bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 182: Rxrα in Microglia Acts as Central Player in the Cleanup and Repair After Ischemic Stroke
Authors: Ting Shun-Ming , Zhao Xiurong , Sun Guanghua , Garrido Juan J , Obertas Lidiya , Aronowski Jaroslaw
Published: October 2018

Microglia/macrophage (MΦ) are immune response cells with function in clearing cell debris and tissue repair after ischemic brain damage. Retinoid X receptor alpha (RXRα) is a pleiotropic transcription factor regulating cell differentiation, lipid/glucose metabolism and immune responses, including in MΦ. Studies from this lab suggest that the dimerization of RXRα with the peroxisome proliferator-activated receptor γ (PPARγ) to form a transcriptionally active structure plays critical roles in enhancing MΦ polarization toward the “healing” phenotype. All studies were performed applying scientific rigor. First, we showed that treatment of microglia in culture with selective agonist of the RXRα, bexarotene (BEX), promotes microglia’ polarization toward “beneficial” phenotype including enhancement of phagocytic functions toward engulfment of dead neurons. Next, we showed that BEX (5mg/kg, i.p.) given daily to rats after thromboembolic stroke reduced the infarct volume at d7. The neurological deficit was reduced by BEX at d7, but not at d3 after stroke. This suggest that the beneficial effects of BEX takes place during the sub-acute phase post-stroke. To further investigate the role of MΦ RXRα in ischemia, we generated macrophage-targeting RXRα knockout mice (MacRXRα
-/-
) by crossing Lyz-Cre mice with RXRα
flox/flox
mice. We subjected MacRXRα
-/-
and RXRα
flox/flox
(control) mice to a 60 min MCA/CCA reversible occlusion. 24h later mice received BEX (5mg/kg once a day for 7 days, i.p.) or vehicle. We conducted behavioral evaluations for 28 days. We showed, in agreement with the rat data, that control mice receiving BEX showed significant improvement in long-term neurological recovery and had reduced brain atrophy volume at d28 after stroke. We also showed that beneficial effect of BEX is significantly reduced in MacRXRα
-/-
mice, as compared to control mice. Limitation: Since MacRXRα
-/-
mice may also have RXRα deficiency in neutrophils, we are now conducting parallel studies to evaluate the role of RXRα deficiency in neutrophils. Our study suggests that RXRα in the MΦ may play important role in coordinating the cleanup and repair during post-stroke recovery phase. Also, we showed that BEX has the uniquely long 24h therapeutic window.
Abstract 183: Determinants of Hypertension-related Intracerebral Hemorrhage in West Africans: Findings From the SIREN Study
Authors: Owolabi Mayowa O , Sarfo Fred
Published: October 2018

Background:
Hemorrhagic strokes are highly prevalent among Africans and contribute to significant morbidity and mortality from stroke in Lower and Middle Income Countries. Although hypertension is the most dominant risk factor for intracerebral hemorrhage (ICH), other risk factors may contribute to its occurrence.

Objective:
To identify and quantify the contributions of concomitant risk factors for hypertension-related ICH among patients in the SIREN study.

Methods:
The Stroke Investigative Research and Educational Network (SIREN) is a multicenter, case-control study involving 15 sites in Nigeria and Ghana. Cases included adults aged >18 years with CT/MRI confirmed stroke and hemorrhagic strokes were etiologically subtyped using the SMASH-U protocol. Controls were age-and-gender matched stroke-free adults recruited from the communities in catchment areas of cases. Comprehensive evaluation for vascular, lifestyle and psychosocial factors was performed using standard instruments. We used conditional logistic regression to estimate odds ratios (OR) with 95% CIs.

Results:
Among a cohort of 2,118 stroke subjects, 682 (32.2%) had ICH. The mean age of ICH cases and controls were 53.7 ± 12.5 and 52.6 ± 12.5 years respectively. Using the SMASH-U etiologic classification of hemorrhagic strokes, 93.9% were hypertensive, 7.2% were related to structural lesions such as aneurysms, 2.2% cerebral amyloid angiopathy, 1.8% systemic diseases, 1.1% medication-related and 1.8% undetermined. Hypertension-related hemorrhagic strokes were associated with the following risk factors (aOR, 95% CI): diabetes mellitus 2.33 (1.33-4.09), stress 2.22 (1.20-4.11), dyslipidemia 1.69 (1.01-2.83), tobacco use 10.01 (1.06-94.41) while green leafy vegetable consumption 0.36 (0.20-0.66) was strongly protective.

Interpretation:
ICH affects a predominantly young and productive population in Africa. In this population, stress and green leafy vegetable consumption are novel factors with potential opposing modulating effects on occurrence of hypertensive hemorrhagic stroke.

Funding:
U54-HG007479
Abstract 184: Sex Differences in the Effect of Hypertension on Stroke Risk in the REasons for Geographic and Racial Differences in Stroke Study
Authors: Madsen Tracy E , Howard George , Kleindorfer Dawn O , Furie Karen L , Liu Simin , Oparil Suzanne , Howard Virginia J
Published: October 2018

Introduction:
We sought to determine if there are sex differences in the association of severity of hypertension (HTN) or treatment of HTN with the risk of ischemic stroke (IS).

Methods:
We analyzed data from the REasons for Geographic and Racial Differences in Stroke Study, a national longitudinal cohort study of >30,000 black and white adults ≥45 years old. Participants stroke-free at baseline were assessed regarding their age, race, sex, systolic blood pressure (SBP), and number of antihypertensive medications during in-home assessments, after which telephone surveillance for IS incident events was performed every 6 months (with physician adjudication of medical records of suspected events). Proportional hazards regression was used to assess the sex-specific association of SBP as a categorical variable (normotensive, pre-HTN, Stage 1 HTN, Stage 2 HTN) and the number of antihypertensive medications after adjustment for age, race, and an age-by-race interaction.

