bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract W P52: Safety of Intravenous Thrombolysis (IVT) in Stroke Mimics: A Prospective Five-year Study and Comprehensive Meta-analysis of Reported Case Series
Authors: Tsivgoulis Georgios , Zand Ramin , Katsanos Aristeidis H , Goyal Nitin , Uchino Ken , Alexandrov Anne W , Malkoff Marc D , Alexandrov Andrei V
Published: July 2021

Background&Purpose:
Shortening door-to-needle time may lead to intravenous thrombolysis (IVT) administration in stroke mimics (SM). We sought to determine safety of IVT in SM using prospective, single-center data and by conducting a comprehensive meta-analysis of reported case series.

Subjects&Methods:
We analyzed consecutive IVT-treated patients during a 5-year period (2009-2013) at a tertiary care stroke center. Non-contrast head CT, NIHSS pre-treatment and modified Rankin scores (mRS) at discharge were obtained as standard of care. SM was defined as no acute ischemic lesions on MRI and the final non-stroke diagnosis established by radiologists and treating physicians unaware of the purposes of this study. Symptomatic intracerebral hemorrhage (sICH) was defined as imaging evidence of ICH with NIHSS increase of 4 or more points. Functional independence (FI) was defined as mRS 0-1. We also conducted a comprehensive meta-analysis of all available case-series reporting safety of IVT in SM using PRISMA guidelines.

Results:
Of 516 consecutive IVT patients at our tertiary care center (50% men; mean age 60±14years; median NIHSS 11, range 3-22), SM comprised 75 cases (14.5%, 95%CI by adjusted wald method: 11.7%-17.9%). sICH occurred in one patient (1.3%; 95%CI:0%-7.9%), while we documented no cases of orolingual edema (OE) or major extracranial hemorrhagic complications (0%; 95%CI:0%-4.2%). Two patients experienced minor extra-cranial hemorrhagic complications (1 case of gingival & 1 case of nose bleeding). Meta-analysis of 9 studies including 8,942 patients treated with IVT and reporting safety outcomes in 392 SM showed pooled rates of sICH and OE 0.5% (95%CI: 0%-2%) and 0.3% (95%CI: 0%-2%) respectively. We documented no heterogeneity between estimates of sICH (I squared statistic=0%; p=0.941 Cohran Q test), and OE (I squared statistic=0%; p=0.913 Cohran Q test).

Conclusions:
Our prospectively collected data coupled with the findings of the comprehensive meta-analysis underscore the safety of IVT in SM given the low prevalence of hemorrhagic and systemic complications and the lack of heterogeneity across reported case-series.
Abstract W P70: Pharmacokinetic Properties and Toxicity/safety Profiles of SP-8203, a Novel Neuroprotectant for Treatment of Cerebral Ischemic Stroke
Authors: Ryu Jei-Man , Cho Il-Hwan , Kim Won-Seok , Kim Byung-Su , Lee Yong-Hyun , Kim Won-Ki , Lee Eun-Bang
Published: July 2021

We recently identified a multi-target directed neuroprotectant SP-8203, which is now undergoing phase 1 clinical trial. Here we report the preclinical and clinical toxicity/safety profiles and pharmacokinetic properties of SP-8203. Single-dose and 28-day repeated-dose toxicity tests in Sprague Dawley rats, Beagle dogs, and Cynomolgus monkeys were performed by Chemon (Korea), MPI Research (USA), and Toxikon (USA) and Phase 1 clinical trial by ASAN medical center (korea). The genotoxicity was examined by the bacterial reverse mutation assay (AMES test), the chromosome aberration assay using Chinese hamster ovary and lung cells, and the micronucleus test in rat bone-marrow erythrocytes. The safety pharmacology studies evaluate acute neurobehavioral toxicities and pulmonary functions in male rats and cardiovascular toxicities in male Cynomolgus monkeys. Following a single-dose intravenous administration, the minimum lethal dose of SP-8203 was estimated to 60 mg/kg and the lethal dose 50 (LD50) was 83.3 mg/kg in rats. The No-Observable-Adverse-Effect-Level (NOAEL) of 4 week repeated dose of SP-8203 was 20 mg/kg/day in rats and 12 mg/kg/day in monkeys, when administered as an intravenous slow bolus injection for 5 min. However, when administered as an intravenous infusion for 30 min, the NOAEL in rats increased to 80 mg/kg/day or more. SP-8203 did not exert any genotoxicity. Safety pharmacology studies showed that NOAELs of neurobehavioral toxicity, pulmonary functions, and cardiovascular effects were 30 mg/kg, 30 mg/kg, and 10 mg/kg, respectively. In a single accelerating dose study in phase 1 clinical trial, no toxic responses were observed at doses up to 240mg in healthy subjects. Pharmacokinetics of SP-8203 evaluated after its intravenous administration in humans and rats showed that the AUCs and half-lives of SP-8203 were dose-dependently increased; thus the dose-normalized AUCs and half-lives were significantly elevated with increasing doses. However, the nonlinear PK properties are within safe ranges in humans and rats. Taken together, a series of toxicity/safety assessments showed that SP-8203 is quite safe and non-toxic at the doses for the treatment of cerebral ischemic stroke in humans.
Abstract W P8: "Double Trouble": Endovascular Treatment of Tandem Arterial Occlusions in Acute Ischemic Stroke
Authors: Grigoryan Mikayel , Haussen Diogo , Lima Andrey , Grossberg Jonathan , Doppelheuer Shannon , Schindler Kiva M , Braimah Janet , Belagaje Samir R , Anderson Aaron , Nahab Fady , Frankel Michael , Nogueira Raul G
Published: July 2021

Background:
Tandem extracranial/intracranial arterial occlusions in acute stroke present treatment challenges both due to suboptimal response to systemic intravenous thrombolysis as well as complex endovascular approach. We report our experience in treating this cohort of acute stroke patients with the analysis of angiographic and clinical outcomes

Materials and Methods:
We retrospectively reviewed clinical and imaging data of all consecutive acute stroke patients with proximal intracranial arterial occlusion and additional extracranial occlusion/critical stenosis, treated with endovascular techniques between February 2011 and February 2014 at two hospitals. We analyzed patients’ demographics, clinical presentation, treatment strategies, time to recanalization, imaging and clinical outcomes.

