bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 49: Withdrawal of Care in the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) Study
Authors: Sheth Kevin N , Martini Sharyl R , Tirschwell David L , Becker Kyra J , Worrall Bradford B , James Michael L , Sung Gene , Brown Mark , Langefeld Carl , Osborne Jennifer , Moomaw Charles J , Woo Daniel ,   "ERICH Investigators"
Published: July 2021

Introduction:
Withdrawal of care (WOC) during hospitalization is the most common cause of death after intracerebral hemorrhage (ICH). Prior work suggests minority groups are less likely to choose WOC. Our goal was to evaluate for differences in rates of WOC among racial/ethnic groups from the ERICH cohort.

Methods:
ERICH is an ongoing multicenter study of genetic and environmental risk factors for spontaneous ICH. We analyzed data from the first 725 individuals. Baseline characteristics,do not resuscitate (DNR) status, intensive care procedures, and WOC were prospectively recorded. A central core analyzed all imaging. We compared characteristics among patients with and without eventual WOC and by race/ethnicity. Logistic regression was used to identify variables independently associated with WOC and associations are presented as the odds ratio (95% confidence interval).

Results:
9.9% (72/725) of patients underwent WOC. After controlling for age, ICH volume, initial Glasgow Coma Scale (GCS) score, and presence of intraventricular hemorrhage (IVH), there were no significant differences in WOC between non-Hispanic white, non-Hispanic black (OR 1.82; CI 0.78-4.25), and Hispanic (OR 2.16; CI 0.93-5.00) patients. There were also no differences in rates of DNR/DNI status across racial/ethnic groups. In multivariate analysis, patients who underwent WOC had larger ICH volume (1.75; 1.13-2.73); were older (1.43; 1.27-1.61), more likely to have IVH (3.21; 1.53-6.73), and had lower GCS (2.41; 1.63-3.56). While patients who underwent WOC were more likely to have a DNR/DNI order (12.7; 4.69-34.7), intubated patients were more likely to undergo WOC (4.09; 1.08-9.25), even after adjusting for ICH severity.

Conclusions:
In our cohort, we were able to model ICH severity and factors predictive of WOC. There were not significant racial/ethnic differences in WOC rates. Intubated patients are more likely to undergo care limitations, independent of ICH severity.
Abstract 50: Impact of Acute Cocaine use on Aneurysmal Subarachnoid Hemorrhage
Authors: Naval Neeraj S , Chang Tiffany , Kowalski Robert , Caserta Filissa , Carhuapoma Juan R , Tamargo Rafael J
Published: July 2021

Objective:
To analyze the impact of acute cocaine use on presentation and outcomes following aneurysmal subarachnoid hemorrhage (aSAH).

Background:
Acute cocaine use has been temporally associated with aSAH but there are varying reports describing how it affects patient presentation, complications and outcomes.

Design/Methods:
Data of aSAH patients admitted to our institution between 1991-2009 were reviewed to determine which patients had used cocaine within 72 hours of aSAH based on positive urine toxicology or a history of cocaine use within 72 hours (C). These patients were then compared with aSAH patients without recent cocaine exposure (NC) in relation to their clinical and radiological presentations, complications such as DIND (delayed ischemic neurological deficit defined by vasospasm mediated cerebral infarcts) and outcomes defined by hospital mortality.

Results:
Data of 1134 patients were reviewed; aSAH in142 patients (12.5%) was associated with cocaine use. Cocaine users were more likely to be younger (mean age: C:49, NC:53, p0.05), admission GCS 0.05), associated IVH (C:56%, NC:51%, p>0.05) or hydrocephalus on admission CT (C:49%; NC:52%, p> 0.05). Cocaine users were more likely to have vasospasm related infarcts when compared to non-cocaine users (C:22%; NC:16%, p<0.05) but after correcting for other factors impacting vasospasm, cocaine use was not independently associated with DIND. Cocaine users had higher rates of aneurysm re-rupture (C:7.7%, NC:2.7%, p0.004). Cocaine users were less likely to survive hospitalization compared to non-users following univariate analysis (Mortality: C:26%, NC:17%, p< 0.05); the adjusted odds of hospital mortality were 2.9 times higher among cocaine users following multivariate analysis (p<0.001).

Conclusions:
Acute cocaine use was associated with a higher risk of aneurysm re-rupture and hospital mortality following aSAH. The various mechanisms for the nearly threefold increased odds of death associated with cocaine use warrants further investigation.
Abstract 57: Impact of Collaterals on Successful Revascularization in SWIFT
Authors: Liebeskind David S , Jahan Reza , Nogueira Raul G , Zaidat Osama O , Saver Jeffrey L ,   for the SWIFT Investigators
Published: July 2021

Background:
Collaterals are a potential determinant of recanalization and tissue fate after endovascular therapy. We analyzed angiographic collateral grade to ascertain impact on the novel endpoint of successful revascularization without symptomatic hemorrhage, a “metric of unqualified success” in the SWIFT trial.

Methods:
Collateral grade was independently assessed with the ASITN/SIR scale on baseline angiography, blind to core lab and other data. Univariate and multivariate regression analyses detailed the relationship of collateral grade with clinical, laboratory and imaging parameters.