Results:
Among 26,461 participants (55.4% women, 40.2% black), there were 1084 IS events during a follow-up averaging 8.7 years. After adjustment for covariates, the increased risk of IS per each level of HTN was higher in women (HR 1.32, 95% CI 1.19-1.46) than men (HR 1.16, 95%CI 1.04-1.29) (sex-SBP interaction term p = 0.087 for trend test) (See Figure). There were no sex differences in the impact of the number of antihypertensive medications on IS risk (p = 0.60). Compared to those on no medications, those on 1, 2 or 3+ medications were at 1.31 (95% CI: 1.10-1.55), 1.48 (95% CI: 1.25 - 1.75), and 1.88 (1.57 - 2.25) times higher IS risk, respectively.

Conclusions:
The risk of IS associated with increasing levels of HTN was significantly greater in women than men. Being on more antihypertensive medications was associated with increased IS risk for both women and men. Further investigations on the biological mechanisms for sex differences in HTN and the potential need for sex-specific clinical guidelines are warranted.
Abstract 188: The Burden of Stroke in Mexico: An Analysis of the Global Burden of Disease 1990-2015
Authors: Cantu-Brito Carlos , Chiquete Erwin , De la Cruz-Gøngora Vanessa , Montoya-Rodríguez Alejandra , Cahuana Lucero , Lozano Rafael , Roth Gregory A , Gomez–Dantes Hector
Published: October 2018

Background and purpose:
Stroke incidence, prevalence and mortality have decreased in high-income countries, while in the last decades there has been an increasing trend in low- to middle-income nations, where ischemic (IS) and hemorrhagic stroke (HS) are still major causes of death and disability. The lack of updated epidemiological information of stroke in Mexico has motivated the performance of current estimations based on available direct data sources and published research.

Methods:
We analyzed available information cases related with cerebrovascular disease included in the Global Burden of Disease (GBD) 2015 data source. Sources available from Mexico included vital registration data and information on stroke incidence, prevalence and mortality from the scientific literature about inpatient hospital data, population surveys and mortality registries for the period 1990-2015.

Results:
The absolute number of stroke deaths increased substantially in the last 25 years. In 1990 there were 10,572 IS and 11,158 HS deaths, compared with 18,649 and 21,396 respectively in 2015. Conversely, age-standardized mortality rates for IS were significantly reduced by 27.8%, from 30.1 per 100,000 in 1990 to 21.8 in 2015; while the decrease for HS in the same period was 12.4%, from 26.8 to 23.5 per 100,000. However, the decrease trend in mortality for both types of stroke was observed only during the 1990-2005 period, and remained stable from 2005-2015. The age-standardized IS prevalence diminished (-27.6%) from 116.3 per 100,000 in 1990 to 84.2 in 2015, while HS decreased (-23%) from 88.6 to 68.3. Age-standardized IS incidence diminished (-34%) from 37.4 per 100,000 in 1990 to 24.6 in 2015. For HS, incidence rate decreased (-32%) from 23.2 to 15.7 per 100,000. Nevertheless, incident cases for both conditions did not show any decrease after 2005.

Conclusion:
Mexico exhibit an epidemiological pattern of transition, characterized by both low mortality and prevalence, which contrasts with findings for high and low- to middle-income countries. This study provides a unique insight on epidemiological trends associated with a transition towards development in a Latin American country.
Abstract 194: Machine Learning-Based Model Can Predict Stroke Outcome
Authors: Heo JoonNyung , Yoon Jihoon , Park Hyung Jong , Kim Young Dae , Nam Hyo Suk , Heo Ji Hoe
Published: October 2018

Introduction:
Prediction of outcome in stroke patients can help both physicians and patients in making treatment decisions and managing prognostic expectations. Machine learning techniques are being increasingly used in the field of medical research.

Hypothesis:
We hypothesized that models developed with machine learning techniques are useful for predicting long-term functional outcomes in patients with acute ischemic stroke.

Methods:
The model was developed with a prospective cohort of acute ischemic stroke patients. This cohort registers stroke patients who were admitted within 7 days from the onset of symptoms. For this study, we included all patients admitted between January 1, 2010, and December 31, 2014. We excluded patients with pre-stroke modified Rankin Scale (mRS) score >2 or missing 3-month mRS score. Univariate analysis was performed to guide in variable selection for machine learning models. Machine learning models were trained to classify patients likely to have unfavorable outcome, defined as 3-month mRS score >2. Developed models included artificial neural network, random forest, support vector machine, and logistic regression models. Area under the receiver-operated characteristic curve (AUC) was used to compare effectiveness of each model. Google’s TensorFlow and scikit-learn toolkit were used for training of machine learning models.

Results:
Total of 3,524 patients were admitted during the study period. After excluding 454 patients with unavailable 3-month mRS scores, 60 patients with pre-stroke mRS score >2, and 87 patients with missing laboratory tests or clinical data, 2,923 patients were finally enrolled. Of the 2,923 patients, 695 (24%) patients had unfavorable outcome (mRS>2) at 3 months. The AUC was 0.888 for Artificial neural network model, 0.810 for random forest model, 0.836 for support vector machine model, and 0.842 for logistic regression model. We calculated the AUC of ASTRAL score for reference, which showed 0.839 in our study group.

