk in stroke survivors and greater stroke mortality risk in the general population. A global approach towards addressing the modifiable indicators in the ALI may improve survival in these populations.
Abstract TMP106: Pooled Analysis Of Five Randomized Trials Comparing Device Closure Of Patent Foramen Ovale After Stroke To Medical Treatment: Impact Of Residual Shunt On Stroke Outcomes
Authors: Thaler David E , Saver Jeffrey L , Kasner Scott , Carroll John , Furlan Anthony J , Herrmann Howard C , Juni Peter , Kim Jong S , Koethe Benjamin , Lee Pil Hyung , Lefebvre Bénédicte , Mas Jean-Louis , Mattle Heinrich P , Meier Bernhard , Nelson Jason , Reisman Mark , Smalling Richard W , Soendergaard Lars , Song Jae-kwan , Kent David M
Published: February 2022

Introduction:
Patent foramen ovale (PFO) closure is effective for secondary stroke prevention in well selected patients. After device implantation some patients have residual shunting. There was no impact of incomplete closure on recurrent stroke risk in any of the trials but outcome rates are low with little power to detect an effect.

Hypothesis:
Patients with residual shunts after PFO closure have more recurrent strokes than those with complete elimination of shunting.

Methods:
We pooled individual patient data from 5 of 6 randomized clinical trials comparing medical therapy to PFO closure + medical therapy. Residual shunt data were not available for 1 trial. This analysis only includes PFO closure subjects. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated with Cox proportional hazards regression, adjusted for age, sex, coronary disease, diabetes, hypertension, hyperlipidemia, prior stroke/TIA, smoking, index event (stroke vs TIA), hypermobile septum, shunt size (large vs small) and infarct location (superficial vs deep). Multiple imputation of missing values for adjusted variables was used.

Results:
Among 1475 patients treated with PFO closure and with non-missing residual shunt data, 149 (10%) had incomplete closure. The median time from procedure to shunt measurement was 204 days (25
th
-75
th
percentile, 181-722). In the complete closure group the primary endpoint of recurrent ischemic stroke occurred in 30 patients (2.3%; 95% CI 1.5-3.2%) compared to 4 (2.7%; 95% CI 0.7-6.7%) with incomplete closure. Unadjusted and adjusted HRs comparing incomplete vs complete closure were 1.37 (0.48, 3.92) and 1.69 (0.37, 4.95) respectively. The secondary endpoint of recurrent ischemic stroke, TIA, or vascular death occurred in 66 (5.0%; 95% CI 3.9-6.3%) patients with complete closure compared to 9 (6.0%; 95% CI 2.8-11.2%) without. Unadjusted and adjusted HRs were 1.26 (0.63, 2.54) and 1.39 (0.68, 2.83) respectively.

Conclusions:
Our pooled analysis of individual subjects after PFO closure from 5 of 6 relevant randomized clinical trials, showed no association between residual shunt and recurrent stroke events. This analysis was limited by low rates of residual shunt and recurrent events even in this large, combined dataset.
Abstract TMP11: Predictors Of Timely Treatment Of Aneurysmal Subarachnoid Hemorrhage - The Reddish Study
Authors: Nguyen Thuy P , Stirling Christine , Nichols Linda , Chandra Ronil V , Rehman Sabah , Buscot Marie-Jeanne , Smith Karen L , Blizzard Leigh , Lai Leon , Asadi Hamed , Arvind Dubey , Froelich Jens , Thani Nova , Reeves Mathew J , Thrift Amanda G , Gall Seana L
Published: February 2022

Background:
Receiving early treatment for aneurysmal subarachnoid hemorrhage (aSAH) is associated with better outcomes for the patient. However, delays in treatment of aSAH are common but the causes are not well understood. We explored predictors of early treatment within 12.5 hours or 24 hours after aSAH.

Methods:
Consecutive cases of confirmed first-ever aSAH were identified from two Australian tertiary referral centers between 2010 and 2016. We used medical and ambulance records to extract details of participants, including time from onset to definitive treatment of either endovascular coiling or neurosurgical clipping, demographics, severity of aSAH (modified Fisher grade; World Federation of Neurosurgeons Scale [WFNS]), risk factors, pre-hospital care, and presenting symptoms. Factors associated with treatment to secure the aneurysm within 12.5 hours or 24 hours on univariable logistic regression were entered into a multivariable model to identify factors independently associated with (odds ratio [OR], 95% CI) earlier treatment.

Results:
Among 482 patients (mean [SD] age 54.1 [14.5]; 69.9% female) with aSAH, median (IQR) time to treatment was 19.4 (10.6, 31.0) hours, 30% were treated <12.5h and 62% were treated <24h from onset. In multivariable analyses (see figure), arriving by ambulance, urgent triage category (1-2) and severe aSAH (modified Fisher Scale 3-4) predicted treatment <12.5h and <24h. Less severe aSAH (WFNS score 1-3) and arriving overnight (11pm to 7am) were associated with treatment <24h. In contrast, people with no risk factors for aSAH (smoking, hypertension or alcohol use), presenting with a stiff neck or interfacility transfer more often had treatment ≥12.5h.