Results:
A total of 66 patients were included. The mean NIHSS on presentation was 19. Extracranial carotid with concomitant intracranial anterior circulation occlusions were present in 95% of the patients (63/66), while 5% (3/66) had tandem vertebrobasilar occlusions. 41% of the patients (27/66) received intravenous rt-PA. With regards to endovascular treatment, in 70% of the cases (46/66), extracranial lesion was treated with a stent placement. Stentrievers were used in 50% (33/66) of the patients for intracranial thrombectomy. Thrombolysis in Cerebral Infarction (TICI) >= 2B reperfusion was achieved in 77% of all the patients (51/66) and in 97% (32/33) of the stentriever patients. Good clinical outcome at 90 days (mRS<=2) was seen in 42% of the patients. Symptomatic intracerebral hemorrhage (PH-2)occurred in 9% (6/66) of the patients.

Conclusions:
Endovascular treatment of tandem arterial occlusions in acute ischemic stroke is relatively safe, feasible, and may yield excellent angiographic and good clinical outcomes.
Abstract W P93: MiR-122 Improves Stroke Outcomes after Middle Cerebral Artery Occlusion in Rats
Authors: Liu DaZhi , Jickling Glen C , Ander Bradley P , Hull Heather , Zhan Xinhua , Dykstra-Aiello Cheryl , Stamova Boryana , Sharp Frank R
Published: July 2021

MicroRNA (miRNA) are recently discovered small (~22 nucleotides), non-coding RNA that regulate translation of messenger RNA (mRNA) to protein. Though there are only hundreds of miRNAs, each of them can potentially regulate hundreds of target genes, via base-pairing with complementary sequences in mRNA. This provides one approach that targets a single miRNA to have effects on multiple genes.

Our previous genomic studies have demonstrated that miR-122 decreased significantly in blood of experimental strokes produced by middle cerebral artery (MCA) occlusion in rats as well as in blood of patients with ischemic strokes. Therefore, we hypothesized that elevating blood miR-122 has the potential for treating stroke. Using the newly developed in vivo polyethylene glycol-liposome based miRNA transfection system and rat suture MCAO occlusion model, we show that injection of chemically modified mimic miR-122 (600ug/rat, i.v.) through tail vein immediately after MCAO occlusion significantly decreases the neurological impairment and significantly attenuates brain infarct volumes. Ongoing studies are identifying the target genes that are associated with the neuroprotective effects of miR-122 following stroke.

Acknowledgements:
This study was supported by NIH grant R01NS066845 (FRS). There were no conflicts of interest.
Abstract 100: Extracranial Vertebral Artery Atherosclerotic Disease in Patients With Symptomatic Stenosis of the Internal Carotid Artery. The North American Symptomatic Carotid Endarterectomy Trial
Authors: Qureshi Adnan I , Miran Muhammad Shah , Malik Ahmed A , Adil Malik M , Zafar Aiman , Suri M.Fareed K
Published: July 2021

Background and Purpose:
The prevalence of atherosclerotic disease of extracranial vertebral artery and associated long-term outcomes in patients with stenosis of the internal carotid artery (ICA) are not well defined.

Methods:
We ascertained the rates of any stroke, vertebrobasilar stroke, and all-cause mortality over 5 years associated with various categories of extracranial vertebral artery disease based on angiographic severity (<30%, 30-69%, 70-99%, and occlusion) in patients with symptomatic ICA stenosis who participated in the North American Symptomatic Carotid Endarterectomy Trial (NASCET). We also studied the relative benefit of carotid endarterectomy in reduction of ipsilateral stroke in patients with various categories of extracranial vertebral artery disease after adjusting for age, gender, and severity of ICA stenosis.

Results:
Among the 798 patients who underwent angiographic catheterization of extracranial vertebral artery, the severity of stenosis was categorized as <30% (n=342), 30-69% (n=164), 70-99% (n=70), and occlusion (n=30). Compared with those with stenosis <30%, the relative risk of any stroke was similar between those with 30-69% (relative risk (RR) 1.1, 95% confidence interval [CI] 0.9-1.3 ), 70-99% (RR 0.9, 95% CI 0.7-1.3), and occlusion (RR 1.2, 95% CI 0.8-1.9) after adjustment for age, gender, severity of ICA stenosis, and allocated treatment (endarterectomy versus medical treatment). The relative risk of vertebrobasilar stroke was two folds higher in patients with extracranial vertebral artery stenosis 70-99% compared with those with <30% stenosis (RR 2.1, 95% CI 0.8-5.2) after adjusting for potential confounders. The relative benefit of carotid endarterectomy over medical treatment was similar according to categories of extracranial vertebral artery disease: <30% (RR 0.6, 95% CI 0.3-0.9), 30-69% (RR 0.3, 95% CI 0.2-0.9), 70-99% (RR 0.6, 95% CI 0.2-2.4), and occlusion (RR 0.4, 95% CI 0.07-2.9)

Conclusions:
The increased risk of vertebrobasilar stroke in patients with symptomatic ICA stenosis who have concurrent extracranial vertebral artery disease supports critical evaluation of additional endovascular treatment options in such patients.
Abstract 112: Predicting REcovery Potential of Upper Limb Function After Stroke to Increase Rehabilitation Efficiency
Authors: Stinear Cathy M , Ackerley Suzanne J , Byblow Winston D , Barber P A , McRae Anna , Lee Henrietta
Published: July 2021

Introduction:
The PREP algorithm combines clinical assessment [Shoulder Abduction Finger Extension (SAFE) score], transcranial magnetic stimulation (TMS) and diffusion-tensor imaging to predict potential for upper limb recovery following stroke. Patients’ recovery potential is predicted to be Complete, Notable, Limited or None.