Results:
Angiographic data on collaterals were available in 119/144 subjects (mean age 67±12 years, 52% female, median NIHSS 18 (range 8-28)). Collateral grade was 0-1 (none or marginal) in 32 (27%), 2 (partial) in 48 (40%), 3 (complete but delayed) in 35 (29%), and 4 (complete and early) in 4 (3%). Collateral vigor was unrelated to age or gender. Elevated baseline blood glucose was noted with worse collaterals (0-1 - mean 154±65 mg/dL; 2 - 140±75; 3 - 124±33; 4 - 99±10; p=0.013). Elevated baseline systolic BP was also associated with worse collaterals (0-1 - mean 149±24 mm Hg; 2 - 137±23; 3 - 137±24; 4 - 138±10; p=0.039). Multivariate predictors of partial or worse collaterals included absence of prior hypertension (OR 4.049, p=0.012), smoking history (OR 3.822, p=0.013) and higher blood glucose (OR 1.017, p=0.022). Collaterals were strongly related to ASPECTS at baseline (0-1 - median 8 (3-10); 2 - 9 (5-10); 3 - 9 (7-10); 4 - 9 (8-10); p<0.001) and 24 hours (0-1 - median 1 (0-5); 2 - 6 (0-10); 3 - 8 (0-10); 4 - 8 (4-8); p<0.001). Partial or worse collaterals were associated with symptomatic hemorrhage (p=0.075). Better collaterals were linked with TICI 2b/3 reperfusion (p=0.019), better median NIHSS at Day 7/discharge (p<0.001) and better Day 90 mRS (p<0.001). Better collaterals were noted in patients with successful revascularization without symptomatic hemorrhage, mean 2.3 (95% CI 2.1-2.5) vs. 1.9 (95% CI 1.7-2.2), p=0.021.

Conclusions:
Collateral rigor was associated with lower glucose, lower BP, and smaller baseline infarcts in SWIFT. Better collaterals predicted greater likelihood of successful revascularization without hemorrhage and better clinical outcomes.
Abstract 71: Diffusion Imaging Of Cerebral Diaschisis In Neonatal Arterial Ischemic Stroke
Authors: Roe Jamie , Rajapakse Thilinie , deVeber Gabrielle , Wei Xing-Chang , Kirton Adam
Published: July 2021

Objectives:
Diffusion MRI (DWI) corticospinal changes remote from neonatal arterial ischemic stroke (NAIS) correlate with physiology and outcome. We hypothesized that DWI can quantify acute alterations in other remote connected structures (“diaschisis”).

Methods:
Children from Calgary and SickKids Stroke Programs were studied with unilateral NAIS, DWI <10 days from term birth and follow up (Pediatric Stroke Outcome Measure). Image J thresholding quantified DWI diaschisis in connected structures according to validated methods (figure). Subsequent atrophy was measured volumetrically on MRI >12 mos (OsiriX). Primary outcome was total diaschisis signal (TD) which was then corrected for stroke volume (% brain infarcted). Scores were regionalized by cerebral structure. Associations with MRI timing and outcome were sought (nonparametric statistics). Method reliability was confirmed.

Results:
Twenty neonates met criteria (55% male). Median age at MRI was 72 hours. Diaschisis was common, observed in 16 (80%). Thalamic diaschisis was most common (100%), followed by callosal (50%) and striatal (15%). Perilesional diaschisis estimates were highly variable. Structures manifesting acute diaschisis atrophied on follow-up imaging. TD correlated with stroke volume (p=0.001). TD correlation to poor outcome (p=0.01) did not persist with correction for infarct volume. TD did not correlate with age at MRI. Method reliability was good (ρ >0.80).

Conclusion:
DWI diaschisis is common and measureable in NAIS. As a possible early imaging marker of network injury, larger studies are required to determine clinical relevance.
Abstract 73: Neurophysiology Of Ipsilateral Corticomotor Projections After Perinatal Stroke
Authors: Damji Omar , Kotsovsky Oleg , Chen Robert , Kirton Adam
Published: July 2021

Objectives:
Perinatal stroke (PS) causes most hemiparetic cerebral palsy. Persistence of ipsilateral corticomotor connections from unlesioned hemisphere to affected hand are established. Their neurophysiology is not understood and developmental plasticity models suggest they are a therapeutic target. We hypothesized that ipsi projections have distinct neurophysiology that correlates with motor disability.

Methods:
Children 6-18 years with PS (arterial or PVI) and hemiparesis were recruited (Alberta Perinatal Stroke Project). Transcranial magnetic stimulation (TMS) protocols were applied to the non-lesioned M1. Outcomes included rest motor thresholds and bilateral stimulus response curves (SRC). Paired pulse TMS at 2 and 10 ms (90% active motor threshold conditioning) explored short-latency intracortical inhibition (SICI) and intracortical facilitation (ICF). Ipsi motor evoked potentials (MEPs) were quantified (≥0.05mV at 120% RMT in ≥5/20 trials). Motor outcomes were Assisting Hand (AHA) and Melbourne (MA) assessments. Ipsi physiology was compared to contra and motor outcome (t-test, (rm)ANOVA). Safety and tolerability was assessed.

Results:
Of 35 children (20 male; 55% arterial, 45% PVI), 14 (40%) met ipsi criteria. Presence of ipsi projections correlated with motor disability (AHA, p=0.03, MA p=0.10) but not stroke type. Ipsi intensity correlated with AHA (r=-0.58; p=0.004) and MA (r=-0.45; p=0.013). Ipsi SRC slope was lower than contra (p=0.01). SICI (contra -38.5%, ipsi -30.7%; p<0.05) and ICF (contra +15.4%, ipsi +23.1%; p<0.05) were present and differed between sides (p= 0.004). Procedures were well tolerated.

Conclusions:
Cortical physiology of ipsilateral projections can be measured in children with PS. Differences between ipsi and contralateral physiology may be relevant central therapeutic targets.
Abstract 8: Early MRI in TIA And Minor Stroke: Do it or Lose it
Authors: Moreau Francois , Modi Jayesh , Almekhlafi Mohamed , Bal Simer , Goyal Mayank , Hill Michael D , Coutts Shelagh B
Published: July 2021

Background:
MRI is not always completed early after TIA or minor stroke and this may affect its utility. We measured the impact of scanning an individual patient late versus early in the investigation of TIA and minor stroke.