Conclusion:
Machine learning models, particularly the artificial neural network model, achieved high accuracy of prediction for functional outcome in stroke. This study showed the feasibility of machine learning approach for predicting outcomes in stroke.
Abstract 195: Drip and Ship vs. Mothership: a Comparison of Two Different Conditional Probability Models
Authors: Holodinsky Jessalyn K , Williamson Tyler S , Demchuk Andrew M , Zhao Henry , Coreas Alan , Francis Michael , Pfannmuller Bradley , Goyal Mayank , Hill Michael D , Kamal Noreen
Published: October 2018

Introduction:
There is uncertainty about the best treatment method for patients with suspected large vessel occlusion (LVO) stroke. The drip and ship [alteplase at a Primary Stroke Centre (PSC) and then transfer to a Comprehensive Stroke Centre (CSC) for endovascular therapy (EVT)] and mothership (bypassing the PSC in pursuit of EVT at a CSC) transport methods have been proposed. Earlier, these two methods were evaluated for patients with assumed known LVO. As LVO cannot be diagnosed without imaging we present an update for patients with suspected LVO using the Los Angeles Motor Scale (LAMS) screening tool.

Methods:
The expected distribution of LVO, non-LVO occlusions (nLVO), intracranial hemorrhages (ICH), and stroke mimics (SM) for patients with LAMS≥4 was combined with time dependent probability of good outcome for alteplase (for LVO and nLVO) and EVT, and probability of good outcome for ICH and SM to create conditional probability models for drip and ship and mothership scenarios. Results were mapped and compared with the previous model.

Results:
For patients with LAMS≥4 drip and ship and mothership predict equivalent outcomes in most areas (Figure-Panel A). Drip and ship is only relevant at PSCs that are far from CSCs. Increasing door to needle time (DNT) decreases the size of drip and ship areas. This contrasts with the prior model (Figure-Panel B) where mothership is more dominant especially as DNT increases.

Conclusions:
The inclusion of nLVO, ICH, and SM patients introduces important differences in modelling patient transport. This diagnosis uncertainty decreases the relative difference between the probabilities of good outcome for the two transport options.
Abstract 2: Co-administration of Proton-Pump Inhibitors with Thienopyridines Increases Risk of Adverse Cerebrovascular Outcomes
Authors: Malhotra Konark , Katsanos Aristeidis H , Ishfaq Muhammad F , Goyal Nitin , Tsivgoulis Georgios
Published: October 2018

Background:
Pharmacokinetic and prior interaction studies on thienopyridine-proton pump inhibitors (PPI) provide conflicting data for cardiovascular outcomes. There is no established evidence on the association of concomitant use of PPI-thienopyridine with adverse cerebrovascular outcomes.

Methods:
We conducted a systematic review and meta-analysis of randomized controlled trials (RCT) and cohort studies from inception to December 2016, reporting following outcomes among patients treated with thienopyridine + PPI vs. thienopyridine alone: 1. ischemic stroke (IS), 2. combined ischemic and hemorrhagic stroke, 3. composite outcome of stroke, myocardial infarction (MI) and cardiovascular (CV) death, 4. MI, 5. all-cause mortality, and 6. major or minor bleeding events. We performed subgroup analyses to assess IS recurrence rates for eligible studies, and assess outcomes amongst the two study designs. We calculated pooled relative risk (RR) ratios and 95% CI using random-effects models.

Results:
We identified 22 studies (12 RCTs and 10 cohort studies) with 131,714 participants. Concomitant use of PPI and thienopyridines was associated with increased risk of IS [RR=1.75 (95%CI: 1.41-2.16), I
2
=0%], composite stroke/MI/CV death [RR=1.14 (95%CI 1.01-1.29), I
2
=74%], and MI [RR=1.19 (95%CI: 1.0-1.4), I
2
=80%]. The co-administration of PPI and thienopyridines was not associated with the risk of combined ischemic and hemorrhagic stroke, cardiovascular death, major or minor bleeding, and all-cause mortality. Subgroup analyses demonstrated increased risk of IS [RR=1.6 (95%CI: 1.1-2.3), I
2
=33%] and combined ischemic and hemorrhagic stroke [RR=1.34 (95%CI: 1.1-1.63), I
2
=0%] in cohort studies, while RCTs demonstrated significant risk for composite stroke/MI/CV death [RR=1.17 (95%CI: 1.04-1.32), I
2
=72%]. PPI-thienopyridine co-prescription did not increase the risk of stroke recurrence in patients with prior IS.

Conclusions:
PPI-thienopyridine co-prescription increases the risk of IS and composite stroke/MI/CV death. Our findings highlight the need for pharmacovigilance and corroborate with current guidelines for PPI deprescription, especially in patients treated with thienopyridines for the prevention of cerebrovascular events.
Abstract 22: Late Functional Improvement in Acute Ischemic Stroke Patients: Pooled Analysis of Three Multicenter Clinical Trials
Authors: Qureshi Adnan I , Afghan Sher , Malik Ahmed A , Saeed Omar , Janjua Nazli A
Published: October 2018

Background:
Most studies recruiting patients with acute ischemic stroke ascertain the final functional status at 3 months post symptom onset. The rates and predictors of late functional improvement (>3 months) in acute ischemic stroke patients has not been systemically studied.

Methods:
We analyzed data from three phase-III randomized multicenter clinical trials that recruited acute ischemic stroke patients within 3 or within 5 hours of symptoms onset. Late improvement was defined by an improvement of 1 or more grade in modified Rankin scale between ascertainments performed at 3 and 12 months post randomization. We analyzed the rates of late improvement in three groups of patients; patients treated with IV (recombinant tissue plasminogen activator [rt-PA], those treated with endovascular treatment, and those not treated with any acute reperfusion treatment. Multivariate analysis was performed to identify predictors’ of late functional improvement.