Hypothesis:
The PREP algorithm may be used in a ‘real world’ clinical setting to set individual rehabilitation goals.

Methods:
This study recruited 194 patients with upper limb weakness within 3 days of stroke. Assessments were made at baseline and 12 weeks by assessors blinded to PREP algorithm prediction. The initial benchmarking phase recruited 85 patients and PREP algorithm information was not shared with clinical teams or patients. The results were used to refine the algorithm and guide implementation in three ways. First, patients with a SAFE score > 7, predicted to have Complete upper limb recovery, were given a self-directed therapy program. Second, patients with a SAFE score of 5-7 could be given a Notable recovery prognosis, without requiring TMS. Third, 19% of patients exceeded their predicted upper limb recovery, so this possibility was conveyed to patients and clinical teams. The implementation phase recruited 109 patients, and PREP algorithm predictions were shared with patients and clinical teams.

Results:
Interim analyses (n = 135) find that the PREP algorithm correctly predicted upper limb function at 12 weeks for 85% of patients. Implementation of the algorithm decreased length of stay by 7 days (95%CI 2 - 15 days, p < 0.05) and increased the proportion of patients discharged home from the acute stroke unit from 28% to 49% (p < 0.01). Implementation also decreased upper limb therapy dose (p < 0.01), yet patient outcomes were similar between the two phases. Primary endpoint analysis will be complete in November 2015.

Conclusions:
Making predictions about the potential for recovery of upper limb function, and setting individual rehabilitation goals accordingly, may increase the efficiency of post-stroke rehabilitation.
Abstract 127: Class IIa Histone Deacetylases Are Essential for Neuronal Remodeling and Functional Recovery After Stroke
Authors: Shehadah Amjad , Kassis Haifa , Li Chao , Zhang Yi , Cui Yisheng , Roberts Cynthia , Sadry Neema , Liu Xianshuang , Chopp Michael , Zhang Zheng Gang
Published: July 2021

Background:
Histone deacetylases (HDACs) have recently emerged as a potential therapeutic target for stroke. We have previously demonstrated that stroke induces nuclear shuttling of class IIa HDAC isoform 4 (but not 5) in neurons. In this study, using a rat model for middle cerebral artery occlusion (MCAO), we tested whether class IIa HDACs are essential to endogenous neuronal remodeling and functional recovery after stroke.

Methods:
Adult male Wistar rats (n=13/group) were subjected to MCAO. At 1 day after MCAO, rats were gavaged with: SAHA (non-selective HDAC inhibitor, 25 mg/kg/d), MC1568 (selective inhibitor of class IIa HDAC, 25 mg/kg/2d) or vehicle for 7 days. A battery of behavioral tests was performed. Lesion volume was measured at 28 days after MCAO and immunohistochemistry was performed using antibodies against microtubule associated protein 2 (MAP2, dendrites), phosphorylated neurofilament heavy chain (pNFH, axons) and myelin basic protein (MBP, myelination). Nuclear HDAC activity was measured using a colorimetric assay.

Results:
Stroke significantly increased total HDAC activity in the ipsilateral hemisphere compared to the contralateral hemisphere (2 fold; p<0.05). Stroke-increased HDAC activity was significantly decreased by the administration of SAHA, as well as by MC1568. However, SAHA, but not MC1568, significantly improved functional outcome compared to vehicle-control. Selective class IIa inhibition with MC1568 increased mortality and lesion volume (43% vs. 35% in vehicle-control, p<0.05). In addition, MC1568 significantly decreased MAP2, pNFH and MBP immunoreactivity in the peri-infarct cortex compared to vehicle-control. Quantitative RT-PCR analysis of neurons isolated by laser capture microdissection revealed that MC1568, but not SAHA, downregulated CREB and c-FOS expression (p<0.05). Additionally, MC1568 decreased the expression of phosphorylated CREB (active) in neurons compared to vehicle-control.

Conclusions:
Selective inhibition of class IIa HDACs impairs neuronal remodeling and neurological outcome. Inactivation of CREB and c-FOS by MC1568 likely contributes to this detrimental effect. Thus, class IIa HDACs play a crucial role in regulating brain remodeling and functional recovery after stroke.
Abstract 141: Endothelial TRPA1 Channel is Protective Against Ischemia and Hemorrhagic Strokes in Mice
Authors: Pires Paulo W , Sullivan Michelle N , Earley Scott
Published: July 2021

The transient receptor potential ankyrin 1 (TRPA1) cation channel is more selective for Ca
2+
versus Na
+
ions (∼8:1). We showed that TRPA1 is located in the endothelium of cerebral arteries (eTRPA1) and that reactive oxygen species (ROS)-induced channel activity generates localized Ca
2+
signals (TRPA1 sparklets) that initiate endothelium-dependent hyperpolarization and vasorelaxation. Cerebrovascular disease is associated with increased ROS generation and oxidative stress. Thus, we hypothesized that eTRPA1 activity is protective against stroke. Tissue-specific deletion of eTRPA1 in mice was achieved using the
Cre
-recombinase (Tie2 promoter) / loxP system. Ischemic strokes were induced by permanent middle cerebral artery occlusion (pMCAO). Neurological function after pMCAO was assessed by a modified neurological severity scale, ranging from 0 to 4 (0: normal behavior; 1: failure to extend contralateral paw; 2: circling; 3: rolling to one side; 4: stupor). Deletion of eTRPA1 increased post-stroke (24 hours) neurological damage in eTRPA1
-/-
versus WT mice, as shown by a higher severity score (2.6±0.4 vs 3.8±0.2, p<0.05), and larger infarct size (%hemisphere infarcted: 45±7 vs 62±4%, p0.05, N=8), eTRPA1
-/-
mice were significantly more susceptible to hemorrhagic strokes compared to WT. Kaplan-Meyer survival plots showed a higher survival rate for WT vs eTRPA1
-/-
at day 10 (61 vs 54%), day 15 (44 vs 21%) and day 20 (22 vs 8%) (p<0.05, N=25). All of the eTRPA1
-/-
mice suffered hemorrhagic strokes by day 22, whereas some of the WT mice survived until day 52. Further, eTRPA1
-/-
mice showed a higher number of hemorrhagic lesions in the cerebral cortex when compared to WT (12±4 vs 23±4 lesions per animal, p<0.05, N=25 mice per group). These data suggest that eTRPA1 protects against major cerebrovascular accidents and may be considered as a therapeutic target for reducing cerebral infarct after ischemia and as a preventive agent against hemorrhagic strokes.
Abstract 146: Inducible Conditional Deletion of Dicer in Neural Progenitor Cells Induces Cognitive Impairment
Authors: Zhang Rui Lan , Chopp Michael , Pan Wanlong , Zhang Xiaoming , Liu Xianshuang , Wei Min , Roberts Cynthia , Roberts Cynthia , Wang Xinli , Zhang Zheng Gang
Published: July 2021