Methods:
263 patients with a TIA or minor stroke (NIHSS <4) from the CATCH study were included in this analysis. To be included in this sub study patients needed to have had a baseline MRI completed within 24 hours of symptom onset and a follow-up MRI at 90 days. All MRI images were acquired on a 3.0 Tesla GE scanner. Baseline and 90 day scans were assessed independently for the presence of any stroke lesion. The presence and pattern of any stroke lesion was then compared at the two time points. Lesion patterns were classified as: no definite stroke, single territory cortical stroke(s), multiple territory cortical strokes, single territory subcortical only stroke(s), multiple territory subcortical only strokes, and multiple strokes in one territory including a cortical stroke

Results:
Stroke of any age, in any location was more common on the baseline MRI versus 90day MRI (68% versus 58%, p=0.005). A substantial proportion of the negative scans at 90 days had a clearly identifiable stroke on the baseline scan (35/115: 30%) that was missed on the 90day scan. All of these lesions were acute or subacute DWI lesions on the baseline scan showing non-specific white matter hyperintensity or no abnormality on the 90day scan. Among 104 patients with a stroke lesion on the 90 day MRI considered as a cause for the presenting symptoms, this lesion was the correct lesion in only 78 (53%) patients. 89 (34%) patients had a different lesion pattern on the baseline scan versus the 90day scan. The main difference observed was that patients with multiple DWI lesions on the baseline scan were either seen as a single or no lesions on the 90day MRI.

Conclusion:
Completing an MRI in a delayed fashion after TIA or minor stroke reduces the diagnostic yield of the imaging. Not only does it reduce lesion detection, but also the pattern of the lesions is missed. Conclusions regarding the original event may be false if based only on a delayed MRI. If minor stroke and TIA patients are going to be scanned with MRI this should be completed early after symptom onset.
Abstract 87: Neuroimaging, Not Clinical Assessment Predicts Post-Stroke Motor Outcome in Severely Impaired Stroke Patients
Authors: Feng Wuwei , Wang Jing , Doughty Christopher , Holmstedt Christine , Schlaug Gottfried
Published: July 2021

Background:
Initial motor impairment by clinical assessment and neuroimaging measures of corticospinal tract injury have been shown to predict 3-month motor outcome in mild-to-moderately impaired stroke patients. Clinical assessment alone is good to predict outcome of more severely impaired patients. This study aims to compare clinical assessment with neuroimaging in severely impaired patients.

Methods:
This study followed 27 first-ever ischemic stroke patients who presented with severe motor impairment at baseline( between 2- 5 days after stroke) which is defined as Upper Extremity Fugl-Meyer (UE-FM) Scale was <=5. Patients will be assessed at 3 months (90 ±14 days) again with UE_FM. A weighted CST lesion load (wCST-LL) was calculated by overlaying each patient’s lesion map on MRI with a probabilistic CST constructed from healthy subjects. A regression analysis was applied to assess the predictive value of wCST-LL and initial motor impairment.

Results:
Initial motor impairment has no predictive value (p=0.25, R
2
=0.05) while wCST-LL has a strong prediction (p=0.002, R
2
=0.31) for post-stroke motor outcome in this severely impaired stroke group. If wCST is more than 7 cc, no patient recovers more than 20 on UE_FM at 3 months.

Conclusion:
Compared with clinical assessment, a neuroimaging measure of CST injury excels in post-stroke motor outcome prediction in a severely impaired subgroup.
Abstract 91: Remodeling After Stroke: The Recovering Brain Is Vulnerable To Lipoxygenase-dependent Semaphorin Signaling
Authors: Pekcec Anton , Yigitkanli Kazim , Jung Joo Eun , Karatas Hulya , Lo Eng H , Van Leyen Klaus
Published: July 2021

Background and Purpose—
Recovery from stroke is limited in part by an inhibitory environment in the post-ischemic brain, but factors preventing successful remodeling are not well known. We sought to investigate if signaling from the axon guidance molecule semaphorin 3A (Sema3A) via eicosanoid second messengers can contribute to this inhibitory environment, and if blocking the Sema3A pathway can provide a benefit following experimental stroke.

Methods—
Cultured cortical neurons from mice were treated with recombinant Sema3A, or with the eicosanoids 12-HETE and 12-HPETE. Neurons from ALOX15 knockout mice, and a human brain endothelial cell line, were treated similarly. The filament model of MCAO was used to induce experimental stroke in mice, in some of which Sema3A was injected stereotactically into the striatum. The 12/15-LOX inhibitor LOXBlock-1 was injected intraperitoneally one week after MCAO.

Results—
Expression levels of 12/15-lipoxygenase (12/15-LOX) were increased within two hours after exposure of primary neurons to 90nM recombinant Sema3A. Either Sema3A, or the 12/15-lipoxygenase (12/15-LOX) metabolites 12-HETE and 12-HPETE at 300nM, blocked axon extension in neurons compared to solvent controls, and decreased tube formation in endothelial cells. The Sema3A effect was reversed by inhibiting 12/15-LOX, and neurons derived from 12/15-LOX knockout mice were insensitive to Sema3A. Following middle cerebral artery occlusion to induce stroke in mice, immunohistochemistry showed both Sema3A and 12/15-LOX are increased in the cortex up to two weeks. To determine if a Sema3A-dependent damage pathway is activated following ischemia, we injected recombinant Sema3A into the striatum. Sema3A alone did not cause injury in normal brains. But when injected into post-ischemic brains, Sema3A increased cortical damage by 79%, and again this effect was reversed by 12/15-LOX inhibition. Administration of the 12/15-LOX inhibitor LOXBlock-1 7 days after transient MCAO increased vascularization in the infarcted and peri-infarct area one week later.

Conclusions—
Our findings suggest that blocking the semaphorin pathway may provide a novel therapeutic strategy to improve stroke recovery.
Abstract 94: Protection Against Blood-Brain Barrier Disruption in Focal Cerebral Ischemia by Docosahexaenoic Acid
Authors: Hong Sung-Ha , Khoutorova Larissa , Anzola Daniela , Wu Qiang , Jun Bokkyoo , Bazan Nicolas G , Belayev Ludmila
Published: July 2021

INTRODUCTION:
Docosahexaenoic acid (DHA; 22:6n-3) is an omega-3 essential fatty acid family member and the precursor of neuroprotectin D1, a lipid mediator which downregulates apoptosis and promotes cell survival. Recently, we have shown that DHA therapy improves functional and histological outcomes following experimental stroke. We examined the effect of DHA on blood-brain barrier (BBB) integrity after middle cerebral artery occlusion (MCAo) in rats. Damage to the BBB was judged by extravasation of Evans Blue (EB) dye.