Conclusions:
A substantial proportion of people after aSAH were not treated within timeframes associated with better outcomes. Recognition of the urgency and severity aSAH cases were associated with more timely treatment of aSAH.
Abstract TMP118: Novel Regulation Of Peripheral Derived Immune Cells In The Remodeling Of Pial Collateral Vessels Following Ischemic Stroke
Authors: Ju Jing
Published: February 2022

Introduction:
Stroke is a leading cause of neurological morbidity and mortality in the United States. Remodeling of pial collateral (PC) vessels (arteriogenesis) is vital to restore blood perfusion into the ischemic penumbra to reduce damage. Previous reports showed perivascular monocyte /macrophage (MM) accumulation in hind limb ischemia and myocardial infarction, suggesting that MM are key regulators of inflammatory milieu following stroke. We reported EphA4 as a negative regulator of PC remodeling. However, the role of EphA4 during peripheral derived immune cell (PDI) mediated arteriogenesis after permanent middle cerebral artery occlusion (pMCAO) remains unknown. This study explores the role of EphA4 in regulating PDI-mediated arteriogenesis after pMCAO and interrogates if MM-specific EphA4 contributes to the neuroinflammatory milieu during remodeling process.

Methods:
GFP reporter EphA4 bone marrow chimeric knockout (KO
BMCs
) and wild-type mice (WT
BMCs
) were euthanized 1d post pMCAO. Vessel painted whole brains were used for immunostaining, infarct volume measurement, and confocal histological analysis including PC remodeling and GFP+ perivascular immune cell recruitment. Blood from sham and pMCAO mice was collected for flow cytometry to analyze EphA4 expression on circulating immune cell types. We performed rotarod test to assess behavioral recovery, and used clodronate liposome for MM depletion in both WT
BMCs
and KO
BMCs
to further explore the function of EphA4 MM after stroke.

Results:
This study developed a novel methodology to evaluate MM-specific EphA4 role after pMCAO. EphA4 was highly expressed on Ly6G+ neutrophils, Ly6Chi, and Ly6Clo MM in whole blood 24h after pMCAO. KO
BMCs
mice had enhanced growth of ipsilateral PC compared to WT
BMCs
mice after pMCAO. These findings correlate with KO
BMCs
reduced infarct volume and improved motor function compared to WT
BMCs
. Finally, WT
BMCs
displayed a significant increase in GFP+ PDI recruitment to the PC wall in KO
BMCs
compared to WT
BMCs
mice.

Conclusions:
PDI-specific EphA4 expression negatively regulates arteriogenesis and suppresses PDI accumulation on PC. The acute neurovascular inflammation may be dependent on the EphA4 expression of MM in the peripheral circulation after stroke.
Abstract TMP12: Artificial Intelligence Prediction Of Delayed Cerebral Ischemia After Cerebral Aneurysm Rupture
Authors: Moein Taghavi Reza M , Zhu Guangming , Wintermark Max , Christensen Soren , Heit Jeremy J
Published: February 2022

Background:
Aneurysmal subarachnoid hemorrhage (aSAH) results in significant mortality and disability, which is worsened by the development of Delayed Cerebral Ischemia (DCI). Tests to identify patients with DCI prospectively are needed.

Objective:
We created a machine learning (ML) system based on clinical variables to predict DCI in aSAH patients and to determine which variables have the most impact on DCI prediction.

Methods:
We performed a retrospective cohort study of aSAH patients from January 2006 to September 2014. The ML algorithm was trained on age, sex, HTN, diabetes, hyperlipidemia, CHF, CAD, smoking history, family history of aneurysm, Fisher Grade, Hunt and Hess score, and external ventricular drain (EVD) placement. Prediction outcome of the ML algorithm was DCI+, which was defined as new neurologic deterioration that could not be attributed to aneurysm re-bleeding, hydrocephalus, infection, seizure, hyponatremia or other metabolic abnormality. SHAP was used to explain and visualize the role of each feature’s contribution to the model prediction.

Results:
500 aSAH patients were identified and 369 met inclusion criteria: 70 patients developed DCI (DCI+) and 299 did not (DCI-). Random Forest was selected for this project after a 5-fold cross validation. 276 cases (222 DCI- and 54 DCI+) were used for training and 93 cases (77 DCI- and 16 DCI+) were used for testing the algorithm. The Random Forest ML algorithm predicted DCI: Accuracy: 81.7%, Sensitivity: 12.5%, Specificity: 96.1%, PPV: 40%, and NPV: 84.1%. SHAP value demonstrated Age, EVD placement, Fisher Grade, and Hunt and Hess score, and HTN had the highest predictive values for DCI. Lower age, absence of hypertension, higher Hunt and Hess score, higher Fisher Grade, and EVD placement increased risk of DCI.

Conclusion:
ML models based upon clinical variable predict DCI with high specificity and modest accuracy. The addition of imaging or other biomarkers may improve the sensitivity of the ML algorithm.