Background:
MicroRNAs regulate adult neurogenesis. Conditional deletion of Dicer in neural stem cells (NSCs) causes postnatal death. The functional role of Dicer in adult neurogenesis remains unknown. Using mice with inducible conditional knock-down of Dicer in adult NSCs, we investigated the effect of ablation of Dicer on neurogenesis and cognitive function.

Methods and Results:
Young adult Ascl1-CreER:Dicerflox/flox mice (Dicer Cko, n= 32) were administered (i.p) with tamoxifen daily for 5 consecutive days and age matched wild-type litters (n= 30) were used as control. The mice were sacrificed at 2, 14 or 30 days after injection. Immunstaining was performed to detect phenotypes of subventricular zone (SVZ) cells. An array of cognitive tests including Morris Water Maze, odor-based novelty recognition, and sociability test were performed. Primary NPCs were isolated from the SVZ for vitro studies. Compared to control, Dicer CKo had 54% reduction of Dicer protein in NPCs. Cognitive tests showed that CKo spent 35% less time in the correct quadrant (p<0.05) of Morris Water Maze, significantly reduced time exploring new odor objects, 44 ±10% (p<0.05) in Cko animals compared with 77 ±10% in control, and significantly less time with other mice when they encountered a strange mouse during the sociability test (70 ± 9 vs 118 ±7 seconds, p<0.05). CKo significantly (p<0.05) reduced BrdU+ (16±2% vs 24±3%), and Ki67+ NPCs (25±3% vs 33±3%), doublecortin (DCX)+ neuroblasts (2± 0.6% vs 6± 1%), and Ng2+ oligodendrocyte progenitor cells (OPCs, 8±1% vs 12± 2%) in the SVZ. However, Dicer CKo animals exhibited a significant increase (p<0.05) of apoptotic NPCs (14±0.5% vs 10 ±0.3%). These in vivo findings were consistent with data from cultured NPCs. Dicer CKo also showed significant (p<0.05) reduction DCX+ neuroblasts in the rostral migratory stream and APC+ mature oligodendrocytes in the corpus callosum.

Conclusion:
Our data demonstrated that inducible conditional ablation of Dicer in Ascl1 lineage NPCs impairs neurogenesis and oligodendrogenesis in adult SVZ niche and white matter, and induces cognitive impairment, indicating that Dicer in adult NPCs is essential for maintaining neurogenesis and oligodendrogenesis and is important for cognitive function.
Abstract 195: Nosocomial Infections are Associated with Delayed Cerebral Ischemia in Aneurysmal Subarachnoid Hemorrhage
Authors: Foreman Paul M , Chua Michelle , Harrigan Mark R , Fisher Winfield S , Vyas Nilesh A , Lipsky Robert H , Walters Beverly , Tubbs R. Shane , Shoja Mohammadali M , Griessenauer Christoph J
Published: July 2021

Background and Purpose:
Delayed cerebral ischemia (DCI) is a recognized complication of aneurysmal subarachnoid hemorrhage (aSAH) that contributes to poor outcome. This study seeks to determine the effect of nosocomial infection on the incidence of DCI and patient outcome.

Methods and Subjects:
An exploratory analysis was performed on 156 aSAH patients enrolled in the Cerebral Aneurysm Renin Angiotensin System (CARAS) study. Clinical and radiographic data were analyzed with univariate analysis to detect risk factors for the development of DCI and poor outcome. Multivariate logistic regression was performed to identify independent predictors of DCI.

Results:
One hundred and fifty three patients with aSAH were included. Delayed cerebral ischemia was identified in 32 (20.9%) patients. Nosocomial infection, ventriculitis, aneurysm rerupture, and clinical vasospasm were independently associated with the development of DCI [3.5 (1.93 - 6.35), p < 0.00; 25.3 (4.39 - 110.9), p = 0.03; 7.55 (2.72 - 20.9), p = 0.05; 43.4 (23.6 - 79.8), p < 0.00; respectively]. Diagnosis of nosocomial infection preceded the diagnosis of DCI in 15 of 21 (71.4%) patients. Patients diagnosed with nosocomial infection experienced significantly worse outcomes as measured by mRS at discharge and 1 year (p < 0.00 and p = 0.03, respectively).

Conclusions:
Nosocomial infection is independently associated with DCI. This association is hypothesized to be partly causative through the exacerbation of systemic inflammation leading to thrombosis and subsequent ischemia.
Abstract 196: Acute Kidney Injury in Aneurysmal Subarachnoid Hemorrhage: Incidence, Risk Factors, and Outcomes
Authors: Rumalla Kavelin , Reddy Adithi , Gummadi Rajiv , Mittal Manoj
Published: July 2021

Introduction:
Acute kidney injury (AKI) increases morbidity and mortality in several acute illnesses. Here, we examine the incidence, risk factors, and in-hospital outcomes of AKI in patients hospitalized for aneurysmal subarachnoid hemorrhage (aSAH).