METHODS:
Male SD rats were anesthetized with isoflurane and subjected to 2 h of MCAo by retrograde insertion of an intraluminal suture. DHA (5 mg/kg) or vehicle (saline) was administered IV at 3 h after the onset of MCAo and animals were sacrificed at 6, 24 or 72 h. Behavioral tests were performed at 5, 24, 48 or 72 h. EB (2% in saline, 4 ml/kg) was administered IV either at 5, 23 or 71 h after onset of MCAo. Fluorometric quantitation of EB was performed 1 h later in six brain regions.

RESULTS:
Physiological variables were stable and showed no significant differences between groups. In the 6 h series (n=9 per group), DHA decreased EB extravasation in the posterior ischemic hemisphere compared to saline (9.2±1.1 vs. 14.3± 1.5, respectively). In the 24 h series (n=8-9 per group), DHA improved behavioral scores on day 1 and decreased EB extravasation in the posterior ischemic hemisphere (4.9±0.41 vs. 8.5±1.0) and cortical area (3.0±0.4 vs. 8.6± 2.0, respectively) compared to saline. In the 72 h series (n=12 per group), DHA improved behavioral scores on days 1, 2 and 3, and decreased EB extravasation in the anterior (6.1±0.8 vs. 9.6±0.9), posterior (5.6±0.7 vs. 9.1±1.2, respectively) ischemic hemispheres compared to saline. In addition, EB extravasation was decreased by DHA in the cortical area (6.2±1.0 vs. 10.1±1.1) and total hemisphere (11.7±1.3 vs. 18.7±1.9, respectively) compared to vehicle.

CONCLUSION:
These data have demonstrated that DHA is an effective neuroprotective drug, diminishing BBB damage in a model of severe focal ischemia. Thus, it is reasonable to hypothesize that DHA may have potential use in treating focal ischemic stroke in the clinical setting. This study was supported by NIH, NINDS grant R01 NS065786 (LB) and R01 NS046741 (NGB).
Abstract 96: Ischemic Postconditioning Did Not Attenuate Acute Infarction But Improved Long-term Outcomes By Promoting mTOR Activity In Nude rats
Authors: Xie Rong , Wang Peng , Ji Xunming , Zhao Heng
Published: July 2021

Introduction:
Ischemic postconditioning provides protective effects against focal ischemia and improves neurological deficits. Recent studies have shown that T cells play important roles in stroke. In this study, we investigated whether postconditioning protects against stroke in nude rats with T-cell deficiency, and examined the potential role of mTOR pathway in the protective effects of postconditioning.

Methods:
Focal ischemia was induced by 30min of transient bilateral CCA occlusion and permanent distal MCA occlusion in nude rats with T-cell deficiency (RNU rats, Charles River). Ischemic postconditioning was conducted immediately after reperfusion by 3 cycles of 30 sec reperfusion and 10 sec occlusion of the bilateral CCAs. Rapamycin, an mTOR inhibitor, was injected into
the
left lateral ventricle 1h before stroke. For the behavior test, home cage, vibrissa-elicited limb use and postural reflex tests were performed until 30d after stroke. Peri-infarct and ischemic core tissues were collected 1, 5, 9 and 24h after stroke for Western blotting. Protein levels of p-mTOR, S6K,
4EBP
-1, Akt and its isoforms (Akt1-3) were also measured.

Results:
Different from wild type rats, the cortical infarction induced by stroke was not significantly reduced by postconditioning in nude rats when measured 2d post-stroke (27.1±4.3% in control ischemia vs 23.7±4.2% in postconditioning, n=6). Despite the unaltered infarct size, Western blot showed that postconditioning significantly increased the protein levels of p-Akt, Akt isoforms, p-mTOR, p-S6K and p-4EBP1, both in the peri-infarct area and core 24h after stroke (p<0.05). In addition, postconditioning improved neurological function when measured 30d after stroke (n=6, p<0.05), and reduced brain damage size from 10.2±1.4% to 4.9±1.6% (n=6, p<0.05). The mTOR inhibitor, rapamycin, significantly attenuated p-mTOR and p-S6K levels both in the peri-infart area and core at 1, 5, 9 and 24h after stroke (p<0.05), and abolished the long-term protective effects of postconditioning.

Conclusions:
Ischemic postconditioning did not inhibit acute infarction but provided long-term protection by enhancing Akt and mTOR activity in the acute phase after stroke in nude rats.
Abstract 97: Intra-Arterial Cell Transplantation Provides Timing-Dependent Cell Distribution and Functional Recovery After Stroke
Authors: Ishizaka Shunsuke , Horie Nobutaka , Fukuda Yutaka , Satoh Katsuya , Nishida Noriyuki , Nagata Izumi
Published: July 2021

Background and Purpose—
Intra-arterial cell transplantation offers a novel therapeutic strategy for stroke; however, it remains unclear how the timing of cell administration affects cell distribution, brain repair processes and functional recovery. Here, we investigate the hypothesis that the timing of cell transplantation changes the behavior of the cell graft and the host environment in a way that affects functional recovery.

Methods—
Rats received human mesenchymal stem cells (hMSCs) via the internal carotid artery at 1, 4 or 7 days (D1, D4 or D7) after middle cerebral artery occlusion and reperfusion. Animals were sacrificed at various time points to assess cell distribution in correlation with the host cerebral hemodynamics, serum levels of matrix metallopeptidase-9 (MMP-9), infiltration of activated microglia, expression of brain derived neurotrophic factor (BDNF), angiogenesis, presence of reactive astrocytes, and neurological recovery.