Results:
A total of 2555 patients (mean age ± SD; 66.4 ± 12.9 years) with acute ischemic stroke were analyzed.Late functional improvement was observed in 447 (17.5%, 95% confidence interval [CI] 15.9 to 19.2]) of 2555 patients analyzed. The rates of late functional improvement according to acute reperfusion treatment were as follows: 248 (22.4%) of 1106 in IV rt-PA treated; 108 (23.9%) of 452 in endovascular treated; and 91 (19.1%) of 477 in patients without any treatment (p= 0.179). In multivariate analysis, patients with age ≥65 years (odds ratio [OR], 0.53; 95 % CI 0.35 to 0.80; P = 0.002), and severity of baseline neurological deficits with National Institutes of Health Stroke Scale [NIHSS] score at 24 hours ≥ 20 (OR, 0.40; 95 % CI, 0.28 to 0.58; P = <0.001), were inversely associated with late improvement.

Conclusions:
Late functional improvement occurs in one fourth of acute ischemic stroke patients and should be considered in estimation of functional recovery in future clinical studies.
Abstract 23: BDNF val
66
met Genotype is Associated With Greater Brain Atrophy After Stroke
Authors: CRAMER Steven C , Liu Brent J , Edwardson Matthew A , See Jill , Wang Ximing , Radom-Aizik Shlomit , Shahbaba Babak , Wolf Steven L , Dromerick Alexander , Winstein Carolee ,   the ICARE study investigators
Published: October 2018

Background:
Genetic factors may be useful to understand differences in outcomes post-stroke. We studied an imaging measure of brain atrophy in relation to two genotypes that may be associated with differences in stroke recovery, the val
66
met genotype for brain-derived neurotrophic factor (BDNF) and the ApoE e4 genotype. Each genotype has been associated with brain atrophy in non-stroke populations. The current study hypothesized that each genotype is associated with brain atrophy after stroke.

Methods:
The ICARE Study examined behavioral outcomes after stroke in relation to motor therapies. Of 361 ICARE enrollees, genetic and neuroimaging data were available in 127. The volume of the ventricles and the brain were measured, and brain atrophy expressed as the Ventricle-Brain Ratio (VBR). For MRI scans, VBR was first extracted from the scans using ALVIN then manually refined. For CT scans, VBR was extracted manually. All VBR measurements were verified by a neuroimaging expert. VBR was examined in relation to the two genotypes of interest, BDNF val
66
met and ApoE e4, controlling for the 3 covariates employed in ICARE: motor deficits, enrollment site, and time post-stroke at study entry.

Results:
There were 61 MRI and 66 CT scans. These were acquired 5±11 days post-stroke, which did not vary according to either genotype. Median ventricle volume=26.1 cc; brain volume=1,163 cc; and VBR=0.024. The BDNF val
66
met genotype was present in 23 subjects; ApoE e4, in 41; both were in HW equilibrium. Presence of the BDNF val
66
met genotype was associated with greater atrophy: median VBR increased 1.97-fold when this genotype was present vs. absent (p=0.01), controlling for above covariates; and remained significant (p=0.04) when also controlling for age. This BDNF gene-imaging correlate did not extend to gene-behavioral findings. The ApoE e4 genotype was not related to VBR (p=0.88).

Conclusions:
Median degree of brain atrophy is 97% greater in patients with stroke when the BDNF val
66
met genotype is present, at least for the mild-moderately impaired subjects enrolled in ICARE. Understanding the biology of inter-subject differences in brain anatomy after stroke can provide insights into patient heterogeneity and inform efforts to individualize stroke recovery therapies.
Abstract 29: Post-stroke Neovascularization and Functional Outcomes Differ in Type 2 Diabetes Depending on the Severity of Ischemia Reperfusion Injury and Sex: Potential Link to Hemorrhagic Transformation
Authors: Valenzuela John P , Li Weiguo , Ward Rebecca , Abdelbary Mahmoud , Ergul Adviye
Published: October 2018

It is a clinically well-established fact that patients with diabetes have very poor stroke outcomes. Yet, the underlying mechanisms are largely unknown. Previously we have shown that male diabetic animals show greater hemorrhagic transformation (HT), profound loss of cerebral vasculature in the recovery period and poor outcomes after ischemic stroke induced by a 90-min or embolic middle cerebral artery occlusion (MCAO). Given that young females have a 3.5-fold higher risk of stroke with the onset of diabetes and women account for the majority of stroke mortality, the current study postulated that diabetes causes greater vascular injury/repair and worsens sensorimotor and cognitive recovery after stroke even in young females. After 8 weeks of type 2 diabetes induced by a combination of high fat diet and low dose streptozotocin (30mg/kg;IP), Wistar rats were subjected to 60-min MCAO and followed for 3 or 14 days for evaluation of neurovascular injury (infarct size, HT, edema) and repair (vascularization patterns and functional outcomes), respectively. Vascular indices measured included branch density, tortuosity, vascular volume and surface area in cortex and striatum using confocal imaging of FITC-filled vasculature. Males had comparable infarct size and edema regardless of disease while diabetic females had greater infarction/edema compared to control. In contrast to our previous studies, there was no difference in HT or vascularization patterns between control and diabetic animals. All groups recovered from functional deficits to the same degree. These results 1) provide evidence that diabetes negates neuroprotection typically seen in female animals, 2) strongly suggest that HT impacts recovery responses and 3) post-stroke vascularization pattern is influenced by the degree of acute vascular injury and correlates with functional recovery in both sexes. Treatment of bleeding that occurs as a result of HT may provide a novel therapeutic strategy in diabetes.
Abstract 30: Upregulation of Pentose Phosphate Pathway after Focal Cerebral Ischemia/Reperfusion Injury in Rat Cerebral Cortex: The Impact of Heat Shock Protein 27 Phosphorylation
Authors: Matsuo Kazuya , Hosoda Kohkichi , Yamamoto Yusuke , Tanaka Jun , Imahori Taichiro , Nakai Tomoaki , Sato Naoko , Irino Yasuhiro , Shinohara Masakazu , Kohmura Eiji
Published: October 2018

Introduction:
We previously reported glucose 6-phosphate dehydrogenase (G6PD) in pentose phosphate pathway (PPP) is activated via heat shock protein 27 (HSP27) phosphorylation by ataxia telangiectasia mutated (ATM) kinase during cerebral ischemia. However, it is unknown whether this potential endogenous anti-oxidative system also works during reperfusion. Thus, we performed a comparative metabolic analysis of the effects of reperfusion in rat cerebral cortex, using middle cerebral artery occlusion (MCAO).