Methods:
The Nationwide Inpatient Sample was queried from 2002 and 2011 for all emergency hospitalizations (age≥18) with a primary diagnosis of aSAH and a secondary diagnosis of AKI. Patients with chronic renal disease, renal transplant, or trauma were excluded from the analysis. The effect of various patient factors on AKI incidence and its impact on length of stay (LOS), in-hospital costs, and in-hospital mortality was examined in bivariate and multivariate analyses.

Results:
Of 250,437 total hospitalizations for aSAH, the overall incidence of AKI was 4.0% (n=10,450) and increased from 2.1% in 2002 to 5.7% in 2011 (p<0.0001). The strongest multivariate predictors of AKI were 60-74 age group (OR: 1.43, 95% CI: 1.31-1.56), 75+ age group (OR: 1.81, 95% CI: 1.63-2.00), male gender (OR: 1.80, 95% CI: 1.69-1.87), Black race (OR: 1.45, 95% CI: 1.35-1.55), Medicaid insurance (OR: 1.29, 95% CI: 1.19-1.40), congestive heart failure (OR: 2.13, 95% CI: 1.98-2.28), liver disease (OR: 2.42, 95% CI: 2.13-2.75), fluid/electrolyte disorder (OR: 3.10, 95% CI: 2.95-3.27), and HIV (OR: 2.24, 95% CI: 1.66-3.01) (all p<0.0001). Aneurysmal coiling (OR: 0.81, 95% CI: 0.75-0.87) and clipping (OR: 0.75, 95% CI: 0.70-0.80) decreased the likelihood of suffering AKI (all p<0.0001). Cardiac arrest, septic shock, and acute lung injury were in-hospital complications that increased the odds of AKI (all p<0.0001). AKI occurrence in aSAH increased the mean LOS by 7.2 days and mean total costs by $28,813 (all p<0.0001). After adjusting for confounding factors, aSAH related AKI patients had increased likelihood of moderate to severe disability (OR: 2.03, 95% CI: 1.89-2.19, p<0.0001) and in-hospital death (OR: 2.14, 95% CI: 2.03-2.26, p<0.0001).

Conclusion:
The incidence of AKI in hospitalized aSAH patients has increased over the past decade and is both detrimental to hospital costs and patient prognosis. We identified patient-centered risk factors for AKI, allowing for the close surveillance of patients at the highest risk for AKI.
Abstract 2: Good Outcome After Successful Recanalization is Time Dependent in the Swift Prime Randomized Controlled Trial
Authors: Goyal Mayank , Jadhav Ashutosh P , Bonafe Alain , Diener Hans , Pereira Vitor , Levy Elad , Baxter Blaise , Jovin Tudor , Jahan Reza , Menon Bijoy , Saver Jeffrey
Published: July 2021

Background and Purpose:
The SWIFT PRIME trial demonstrated superior outcomes in patients presenting with disabling acute ischemic stroke (AIS) who underwent endovascular therapy vs. intravenous tissue plasminogen activator (t-PA) alone. We sought to understand the relationship between functional independence and time to reperfusion in study patients assigned to thombectomy.

Methods:
SWIFT PRIME is a global, multi-center, prospective, randomized, open, blinded endpoint study comparing functional outcomes in AIS subjects treated with either IV t-PA alone or IV t-PA in combination with Solitaire stent retriever device. Among patients in whom substantial reperfusion (TICI 2b/3) was achieved, we analyzed the effect onindependent outcome (mRS 0-2) of time from stroke onset to reperfusion (OTR) and from qualifying imaging to reperfusion

Results:
Among 83 patients undergoing thrombectomy, substantial reperfusion was achieved in 73 (88%). A marked effect of OTR was noted (Figure 1A). The rate of functional independence was 87% if reperfusion was achieved 150 minutes from symptoms onset. The absolute rate of good outcomes decreased by 10% over the next 60 minutes of delay in OTR and by 15% with every 60 minute delay there-after. Faster post-arrival workflow speed improved outcomes among patients presenting directly to study hospitals (Figure 1B).

Conclusions:
Speed of reperfusion is a dominant determinant of functional outcome among patients treated with stent retrievers. In the early period after, every 6 minute delay in reperfusion causes 1 more out of 100 treated patients to not achieve functional independence.
Abstract 212: Andexanet Alfa, a Universal Antidote for Reversal of Anticoagulation of Factor Xa Inhibitors in Healthy Human Volunteers
Authors: Crowther Mark , Gold Alexander M , Lu Genmin , Leeds Janet M , Wiens Brian L , Mathur Vandana , Castillo Janice , Conely Pamela B , Connolly Stuart J , Curnutte John T
Published: July 2021

Introduction:
Andexanet alfa (AnXa) is a recombinant modified fXa molecule that acts as a specific antidote for fXa inhibitors. We report clinical results in healthy subjects anticoagulated with apixaban (apix), rivaroxaban (riva), edoxaban (edox), or enoxaparin (enox), demonstrating rapid and sustained reversal of anticoagulation following administration of AnXa.

Methods:
These were Phase 2/3 randomized, double-blind, placebo-controlled studies in healthy subjects. In Phase 2, about153 subjects age18 - 45 were given one of the fXa inhibitors (apix 5 mg BID, riva 20 mg QD, edox 60 mg QD or enox 40 mg QD) for 6 days. AnXa or placebo (3:1 randomization) was given IV on Day 6, 3hrs after the last inhibitor dose (∼inhibitor Cmax). Safety was followed through Day 48. A range of AnXa doses (bolus or bolus+infusion) was evaluated by correction of biomarkers (anti-fXa activity, free inhibitor concentrations and thrombin generation (TG)).

In Phase 3 (ANNEXA™), older subjects age 50 to 75 were dosed with apix (5 mg BID) or riva (20 mg QD) for 4 days. ANNEXA™-A had 63 subjects treated with apix. AnXa (400 mg bolus; 400 mg bolus plus 4 mg/min x 2hr infusion) or placebo (3:1 randomization) was given on Day 4, 3 hrs after the last apix dose. ANNEXA™-R had 82 subjects treated with riva. AnXa (800 mg bolus; 800 mg bolus plus 8 mg/min x 2hr infusion) or placebo (2:1) was given on Day 4, 4 hrs after the last riva dose. Safety was followed through Day 43.