Results—
hMSCs were widely distributed both in the periinfarct and core in D1, and dominantly in the periinfarct in D4, in parallel with the cerebral hemodynamic change. Very few cells were observed in D7. Only in D1 group, the serum level of MMP-9 is significantly lower than that in control group at 72 hours after cell transplantation. At day 7 post-stroke, activation of microglia was significantly suppressed both in the periinfarct and core in D1, and only in the periinfarct in D4. At day 21 post-stroke, BDNF was widely distributed throughout the periinfarct in D1 and D4, and angiogenesis was enhanced. Motor function improved earlier in D1 and later in D4, but only D1 exhibited reduced atrophy.

Conclusions—
Our results indicate that intra-arterial cell transplantation provides timing-dependent cell distribution and post-stroke functional recovery via a combination of two mechanisms: neuroprotection and neurorestoration.
Abstract 99: Time to Treatment with Intravenous Tissue Plasminogen Activator and Outcome from Acute Ischemic Stroke in the National US GWTG-Stroke Population
Authors: Saver Jeffrey L , Fonarow Gregg C , Smith Eric E , Reeves Mathew J , Grau-Sepulveda Maria V , Pan Wenqin , Olson DaiWai , Hernandez Adrian F , Peterson Eric D , Schwamm Lee H
Published: July 2021

Background:
Randomized clinical trials have shown that the benefit of intravenous (IV) tissue-type plasminogen activator (tPA) in acute ischemic stroke is time dependent. However, the generalizability of clinical trial findings to routine practice is uncertain; and modest sample sizes have limited characterization by trial data of the degree to which onset to treatment (OTT) time influences outcome from thrombolytic stroke therapy.

Methods:
We analyzed data from 58,353 acute ischemic stroke patients treated with tPA within 4.5 hours of symptom onset in 1395 hospitals participating in the Get With the Guidelines-Stroke Program from April 2003, to March 2012. Main outcome measures were 1) independent ambulation at discharge, 2) discharge to home, 3) in hospital mortality, and 4) symptomatic intracerebral hemorrhage. Univariate and multivariate stepwise logistic regression modeling was employed to evaluate the independent impact of OTT time on outcome.

Results:
Among the 58,353 tPA-treated patients, median age was 72, 50.3% were female, median OTT was 144 minutes (IQR=115-170), and 9.3% (5404) had OTT 0- 90 minutes, 77.2% (45,029) had OTT 91-180 minutes, and 13.6% (7920) had OTT 181-270 minutes. Pretreatment NIHSS, documented in 87.7% of patients, was median 11 (IQR 6-17). Multivariate analysis of NIHSS documented cases, showed shorter OTT time was associated with increased odds of independent ambulation at discharge and discharge to home, and reduced odds of in-hospital mortality and symptomatic intracerebral hemorrhage (Table 1).

Conclusions:
In national US clinical practice, earlier ischemic stroke treatment with IV tPA is associated with more frequent independent ambulation at discharge and discharge to home, and reduced SICH and mortality. These findings support intensive efforts to accelerate patient presentation and treatment initiation, such as Target Stroke, to maximize benefit of thrombolytic therapy.
Abstract NS14: Independent Speech and Language Practice with Aphasia Computer Software is an Acceptable Alternative to Face to Face Therapy in the Long Term Post Stroke
Authors: Palmer Rebecca , Paterson Gail , Delaney Audrey , Hughes Helen , Enderby Pam
Published: July 2021

Background:
Speech and language therapy (SLT) for aphasia can be difficult to access in the later stages of stroke recovery, despite evidence of continued improvement with sufficient therapeutic intensity. Computerized aphasia therapy has been reported to be useful for independent language practice, providing new opportunities for continued rehabilitation. The success of this option depends on its acceptability to patients and carers. The purpose of this study was to investigate factors that affect the acceptability of computerized aphasia therapy.

Methods:
A qualitative study was carried out alongside a pilot randomized controlled trial of computer aphasia therapy versus usual care for people more than 6 months post stroke. A SLT tailored computer exercises to individual needs. Participants practised 3 times a week for 5 months at home with monthly volunteer support. Semi structured interviews were conducted with 14 participants who received the intervention and 10 carers. Questions from a topic guide were presented and answered using picture, gesture, and written support. Interviews were audio recorded, transcribed verbatim and analysed thematically. Three research SLTs identified and cross checked themes and subthemes emerging from the data.

Results:
Benefits and disadvantages, need for help/support and comparisons with face to face therapy were key themes. The independence, flexibility, and repetition afforded by the computer was viewed as beneficial and the personalised exercises motivated participants to practise. Participants and carers perceived improvements in word finding and confidence talking. Computer practice could cause fatigue and interference with other commitments. Four participants with severe aphasia did not perceive any improvement. Support from carers/volunteers for motivation and technical assistance was seen as important. Participants generally preferred face to face therapy, however, using a computer for independent language practice was viewed as an acceptable alternative.

Conclusions:
Independent computerized aphasia therapy is acceptable to stroke survivors. Acceptability can be maximised by personalised exercises, access to support and consideration of aphasia severity, fatigue and life style.
Abstract NS7: The Texas Awareness Puppet Experience Leads to Improved Public Awareness of Stroke Symptoms and Response
Authors: SHARKEY SONYA M
Published: July 2021

Background and Purpose:
Stroke treatment rates have been hindered by under recognition of stroke symptoms, delayed presentation and lack of utilization of Emergency Medical Services (EMS). The community is the first link in the chain of survival in Brain Attack. With an increasing trend of multi-generational homes in Texas, education of children on stroke symptoms and the importance of calling 9-1-1 is a prime opportunity for increasing community awareness. The Texas Awareness Puppet Experience (TAPE) is a pilot program seeking to increase the permanence of stroke community education through the use of a multisensory puppet experience. The purpose of this pilot study was to determine the efficacy of the TAPE program in improving community awareness of stroke across a variety of age groups.