Methods:
After the desired period of reperfusion (0, 1, 3, 5, 24-h) following 1-h MCAO (n = 6/group), the rats were sacrificed. Ninety-six metabolites were measured by gas-chromatography/mass-spectrometry (GC/MS), and were analyzed using multivariate statistics. The associated specific metabolic enzymes were further investigated.

Results:
GC/MS showed changes in metabolic states in reperfusion-time-dependent manner (
Fig. 1A
). Enrichment analysis showed PPP was most significantly upregulated during ischemia-reperfusion. In relation to PPP, ischemia-reperfusion induced increase of HSP27 mRNA (69-fold) over time of reperfusion. Immunoblotting showed a slow increase in HSP27 protein and a marked increase in HSP27 phosphorylation (4.5-fold) in reperfusion-time-dependent manner (
Fig. 1B
). G6PD activity was significantly elevated after 1-h MCAO (20%), reduced after 1-h reperfusion, thereafter gradually elevated. Increasing pattern of the NADPH/NADP+ ratio was similar. Furthermore, intracerebroventricular injection of ATM kinase inhibitor (KU-55933) significantly increased the infarct size (50%) after 24-h reperfusion following 90-min MCAO (
Fig. 1CD
).

Conclusions:
G6PD activation via ischemia-induced HSP27 phosphorylation by ATM kinase may be part of an endogenous antioxidant defense neuroprotection mechanism during ischemia-reperfusion. These findings have important therapeutic implications for the treatment of stroke.
Abstract 33: Intra-arterial Saline Flushing Reduces Infarct Size and Improves Sensorimotor Function in a Rat Model of Transient Middle Cerebral Artery Occlusion
Authors: Selvan Prad , Li Jie , Barone Frank C
Published: October 2018

Introduction:
Mechanical thrombectomy (MT) for large vessel occlusive (LVO) stroke provides an opportunity to deliver targeted intra-arterial (IA) adjunctive therapies (ATs) to the ischemic brain. We developed a model of selective IA catheterization after transient middle cerebral artery occlusion (tMCAO) in rats to investigate targeted adjunctive therapies. Here we report the brain protective effects of targeted IA flushing with normal saline as an adjunctive therapy to LVO revascularization.

Methods:
We incorporated a continuous internal carotid artery (ICA) catheter infusion system after tMCAO in Sprague Dawley rats (300-350g). Two groups were studied (N=6/group): Control (tMCAO with IA catheter only) and Flushing (tMCAO with IA catheter and brief intermittent flushing). The Flushing group received 1 min infusions of normal saline at 2cc/min immediately, 1hr, and 2hrs after reperfusion. Laser Speckle Imaging was used to measure microvascular perfusion at baseline, post-occlusion, post-reperfusion, and 24hrs post-reperfusion. Functional measurements and histological analysis were performed at 24hrs post-reperfusion.

Results:
Incorporating a IA catheter system after tMCAO was safe in rats. Flushing saline into the ICA caused a targeted, significantly increased microvascular perfusion of the ischemic MCA territory (P<0.05). Histological analysis demonstrated a significant (P<0.05) decrease in total and cortical infarct size and cortical and striatal swelling. Functional measurements were also significantly decreased (P<0.05) by intermittent flushing.

Conclusion:
Continuous intra-arterial catheter access can be safely incorporated into a rat model of transient middle cerebral artery occlusion. Here we demonstrate that intermittent targeted flushing of the ischemic brain can be effective as an adjunctive therapy to LVO revascularization. It is now possible and necessary to investigate targeted IA therapeutics after tMCAO in rats.
Abstract 34: Predominant Periodontal Bacteria Augments Ischemic Stroke Outcomes
Authors: Ahmad Abdullah S , Chukkapalli Sasanka S , Kamat Pradip K , Hernandez Damian , Jiron Jessica , Aguirre Jose I , Dore Sylvain , Kesavalu Lakshmyya
Published: October 2018

Background:
Chronic infection and persistent systemic inflammation are important risk factors for poor stroke outcomes. Chronic periodontitis (PD) are among the most common chronic immunoinflammatory infections of humans. Interestingly, in 2012, the American Heart Association reported that observational studies support an association between PD and atherosclerotic vascular disease. The association between PD and the occurrence of stroke has been explored clinically in retrospective studies. However, role of PD bacteria in hemorrhagic and ischemic stroke outcomes has not been investigated in preclinical animal models. Here we tested the hypothesis whether PD bacteria augments stroke outcomes.

Methods:
Ten-week-old male C57BL/6NHsd mice were randomly assigned to the infected (PD) and the sham-infected groups. Mice were infected by oral lavage with 4 periodontal bacteria (
Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia,
and
Fusobacterium nucleatum
) as polybacterial infection for 12wks (inoculating 4 times per week every third week) to induce periodontitis. Sham-infected mice was inoculated with vehicle. At the end of the 12wks infection period, mice were subjected to 60min of transient ischemia. Mice were tested for PD [bacterial infection, periodontal inflammation, alveolar bone resorption (ABR)] and functional and anatomical stroke outcomes at 48h post-stroke.

Results:
All bacteria were colonized/infected in the mice gingival surface (83-100%). Polybacterial-infected mice developed mild periodontal inflammation with a trend to increased ABR. We also observed that the neurological deficit score in PD group increased by 32.40±18.56% (p<0.01). Similarly, the infarction volume in the infected mice (n=7) also increased significantly by 44.26±26.04% (p<0.05) as compared with controls (n=8). We also observed a significant difference in parenchymal bleeding in infected mice as compared with the sham-infected mice (30% vs 11%; p<0.001).