Results:
About 298 healthy subjects were enrolled in the studies. AnXa demonstrated rapid and sustained reversal of both direct and indirect fXa inhibitors as measured by correction of biomarkers. The ANNEXA™ studies confirmed findings from Phase 2, and met all primary (reversal of anti-fXa) and secondary endpoints (reduction of free inhibitor concentration and restoration of TG) with high statistical significance. AnXa was well-tolerated with no serious adverse events, thrombotic events, or antibodies to fX or fXa reported.

Conclusion:
AnXa treatment results in rapid and sustained reversal of anticoagulation of fXa inhibitors. A Phase 3b/4 confirmatory study (ANNEXA-4) in patients with acute major bleeds is ongoing.
Abstract 31: Incidence of Recurrence in Posterior Circulation Childhood Arterial Ischemic Stroke: A Prospective Cohort
Authors: Uohara Michael Y , Beslow Lauren A , Billinghurst Lori L , Jones Brianna , Licht Daniel J , Ichord Rebecca N
Published: July 2021

Introduction:
Childhood arterial ischemic stroke (CAIS) affects 1.6 per 100,000/year and recurs in up to 20% at 5 years. Arteriopathies are common, predict recurrence, and affect the carotid (anterior) and vertebrobasilar (posterior) circulations differently. Differences in recurrence between anterior and posterior circulation CAIS have not been evaluated.

Hypothesis:
Recurrence is higher for stroke involving the posterior circulation (PCAIS) than anterior circulation (ACAIS).

Methods:
We analyzed 107 CAIS cases (61 isolated ACAIS, 46 isolated PCAIS) from a single-center prospective consecutive cohort from 1/1/06-1/1/15, with median age 7.7 years (IQR=3.1-13.6) and 70% male. Incidence of recurrent stroke was assessed with Kaplan-Meier survival estimates. Cox proportional hazards models compared recurrence risk between PCAIS and ACAIS.

Results:
Median follow-up was 20.9 months (IQR 8.7-40.4). Recurrent stroke occurred in 9/46 PCAIS cases (19.6%; 8 males; 2 with multiple recurrences) and in 2/61 ACAIS cases (3.3%; 2 males). All PCAIS cases with recurrence were receiving antithrombotic therapy (aspirin or anticoagulant). Stroke risk factors in PCAIS with recurrence were: cervical dissection (4), sickle cell anemia (1), cardiac disease (2), multiple factors (2), thrombophilia (1), and unknown (1). For ACAIS, recurrence-free survival at 1 month, was 100%, and at 1 and 5 years was 96% (95% CI 85-99%). For PCAIS, recurrence-free survival at 1 month, 1 year, and 5 years was 88% (95% CI 75-95%), 81% (95% CI 66-90%), and 74% (95% CI 52-87%) [Figure]. The hazard ratio for recurrence in PCAIS compared to ACAIS was 6.4 (95% CI 1.4-29.8, p=0.017) in univariable analysis and 6.8 (95% CI 1.3-35.7, p=0.023) adjusting for sex, cardiac cause, and dissection.

Conclusions:
At 5 years, 26% of children with PCAIS in our cohort had recurrent stroke compared to only 4% of children with ACAIS. Children with PCAIS may benefit from closer monitoring and additional prevention strategies.
Abstract 34: Low SpO
2
and Lack of Heparin are Associated With Cardiac Catheterization-related Stroke in Children With Congenital Heart Disease
Authors: Parthasarathy Sujatha , Sinclair Adriane , Sandoval Juan-Pablo , Andrade Andrea , Surmava Ann-Marie , Benson Lee , deVeber Gabrielle
Published: July 2021

Introduction:
Stroke is an uncommon yet serious complication associated with cardiac catheterization in children with congenital heart disease. Our objective was to estimate the frequency and predictors of arterial ischemic stroke (AIS) in this specific setting.

Methods:
We performed a case-control study of children with congenital heart disease, who developed stroke in relation to cardiac catheterization performed at the Hospital for Sick Children between 1 January, 1992 and 1 January, 2014. Cases had new AIS (either symptomatic or silent) within 72 hours of cardiac catheterization and controls had cardiac catheterization but no new stroke within this time window. We estimated the frequency of AIS in children who underwent cardiac catheterization in this study period. Predictors of stroke that were tested include age, nature of intra-cardiac shunt, pre-procedural peripheral capillary oxygen saturation (SpO
2
), type of catheterization (diagnostic versus interventional), duration of procedure, right versus left heart protocol, procedural anticoagulation and major/minor complications. Pediatric Stroke Outcome Measure was used to assess the neurological outcome of cases.

Results:
Twenty eight children (mean age1.66years; 64% males) developed stroke among 19414 children who underwent cardiac catheterization during the study period. The frequency of cardiac catheterization related-stroke in children is 1.44/1000 cardiac catheterizations. Univariate analysis revealed that younger age (OR 1.22; 95% CI (1.02,1.45); p=0.030), low SpO
2
pre-catheterization (OR 1.08; 95% CI (1.03,1.12); p=0.004), lack of procedural anticoagulation with heparin (OR 3.57; 95% CI (1.04,11.76); p=0.044), and minor complications during catheterization (OR 7.15; 95% CI (1.51,33.79); p=0.013) were associated with stroke. Low SpO
2
pre-catheterization and lack of procedural

anticoagulation remained significant in multivariate analysis.

Conclusion:
The frequency of stroke after cardiac catheterization in children with congenital heart disease is 1.44/1000 cardiac catheterizations. Low SpO
2
pre-catheterization and lack of procedural anticoagulation appear to be associated with a higher risk of stroke.
Abstract 51: Peripheral Regulatory T cells and Th17 Cells Is Associated With Pathogenesis of Moyamoya Disease
Authors: Weng Leihua , Chen Xiang , Xu Yun
Published: July 2021

Background:
Despite unclear pathogenesis, previous studies have suggested immune responses may play a pivotal role in the process of Moyamoya disease (MMD), a rare cerebrovascular occlusive disorder. The objective of this study is aimed to explore the change of peripheral Treg/Th17 in MMDpatients and whether the change is associated with pathogenesis of MMD.