Methods:
TAPE was guided by Piaget’s Cognitive Development Theory in an effort to educate all age groups. Audiences watch a brief eight minute puppet show on stroke awareness that incorporates local EMS response with a paramedic arriving to the scene. The experience concludes with a hands-on activity of puppet-making. A pre-survey and post-survey was used to assess cognitive improvement related to stroke location, symptoms, and activation of EMS. The survey consisted of one demographic question (age) and three stroke questions with graphics. Chi-square was used to assess for statistical significance in stroke location and symptoms while Fisher’s Exact was used for activation of EMS.

Results:
The post-survey showed statistically significant improvement in all three stroke questions. When comparing the pre-surveys (n=97) with the post-surveys (n=96), the greatest improvement occurred in identification of stroke as occurring in the brain (59.8% pre-survey vs. 91.7% post-survey, p<0.001). The correct identification of stroke symptoms improved from 73.2% to 96.7% (p<0.001) while the need to notify EMS increased from 90.7% to 100% (p=0.003).

Conclusions:
The Texas Awareness Puppet Experience (TAPE) proved to be a beneficial tool when educating the community on stroke awareness. TAPE is effective in educating all age groups on the location of stroke, symptoms, and the need for immediate activation of EMS.
Abstract TMP20: Extraischemic Hematomas Following Intravenous rt-PA For Acute Ischemic Stroke
Authors: Osaki Masato , Koga Masatoshi , Fukuda Mayumi , shigehatake Yuya , Nagatsuka Kazuyuki , Minematsu Kazuo , Toyoda Kazunori
Published: July 2021

Background and purpose:
Extraischemic hematoma (EIH) is defined as hemorrhage that appears in regions of the brain without visible ischemic damage. The frequency, clinical features, disease-related factors, and prognosis of patients with EIH after IV recombinant tissue-type plasminogen activator (rt-PA) are not well known. We aimed to elucidate EIH and associated factors after IV rt-PA for acute ischemic stroke.

Methods:
We studied consecutive stroke patients who received IV rt-PA from 2005 through 2011. EIH was defined as any extra-ischemic hemorrhages identified on the follow-up CT within the initial 36 h after rt-PA.

Results:
Of the total 266 patients (177 men, 73±13 years old) studied, EIH was identified in 11 (4%, 5 men, 77±7 yo, 1 multiple EIH); 8 patients in the parenchyma (5 subcortex, 1 thalamus, 1 corona radiate, 1 cerebellum), 2 in the intraventricule, 1 in the subdural space, and 1 in the subarachnoidal space. As compared with 47 patients with hemorrhagic transformation (HT) from the index infarct (30 men, 73±10 yo) and 208 with “no hemorrhage” (NH, 142 men, 73±14 yo), Fazekas grade of periventricular hyperintensity (PVH) was higher [median 2 in EIH, 1 in HT, 1 in NH; P<0.001), DWI-ASPECTS was lower [7, 7.5, 9; P<0.001), and reduced eGFR (<60 ml/min/1.73 m2) was more common in patients with EIH (82%, 32%, 38%; P=0.007). On multivariate analysis, higher grade of PVH (OR 5.06, 95%CI 1.92-16.09 per 1 point; P<0.001) and reduced eGFR (OR 6.94, 95%CI 1.40-54.69; P=0.02) were associated with EIH. Percentages of the mRS 5-6 at 3 months were 46% in EIH, 36% in HT, and 16% in NH (P=0.001). EIH was an independent predictor of the mRS 5-6 (OR 4.90, 95%CI 1.11-22.35; P=0.036), along with older age, lower DWI-ASPECTS, higher NIHSS score, and prior antithrombotic use. Of 132 patients undergoing T2*-WI before or within several days after thrombolysis, microbleeds were more common in patients with EIH (86%) than the others (19% in HT, 24% in NH, P<0.001).

Conclusions:
EIH developed in 4% of the stroke patients after IV rt-PA. Severe PVH and renal dysfunction were associated with the occurrence of EIH. Severe PVH might indicate prevalent existence of microbleeds. EIH was predictive of unfavorable outcome following IV rt-PA.
Abstract TMP22: Intravenous Glyburide Treatment is Associated with Reduced Matrix Metalloproteinase-9 in Human Acute Stroke
Authors: Pham Ly , O’Connor Sydney , Yarbrough Karen , Jacobson Sven , Stern Barney J , Sheth Kevin N , Kimberly W. Taylor
Published: July 2021

Background:
Elevated matrix metalloproteinase-9 (MMP-9) following acute ischemic stroke is associated with blood-brain barrier breakdown and hemorrhagic conversion. Prior retrospective evidence suggests that sulfonylurea use may be associated with reduced risk of hemorrhagic conversion. We hypothesized that sulfonylureas may reduce MMP-9 level in stroke patients.

Methods:
Using serial plasma samples from six subjects in the Glyburide Advantage in Malignant Edema and Stroke Pilot trial (GAMES-Pilot), we evaluated the level of MMP-9 in human subjects presenting with large hemispheric stroke who were treated with intravenous glyburide (RP-1127). MMP-9 was measured in a control cohort with large ischemic stroke who were not treated with glyburide. Commercially available ELISA kits and gel zymography were used to measure MMP-9 at baseline and at approximately 48 hours after stroke. GAMES subjects had additional time points analyzed until approximately 84 hours after stroke.

Results:
Average MMP-9 level in glyburide-treated stroke patients was 47.2 ± 8.0 ng/mL compared to 143.4 ± 60.35 ng/mL in untreated control subjects (p=0.004). Zymography analysis demonstrated a significant decrease in the pro-enzyme but no change in the active form of MMP-9. There was no difference in the level of the MMP-9 specific inhibitor, TIMP-1. No subjects exhibited parenchymal hemorrhagic conversion on 24 hour head CT scan.