Conclusion:
This is the first report demonstrating that oral bacteria induced significant neurological deficits, infarction volume, and parenchymal bleeding resulting in enhanced ischemic stroke damages.
Abstract 38: Soluble ST2 Predicts Delayed Cerebral Ischemia and Outcome After Subarachnoid Hemorrhage
Authors: Wolcott Zoe , Bevers Matthew B , Bache Søren , Irvine Hannah , Koch Matthew , Patel Amen , Møller Kristen , Kimberly W. Taylor
Published: October 2018

Introduction:
Soluble ST2 (sST2) is a member of the Toll-like receptor superfamily implicated in pro-inflammatory signaling. We investigated whether sST2 predicts delayed cerebral ischemia (DCI) and 90-day clinical outcome in patients with aneurysmal subarachnoid hemorrhage (SAH).

Methods:
Soluble ST2 was measured in plasma samples from 182 patients who presented to a single institution with SAH. Blood samples were collected between days 1 and 5 after onset of SAH, and prior to the onset of DCI. Functional outcome was assessed at 3 months using the modified Rankin Scale (mRS) with good and poor outcome defined as mRS 0-2 and 3-6, respectively. Using a consensus definition, DCI was defined as a 2-point drop in GCS over a sustained period in patients whose clinical deterioration could not be explained by another cause. The relationships between sST2 level, DCI and outcome were assessed in univariable analysis. Multivariable logistic regression, Kaplan-Meier survival analysis, and receiver operating characteristic curves were used to determine the ability of sST2 to predict outcome and mortality. These findings were tested for replication in an independent cohort of 51 SAH patients recruited from a separate institution.

Results:
The discovery cohort consisted of 182 subjects (mean age 56±12 years, 61% women). Elevated plasma sST2 predicted the development of DCI (OR 2.10, 95% 1.06-4.18 CI, P=0.0295), which remained an independent predictor after adjustment for age, World Federation of Neurological Surgeons (WFNS) grading score, modified Fisher score, intra-arterial vasodilator therapy and hydrocephalus (OR 2.78, 95% CI 1.00-7.97, p=0.0453). Elevated sST2 was also independently associated with poor 90-day functional outcome (OR 2.65, 95%CI 1.07-6.59,
P
=0.0304), and mortality (OR 5.36, 95% CI 1.48-19.39, p=0.0039) when adjusted for age, WFNS score, modified Fisher score and hydrocephalus. In the replication cohort (N=51, 88% women), sST2 level was an independent predictor of DCI (OR 5.02, 95% CI 1.46-17.20, p=0.0034) and outcome at 90 days (OR 4.24, 95% CI 1.31-13.74, p=0.0072).

Conclusion:
Plasma sST2 level predicted risk of DCI, outcome, and mortality after SAH. Further study of the potential link between sST2 and brain injury after SAH is warranted.
Abstract 39: Time to Detect Seizures Among Hemorrhagic and Ischemic Stroke Patients Undergoing Continuous EEG (cEEG) Monitoring
Authors: Zawar Ifrah , Hantus Stephen
Published: October 2018

Objective:
Stroke patient have a 13-19% risk of Electroencephalographic (EEG) seizures and frequently undergo continuous EEG (cEEG) monitoring. It is unclear how long cEEG monitoring should be done in hemorrhagic and ischemic stroke patients to exclude subclinical seizures. Our objective is to identify stroke patients who are at risk of delayed seizure detection (>24 hours) and therefore may benefit from prolonged cEEG monitoring.

Methods:
We identified all patients who had cEEG monitoring at a single tertiary center in 2016 (n=2425). Data was analyzed using Wilcoxon Ranksum & chi square tests.

Results:
Among the 2425 patients who had EEG monitoring, 334 had seizures. 25 were excluded because of missing data. Among the 309 patients included, median time to seizure onset was 3 hours. Seizures were detected by 24 hours in 80% (n=248) and within 36 hours of cEEG monitoring in 90 % of all patients with seizures. Patients were divided into ischemic, hemorrhagic and non-vascular etiologies. 19% (n=60) had seizures due to hemorrhage and 13% (n=41) due to ischemic strokes. Among ischemic strokes patients with seizures, seizures were detected by 2 hours 17 minutes in 50%, by 18 hours in 80% and by 34 hours in 90%. However, for hemorrhage patients with seizures, time to detect seizures in 50 % of patients was delayed to 15 hours (p= 0.0004) and seizures were detected by 33 hours in 80% and by 41 hours in 90 % of patients. Hemorrhage patients were more likely to have their first seizure recorded after 24 hours of cEEG monitoring (p=0.0221). Hemorrhages were subdivided into subdural, subarachnoid, parenchymal, epidural and mixed types. Among these, those who had more than one type of hemorrhage were more likely to have their first seizure detected after 24 hours of cEEG monitoring (p=0.0002).

Conclusions:
Patients with hemorrhage particularly with more than one type of hemorrhage are more likely to have delayed seizure detection and require longer cEEG monitoring (>24 hours) to diagnose seizures.
Abstract 40: Biocompatible, Aminocaproic Acid Stabilized Ceria Nanoparticles Rescue the Injured Brain After Subarachnoid Hemorrhage
Authors: Jeong Han-Gil , Kang Dong-Wan , Cha Bong Geun , Kim Do Yeon , Yang Wookjin , Ki Seul-ki , Kim Song I , Han Ju hee , Kim Jaeyun , Lee Seung-Hoon
Published: October 2018

Background and aims:
Despite early aneurysm repair and aggressive management for complications, subarachnoid hemorrhage (SAH) results in at least 25% mortality rate and 50% persistent neurologic deficit. Thus, a novel therapeutic agent that directly targets brain damages after SAH is strongly required. For this purpose, we developed aminocaproic acid stabilized ceria nanoparticles (Amicar-CeNPs), which have incomparable anti-oxidative activity and biocompatibility.