Methods:
In the present study, we collected 26 MMD patients diagnosed by angiography according to the diagnostic criteria of definitive MMD and recruited 32 healthy volunteers. To explore the balance of peripheral Treg/Th17 in MMD patients, lymphocytes in peripheral blood were harvested and flow cytometry was used to measure the percentage of Treg and Th17in CD4+ Tcells, respectively. Meanwhile, relevant cytokines in serum were measured to evaluate the function of Treg and Th17 cells.

Results:
According to Suzuki’s angiographic staging of moyamoya disease, patients were divided into subgroups of the preliminary-term, medium-term and late-term. Cerebral hemorrhage is thefirstsymptom of onset occuringin half of patients, followed bycerebral ischemia.Our data revealed that both the percentage of Treg and Th17 cells in peripheral blood lymphocytes was increased in MMD patients compared with volunteer group. Meanwhile, the levels of IL-6, IL-10,IL-12, IL-17, TNF-α, VEGF and TGF-β in serum were significantly increased in MMD patients. In this study, the level of HMGB-1, a middle-late period inflammation biomarker, in serum of MMD patients is obviously elevated compared with volunteers. However, the ratio of Treg/Th17 had no significant difference in MMD patients compared to healthy volunteers. Intriguingly, our data revealed that ratio of Treg/Th17 was significantly increased in late-term MMD patients compared with medium-term patients as evidenced by elevated percentage of Treg cells.. In addition, TGF-β level in later-term MMD patients was significantly higher than this in medium-term MMD patients. No difference was observed in the way of onset and gender between two groups.

Conclusion:
Enhanced peripheral Treg and Th17 in MMD patients suggested that there may be an immunological component in the pathogenesis of MMD. Peripheral Treg may be associated with pathological process of MMD.
Abstract 55: Selection and Outcomes of Multimodality Interventional Treatment for Unruptured Arteriovenous Malformations in a Single Institution
Authors: Maruyama Daisuke , Mori Hisae , Satow Tetsu , Kataoka Hiroharu , Sugata Sei , Hamano Eika , Orita Yoji , Eguchi Seiichiro , Takahashi Jun
Published: July 2021

Objective:
The present study aimed to evaluate the selection and outcomes of multimodal interventional treatment for unruptured brain arteriovenous malformations (AVMs) in A Randomised trial of Unruptured Brain Arteriovenous malformations (ARUBA)-eligible patients in a single institution.

Methods:
We retrospectively reviewed the data of 94 patients with unruptured and untreated AVMs, who had modified Rankin scale (mRS) scores of 0 or 1 at our institution between 2002 and 2014. The patients were divided into an intervention group and a conservative group, and the outcomes were compared. Similar to ARUBA, we defined the primary outcome as the composite endpoint of death or symptomatic stroke. The mRS was used to assess the functional outcome.

Results:
Of the 94 patients, 75 were included in the intervention group and 19 were included in the conservative group. Additionally, among the 94 patients, 58, 29, and 7 patients had Spetzler-Martin grade I/II, III, and IV/V AVMs, respectively. The number of male patients and the mean age of the patients were significantly lower in the intervention group than in the conservative group (58.6% vs. 84.2%, P=0.03 and 40.8±13.9 vs. 48.4±18.4 years, P=0.04, respectively). However, no significant difference in the proportion of patients with grade I/II AVMs was noted between the groups (65.3% vs. 47.3%). In the intervention and conservative groups, the mean follow-up periods were 59.2±41.6 and 72.8±39.2 months, respectively (P=0.20), and the primary outcome occurred in 9 (12.3%) and 3 (17.6%) patients, respectively (P=0.56). The proportion of patients with a mRS score ≥2 at last follow-up was not significantly different between the two groups (6.9% vs. 11.7%). In the intervention group, the incidence of death or stroke was lower and functional outcomes were better among patients with grade I/II AVMs than among patients with grade III AVMs (4.1% vs. 20%, P=0.003 and 2.0% vs. 15.7%, P=0.04, respectively).

Conclusion:
The present study found that for patients with unruptured AVMs, interventional treatment is not inferior to medical treatment alone. Multimodal interventional treatment is associated with good outcomes in patients with grade I/II AVMs. However, careful selection should be considered for patients with grade III AVMs.
Abstract 57: Main Results of the CTP to Predict Response to Recanalization in Ischemic Stroke Project (CRISP)
Authors: Lansberg Maarten G , Christensen Soren , Kemp Stephanie , Mlynash Michael , Mishra Nishant , Federau Christian , Tsai Jenny P , Kim Sun , Haussen Diogo C , Dehkharghani Seena , Devlin Thomas G , Yavagal Dileep R , Akhtar Naveed , Jovin Tudor , Nogueira Raul G , Bammer Roland , Straka Matus , Zaharchuk Gregory , Marks Michael P , Albers Gregory W
Published: July 2021

Background:
Recent acute stroke trials showed benefit from intra-arterial thrombectomy (IAT) up to 6 hrs. We aimed to assess CT Perfusion (CTP) for selection of patients for endovascular therapy up to 18 hrs.

Hypothesis:
CTP target mismatch profile (TMM) identifies patients likely to benefit from IAT.

Methods:
The CTP to predict Response to recanalization in Ischemic Stroke Project (CRISP) is an NIH funded multicenter cohort study of consecutive acute stroke patients scheduled to undergo IAT within 90 min after a baseline CTP. Volumes for the CTP ischemic core (rCBF<30%) and critically hypoperfused tissue (Tmax>6s) were computed with automated software (RAPID). Target Mismatch (TMM) was defined as a CBF core <70 mL, a
Tmax>6s – core
difference >15mL, a
Tmax>6s : core
ratio >1.8, and a Tmax>10s lesion <100 mL. Reperfusion was defined as >50% reduction in Tmax>6s lesion volume between baseline CTP and follow-up MRI (obtained <36 hrs after CTP), or TICI 2b/3 at completion of IAT if follow-up MRI was not performed/technically inadequate. Good functional outcome (GFO) was defined as mRS 0-2 on day 90.