Conclusions:
Glyburide treatment in human stroke patients with large hemispheric stroke is associated reduced level of MMP-9. Elucidating the underlying mechanism of glyburide’s effect on MMP-9 and the risk of hemorrhagic conversion may highlight future directions of therapy, including in combination with intravenous tissue plasminogen activator (IV t-PA).
Abstract TMP23: Third International Stroke Trial (IST-3): Subgroup Effects of iv rt-PA < 6 hrs in Acute Ischaemic Stroke on Symptomatic Intracranial Haemorrhage and Outcome at 6 Months
Authors: Lindley Richard I , Sandercock Peter A , Wardlaw Joanna M , Dennis Martin S , Cohen Goeff ,   IST-3 Collaborative Group
Published: July 2021

Aim:
In IST-3 patients, our aim was to assess whether effects of iv thrombolysis with recombinant tissue plasminogen activator (rt-PA) on symptomatic intracranial haemorrhage (SICH) within 7 days & Oxford Handicap Score (OHS) at 6 months were modified by baseline characteristics.

Methods:
Randomised trial of iv rt-PA (0.9mg/kg) (n=1515) versus control (n=1520). SICH within 7 days was identified by blinded central review by an expert panel. Functional status was assessed by the OHS at six months by postal questionnaire or blinded telephone interview. OHS was analysed by logistic ordinal regression, and all analyses were adjusted for key baseline prognostic factors (age, NIHSS, hours delay from onset to randomisation, and presence of visible ischaemia on the baseline scan). The trial is registered:
ISRCTN25765518
.

Results:
Fatal or non-fatal SICH within 7 days occurred in 104 (7%) vs 16 (1%), adjusted OR 6·96 (95% CI 3·45-14·0). Among patients allocated rt-PA, the absolute risk of SICH was higher with increasing age, NIHSS, predicted probability of poor outcome, ischaemic change on baseline imaging, systolic or diastolic blood pressure, blood glucose and treatment with antiplatelet agents in the 48 hours before randomisation, but not with time delay to randomisation or presence of AF. However, there were no significant interactions of the adjusted effect of rt-PA on SICH with any of the measured baseline variables except the use of antiplatelet agents. Ordinal analysis of OHS at 6 months favoured rt-PA (adjusted common odds ratio 1·27,95% CI 1·10- 1·47 p=0·001). There were no significant treatment interactions except for a positive interaction with NIHSS (p=0.018).

Conclusion:
Of baseline factors associated with a higher risk of SICH among controls, only prior antiplatelet therapy significantly modified the treatment-related risk of SICH. None of the measured variables significantly modified the favourable shift in OHS score at six months with treatment, except for an unanticipated positive interaction, suggesting that benefit was greater in more severe strokes.
Abstract TMP26: Binding of KLF4 and HDAC2 to The Promoter Region of SM22alpha Mediates Phenotypic Modulation In vitro and In vivo: Implications in Cerebral Aneurysm Formation
Authors: Starke Robert M , Ali Muhammad S , Tjoumakaris Stavropoula I , Jabbour Pascal M , Gonzalez L. Fernando , Starke Robert H , Koch Walter J , Dumont Aaron S
Published: July 2021

Cerebral Vascular Smooth Muscle Cell (VSMC) phenotypic modulation appears to play an important role in cerebral aneurysm formation and progression, yet the molecular mechanisms involved remain unknown. We investigated the role of inflammatory cytokine, Tumor Necrosis Factor-alpha (TNF-α) and cigarette smoke in directly mediating phenotypic modulation in VSMC. We hypothesize that this may, in part, occur through the binding of the transcription factor, KLF4, to the promoter region of SM22alpha, thereby downregulating VSMC differentiation and contractile genes. This may be critical in the pathogenesis of cerebral aneurysm formation.

Methods:
Cultured cerebral VSMC from rat Circle of Willis were treated with increasing doses of TNF-α (10ng/ml & 50ng/ml) and cigarette smoke extract (CSE; 10ug/ml & 40ug/ml) from 2 to 24hrs. VSMC were transfected with siRNA specific to KLF4. In vivo experiments included application of pluronic gel (containing TNF-α & CSE) to rat carotid artery adventitia. Expression of SM22alpha and KLF4 was measured with qPCR. Chromatin Immunoprecipitation (ChIP) was performed both in vitro and in vivo after treatment (TNF-α and CSE) and incubation with anti-KLF4, anti-HDAC2, anti-H4Ac and anti-H3K9Ac.

Results:
Both TNF-α and CSE independently suppress SM22alpha and increase expression of KLF4 in vitro and in vivo. siKLF4 inhibits the effects of TNF-α and CSE on KLF4 and SM22alpha. ChIP assays demonstrate that KLF4 binds directly to the promoter region of SM22alpha and further recruits HDAC2 to the promoter region. This complex leads to histone modifications leading to decreased acetylation of H4 and H3K9, resulting in decreased expression of SM22alpha.

Conclusion:
KLF4 is a key mediator of TNF-α and CSE induced phenotypic modulation of cerebral VSMC. Phenotypic modulation has been implicated in cerebral aneurysm formation in humans. KLF4 dependent regulation of cerebral VSMC phenotypic modulation may be an underlying molecular mechanism involved in the pathogenesis of cerebral aneurysm formation and a target for future therapies.
Abstract TMP29: Prediction of Wall-thinning Area in Unruptured Intracerebral Aneurysms by Computational Fluid Dynamics
Authors: Hayashi Yoshifumi , Yagi Takanobu , Tobe Yasutaka , Iwabuchi Yuki , Yamanashi Momoko , Takamura Kenji , Iwasaki Kiyotaka , Umezu Mitsuo , Ishida Takashi , Nakajima Atsushi , Yoshida Hirotaka , Nishitani Kazutoshi , Ota Yoshihisa , Sugawara Michihito , Okada Yoshifumi , Kubo Toshiro , Kitahara Shigemi
Published: July 2021

[Background and purpose]
During a clipping surgery, an unruptured intracerebral aneurysm often presented a spatially-localized red-colored "wall-thinning" area. The wall thinning was believed to be related with the risk of rupture. The present aim is given to investigate the predictability of a wall thinning area using computational fluid dynamics (CFD).