Methods:
Uniform water-dispersed Amicar-CeNPs were prepared from short sol-gel reaction of cerium (III) ions in aqueous phase with aminocaproic acid. SAH was induced by endovascular perforation of middle cerebral artery of rats. A single dose of Amicar-CeNPs (0.5mg/kg) or saline control were randomly administered intravenously at an hour post-SAH. Neuronal death, macrophage infiltration, SAH grade and brain water content were evaluated at 72 hours. Mortality and neurologic function were assessed for 14 days.

Results:
Amicar-CeNPs, 3-nm in size and with high Ce
3+
to Ce
4+
ratio, demonstrated very potent anti-oxidative, cytoprotective, and anti-inflammatory activities in vitro. In rodent SAH model, Amicar-CeNPs significantly reduced neuronal death (1.1% vs. 90.1%; P<0.01), macrophage infiltration (74 vs. 188; P<0.01) and brain water content (80.2% vs. 80.7%; P<0.05) 72 hours post-SAH as compared with the saline control. SAH grades were comparable between the two groups (13.1±1.7 vs. 12.3±2.6). Amicar-CeNPs reduced mortality (11% vs. 79%; P<0.01) and improved neurological functions (median 9 vs. 3; modified Garcia score; P<0.01) post-SAH.

Conclusions:
Amicar-CeNPs, totally synthesized in aqueous phase, demonstrated very promising results against SAH via potent anti-oxidative, neuroprotective and anti-inflammatory activities. Given the obvious limitations of current therapies for SAH, Amicar-CeNPs are strongly required to be tested in SAH patients as an investigational new drug.
Abstract 41: Systematic Review Identified Some Early Phase Promising Therapeutics for Subarachnoid Hemorrhage
Authors: Shah Neel , Shah Vishank , Venkatasubba Rao Chethan P , Kent Thomas A , Mandava Pitchaiah
Published: October 2018

Introduction:
Many randomized clinical trials (RCTs) have been conducted for subarachnoid hemorrhage (SAH), yet no treatment definitively improves outcome. Predictive ability of early phase trials is uncertain because outcome is strongly related to baseline severity factors, yet imbalances are common in these trials. We previously developed a method for ischemic stroke to identify promising treatments at early phase using a pooled model constructed from the control arms of RCTs and comparing trial outcomes at their own baselines. We applied this method to SAH.

Methods:
SAH predictive models for functional outcome and mortality were developed based on published variables (eg, WFNS, Fisher, age). The outcome model is the best fit 3-d surface bounded on either side by p=±0.1 prediction interval (PI) surfaces. These surfaces incorporate statistical variability to assess whether a treatment differs from expected outcome of a pooled sample. Treatment arms from RCTs and single arm trials for SAH are then visually compared against the pooled controlled arm to see if they surpassed the prediction surfaces at their own baseline conditions.

Results:
The best model fit was for good outcome (modified Rankin Score 0-2) based on WFNS grade 4-5% and age (26 RCTs, 5200 subjects; R
2
=0.54; p<0.001). To confirm the model can identify futility, 7 tirilazad trials were superimposed and all were on the prediction surface (Fig. Top Panel). 3 IV nicardipine trials were within the ±0.1 PI surfaces, while 2 case series using implanted prolonged release nicardipine (Middle: D&E) were above, suggesting promise. While SQ enoxaparin was below the surface (Bottom: A), low dose heparin infusion (B) was above the +p=0.1 surface showing promise. Mortality models did not find an increase with the most promising treatments.

Conclusions:
Outcome models based on percentage of high grade WFNS and age were successfully developed. This approach may be useful to prioritize treatments worthy of further study.
Abstract 43: Rehabilitation Evaluation at 12 Hours Post-tPA
Authors: Espaillat Kiersten , Jones Julia
Published: October 2018

The current national standard of care after IV Alteplase (tPA) for stroke is bedrest for 24 hours. Because of this, rehabilitation assessments are delayed, which causes downstream delays in the patient getting to the next level of care. We sought to evaluate the feasibility, safety, and effect on length of stay in the acute stroke population post tPA. After reviewing the literature, we were able to find one small study that supported very early mobilization. We then gathered historical data and prospectively collected data on our study group. All patients who received tPA were eligible unless otherwise stated by the physician. The data was then used to determine harm, length of stay, and time to rehabilitation assessment. During the study time period, 87 patients were seen after 12 hours at a median of 17 hours post tPA. An additional 60 patients were seen after 24 hours due to being sedated, or staffing. In the pre-study phase there were no falls noted for patients who remained in bed for 24 hours. The study group similarly had no falls. There were also no incidents of worsening, 1 incidence of hypotension, in the study population. The length of stay in the study group was reduced from 4.5 days to 1.9 days. We now are able to safely monitor these patients and use evidence to drive decisions in care. This small study further supports the idea of early mobilization and treatment as safe, effective, and feasible. Stroke patients are safely able to receive more timely care which helps drive them towards further rehabilitation. This change in culture has resulted in greater patient satisfaction, improved flow through the levels of care, and a more evidence based practice.
Abstract 45: A Stroke Self-Management Program to Enhance Self-Efficacy and Outcome Expectation: A Randomized Controlled Trial
Authors: Lo Suzanne H , Chang Anne M , Chau Janita P
Published: October 2018

Introduction:
Evidence has shown maintaining stroke survivors’ confidence and supporting their self-management after discharge were associated with improved stroke recovery.