Results:
Of the 201 patients enrolled, 6 had inadequate baseline CTP (3%), 3 did not undergo angiography, and 2 were lost to follow-up. Therefore, 190 patients were included; mean age 66 yrs, median NIHSS 16, median time from symptom onset to IAT 5.2 hrs (>6 hrs in 40%). Rate of reperfusion was 89% (87% TICI 2b/3) and 55% had GFO. In patients with TMM (n=131), reperfusion was associated with higher odds of GFO (66% vs 29%; OR=4.3; 95% CI 1.4-13). This association remained significant when adjusted for age and NIHSS (OR=8.4; 95% CI 2.5-28). In patients without TMM (n=51), the effect of reperfusion could not be assessed, since almost all patients (95%) reperfused. Independent of reperfusion status, patients with TMM had a higher rate of GFO (61%) than those without TMM (42%, p=0.02).

Conclusion:
In this multicenter study, a technically adequate baseline CTP was obtained in nearly all patients and almost half underwent IAT beyond 6 hrs. Patients with the TMM profile had a high rate of GFO (61%) and a robust association between reperfusion and good outcome. These results support the feasibility of a randomized trial of IAT in an extended window using the CTP-TMM profile for patient selection.
Abstract 63: Novel Imaging of Protein Integrity to Better Define Ischemic Injury After Stroke
Authors: Harston George , Tee Yee Kai , Blockley Nicholas , Msayib Yunus , Sheerin Fintan , Mathieson Philip , Reckless Ian , Shah Ku , Schulz Ursula , Payne Stephen , Jezzard Peter , Chappell Michael , Kennedy James
Published: July 2021

Introduction:
Ischemic injury on MRI is defined acutely by measuring the diffusion of water alone. Chemical exchange saturation transfer imaging (CEST) allows measurement of intracellular pH, and changes in protein structure and mobility using Nuclear Overhauser Enhancement (NOE). When identifying treatment targets, changes to protein integrity have the potential to complement diffusion-weighted imaging (DWI) in distinguishing irreversible from reversible intracellular processes that are amenable to therapeutic intervention.

Methods:
Patients with non-lacunar ischemic stroke underwent serial MRI over 1 month. The imaging protocol included single slice CEST imaging. NOE was quantified using a 3-pool exchange model relative to the contralateral hemisphere (rNOE*). DWI, ASL perfusion imaging, T1-weighted and FLAIR imaging were used to define the tissue outcome: ischemic core, infarct growth, and oligemic tissue that survived. Infarct growth was classified as early or late (before or after 24 hours). Images and masks were registered to CEST native image space for voxelwise and patient-level serial analyses.

Results:
30 patients were included in the analysis. Within 6 hours rNOE* in early infarct growth was significantly lower than ischemic core and late infarct growth (p<0.001 and p<0.001, see Figure). In patient-level analyses, rNOE* dropped over the initial 24 hours in the ischemic core and early infarct growth regions, but not in regions of late infarct growth or oligemia.

Conclusion:
rNOE* showed a discrete temporal profile in tissue that infarcted by 24 hours in contrast to that which survived or infarcted later. This is additive information to that provided by routine acute stroke MRI at presentation, and demonstrates that the imaging of intracellular protein structure and mobility may have a role alongside DWI in helping to predict tissue fate. Further work is required to understand the potential of NOE as a modifiable imaging biomarker.
Abstract 82: Prehospital Enrollment Reduces Race-ethnic Disparities in Enrollment in Acute Stroke Treatment Trials
Authors: Frischmann Lindsey , Sanossian Nerses , Starkman Sidney , Ali Latisha , Kim-Tenser May , Liebeskind David , Restrepo Lucas , Valdes-Sueiras Miguel , Chatfield Fiona , Stratton Samuel , Eckstein Marc , Pratt Frank , Conwit Robin , Saver, for the FAST-MAG Trialists Jeffrey
Published: July 2021

Introduction:
Studies have shown race-ethnic disparities in clinical trial enrollment, including in acute stroke, preventing neurotherapeutics from being well tested in all relevant populations, including commonly underrepresented groups. An important source of disparities is variable clinical care and research recruitment processes at individual hospitals. A promising approach to mitigate this variability is for a central neurologist panel, via prehospital telemedicine, to perform enrollment of all qualifying patients being transported by all ambulances throughout a geographic region.

Methods:
We analyzed all patients enrolled in the NIH FAST-MAG prehospital trial, which recruited in 315 ambulances traveling to 60 hospitals throughout Los Angeles and Orange Counties between Jan 2005 and Dec 2012. Over 98% of patients were enrolled using explicit informed consent, with the patient or on-scene legally authorized representative speaking to on-call central enrolling English and Spanish-speaking neurologists.

Results:
Among the 1700 enrolled patients, race-ethnic distribution was: White, non-Hispanic 54.3%, Hispanic White 23.6%, Black 12.8%, Asian 8.2%, and Other 1.0%. The different race-ethnic groups showed substantial differences in stroke mechanisms, vascular risk factor, age, and additional characteristics that might affect treatment response. In the Los Angeles County region, compared with the race-ethnic population of the County (total 10.1 million persons), the trial population had greater proportion of Black patients (13.5% vs 9.2%, p < 0.0001); and substantial representations of Hispanic and Asian patients, though not equal to County levels (Hisp 24.2% vs 34.2%, Asian 8.1% vs 14.6%). Compared with concurrent, national NIH trials enrolling acute stroke patients after hospital arrival, the FAST-MAG population had substantially higher representation of Hispanic and Asian patients.

Conclusion:
Trial enrollment by a central neurologist accessing acute stroke patients in all ambulances throughout a wide geographic region is associated with substantial reduction in race-ethnic disparities.