[Method]
We chose 16 unruptured aneurysms (12 MCA, 4 ICA) with clipping surgery and 24 wall-thinning areas were detected from the operation video. CFD study was carried out using patient-specific angiographic data. The wall shear stress (WSS) and the wall pressure were evaluated.

[Results]
The WSS magnitude was found to be uncorrelated with wall thinning. On the other hand, 20 wall-thinning areas (83%) exhibited a presence of “flow impingement”, which was defined to give the spatial variation of the WSS vector to be divergent with the local elevation of the wall pressure. From CFD, 27 flow impingements were detected and classified according to the degree of divergence. Seven impingements are full-divergent and all of them (100%) are located in the wall thinning areas. The remaining 20 impingements were partial-divergent and 13 impingements of them (65%) were located in the wall thinning areas. A classification of full-/partial-divergent flow impingement was statistically significant for the prediction of wall-thinning areas (P<0.01).

[Conclusions]
The full-divergent flow impingement was found to be a reliable predictor of the wall thinning area in unruptured intracerebral aneurysms. The present results demonstrated the malignant nature of flow impingement for promoting the thinning of aneurysmal walls.
Abstract TMP33: Progesterone Prevents Hemorrhagic Transformation after tPA Treatment in Experimental Stroke
Authors: won soonmi , Sayeed Iqbal , Wali Bushra , Stein Donald G
Published: July 2021

BACKGROUND:
Tissue plasminogen activator (tPA) is the only FDA-approved treatment for acute stroke. Unfortunately, because of its narrow time window and high risk-to-benefit ratio it is used in less than 3.0% of stroke patients. Our group and others have shown progesterone (PROG) to be beneficial in several ischemic brain injury models. However, before PROG can be tested in stroke patients, how it will interact with tPA, and whether combination with PROG will increase or decrease the risk of bleeding and hemorrhagic conversion, should be determined. In the present study we examined whether PROG would prevent tPA associated hemorrhagic transformation in an experimental stroke model. PROG’s efficacy in preventing tPA-induced impairment of transendothelial electrical resistance (TEER) under hypoxia/reoxygenation (H/R) conditions was evaluated in a mouse brain endothelial cell line.

METHODS:
Male SD rats were subjected to right middle cerebral artery occlusion (MCAO), reperfused at 4.5 hours and then treated with tPA (5 mg/kg b.wt; via femoral vein) at 4.5 hours or PROG (intraperitoneally) at 2 hours plus tPA at 4.5 hours. Rats were killed at 24 hours post-ischemia and brains perfused for evaluation of cerebral hemorrhage, brain swelling, blood-brain barrier (BBB) permeability, MMP-9 activity and cerebral infarction. TEER across the endothelial cell membrane was measured using an EVOM resistance meter.

RESULTS:
Delayed tPA treatment induced significant (p<0.05) hemorrhagic conversion and brain swelling. Combining PROG with delayed tPA administration significantly ameliorated brain hemorrhage, hemispheric swelling, BBB permeability and MMP-9 induction compared to the saline-treated injured group. The reduction in hemorrhagic injury in PROG+tPA-treated rats was 59.0% compared to tPA-treated rats without PROG. PROG treatment also significantly prevented the decrease in TEER induced by tPA under H/R conditions
in vitro
.

CONCLUSIONS:
Our data can be taken to suggest that PROG administration may extend the therapeutic time window for tPA administration in ischemic stroke, while at the same time reducing the risk of hemorrhagic conversion.
Abstract TMP37: Adult Moyamoya Disease : Clinical Presentation, Treatment Outcome and Prognostic Factor
Authors: Jang Dong-Kyu , Lee Kwan-Sung , Rha Hyung-Keun , Huh Pil-Woo , Yang Jiho , Park Ik-Sung , Ahn Jae-Geun , Sung Jae-Hoon , Han Young-Min
Published: July 2021

Background and Purpose:
This study was aimed to investigate treatment results and outcome predictors in adult patients with moyamoya disease.

Methods:
During the period from 2000 to 2011, a clinical database of adult patients with definite moyamoya disease were collected retrospectively from 8 participating centers in Korea during the period from 2000 to 2011. Among total 399 elligible patients, 355 cases were evaluated about clinical and radiological outcomes through medical records. Stroke-free survival rate and prognostic factors for stroke recurrence were measured by Kaplan-Meier and Cox regression methods. Neurologic outcome was assessed according to surgical revascularization and conservative observation.

Results:
The mean age of symptom onset was 39.4 (
±
13.8) years. Male to female ratio was 1 to 2.16. Presenting symptoms were ischemia in 197 (55.5%), hemorrhage in 118 (33.2%), and asymptomatic in 40 (11.3%) patients. The median follow-up was 34.3 months (range 0.4 to 284.8). One hundred thirty seven (38.6%) of the 355 patients received observational conservative management. The remaining 218 (61.4%) patients underwent one of direct, indirect or combined revascularization. In the total adult moyamoya patients, 5 year stroke-free survival rate of surgery and observation group was 82.8% vs 73.4%, respectively. In the ischemic moyamoya cases, 5 year stroke-free survival rate of surgery and observation group was 80.9% vs 76.2%, respectively. In the hemorrhagic moyamoya cases, 5 year stroke-free survival rate of surgery and observation group was 83.7% vs 70.1%, respectively. In the asymptomatic cases, 5 year stroke-free survival rate of surgery and observation group was 95.3% vs 83.1%. There was no significant difference between surgical and observation group in Kaplan Meier Survival analysis. Angiographic stage was only a significant factor for stroke recurrence (HR 3.275, 95% CI; 1.251-8.575, P=0.016). Neurologic outcome tended to be better in the surgical group than the observation group (88.5% vs 81.8%, P=0.074)

Conclusions:
In adult moyamoya patients, the long-term prognosis of surgical treatment may be better than that of conservative observation under real-world setting. Angiographic stage is a predictor of future stroke