Aim:
To test in a randomized controlled trial whether a self-efficacy and outcome expectation enhancing stroke self-management program improved health outcomes.

Methods:
Eligible adult survivors recruited from three acute stroke units were randomized to a new 4-week stroke self-management program (SESSMP) or usual care. The program, underpinned by Bandura’s constructs of self-efficacy and outcome expectation, offered home visits, community group sessions and follow-up phone calls. Primary outcomes included self-efficacy and outcome expectation of self-management. Secondary outcomes included satisfaction with performance of self-management behaviors, health-related quality of life (HRQoL), depressive symptoms and community reintegration. Differential changes of outcomes from baseline to 8-weeks follow-up (one-month post-program) between the two groups were evaluated by generalized estimating equations.

Results:
We recruited 128 participants (mean age 67.46 years, SD 11.95). The SESSMP group in the intention-to-treat (ITT) population showed significantly greater improvements in primary and secondary outcomes except depressive symptoms than the control group across time. Analyses of ITT and per-protocol populations found the changes in scores of all primary and secondary outcomes across time between the two groups comparable. Those receiving all sessions had the greatest and significant increase in self-efficacy, outcome expectation and HRQoL across time compared to those completing only part of the SESSMP and to the control group. No program-related adverse effects were reported. Majority receiving the SESSMP found home visits by nurses and videos about stroke volunteers’ recovery experiences most helpful.

Conclusions:
The results suggested the SESSMP improved survivors’ confidence, positive expectations, self-management behaviors, HRQoL and social outcomes.
Abstract 48: Which Patients With Acute Ischemic Stroke Benefit From the Lower Dosage of Intravenous Tissue Plasminogen Activator? A Cluster Data Analysis
Authors: Dong Yi , Ye Han , Shen Haipeng , Wang Yilong , Li Hao , Ma Sufeng , Wang Yongjun , Dong Qiang
Published: October 2018

Introduction:
Although intravenous alteplase(tPA) in acute ischemic stroke(AIS) has been proved as the standard treatment, there remain concerns about increased risk of symptomatic intracranial hemorrhage. Lower dosage of tPA has been used in Japan and other Asian countries. We aim to find which AIS patients benefit from the lower dosage of intravenous tPA.

Methods:
We used the TIMS-CHINA database of 1440 stroke patients from 67 centers and the 4S database of 2779 patients from 11 centers. Both databases include AIS stroke patients treated with tPA, recorded with similar medical databases structures. The variables include the severity of stroke at baseline (NIHSS score), onset to needle time, dosage of tPA, symptomatic intracranial hemorrhage(sICH), modified Rankin Scale(mRS) at 3 months. We used a machine-learning method of subgroup analysis using decision trees with recursive portioning.

Results:
In this cluster analysis, the appropriate dosage in subsets of acute ischemic stroke patients has been explored. Based on NIHSS score to optimize the interaction effect between t-PA dosage (standard/lower), three subgroups were defined as NIHSS (1) ≤4, (2) 5-14, and (3)≥15. Their risk of sICH and benefit (as mRS0-1) are identified. The estimated difference in log odds of bleeding between standard and lower dosage is: -0.85 (p=0.15) for Group 1, 1.95 (p=0.02) for Group 2, and 0.39 (p=0.56) for Group 3, after effect adjustment of other factors and bias reduction. We are especially careful about bias reduction due to rare events: the number of bleeding cases can be small in certain subgroups. The estimated difference in log odds of efficacy between standard and lower dosage is: 0.16 (p=0.49) for Group 1, -0.16 (p=0.57) for Group 2, and -0.08 (p=0.80) for Group 3, after effect adjustment of other factors.

Conclusion:
Our results advocate using a lower dosage of tPA in moderate stroke, which significantly reduce the bleeding risk while achieving non-inferior performance in efficacy
Abstract 49: Diagnostic Accuracy of Telestroke Consultation
Authors: Ulep Robin D , Stuntz Gage A , Mohammed Alaa E , Yu Caroline G , Mitchell Sara , Vidal Gabriel , Gaines Kenneth J , Iwuchukwu Ifeanyi , McGrade Harold C , Chehebar Daniel , Gropen Toby , Zweifler Richard M
Published: October 2018

Introduction:
Given the rapid expansion of telestroke systems, an increasing number of patients with acute stroke-like presentations are receiving tele-evaluation for guidance of diagnostic and therapeutic decisions. There is limited data, however, regarding the accuracy of telestroke diagnosis. We examined the accuracy of telestroke diagnosis and evaluated predictors of misdiagnosis.

Methods:
We conducted a retrospective study of all telestroke consultations at our center between April 2015 and April 2016. Consultations were classified into one of 3 diagnostic categories: stroke/TIA, mimic, and uncertain. Telestroke diagnosis was compared with final diagnosis determined after review of additional emergency department testing or hospital admission. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for diagnosis of stroke/TIA vs mimic were calculated. Area under receiver-operating characteristic curve (AUC) analysis to predict true stroke was performed. Bivariate analysis based on the diagnostic categories examined association with sex, age, NIH Stroke Scale (NIHSS), stroke risk factors (CAD, DM, HLD, HTN, history of stroke/TIA, smoking), TPA given, bleeding after TPA, symptom onset to last known normal, symptom onset to consult, time of day of consult by 6 hour epoch, and consult duration. Logistic regression (LR) was performed as indicated by bivariate analysis.

Results:
874 telestroke evaluations were included in our analysis. Sensitivity, specificity, PPV, NPV were 97.8%, 82.5%, 93.7% and 93.4%, respectively. AUC (95% CI) was 0.9061 (0.8749-0.9283). LR revealed OR (95% CI) of misdiagnosis for female gender of 1.9 (1.3-2.9).

Conclusions:
Our telestroke system is highly accurate in discriminating between stroke/TIA and stroke mimics with a tendency towards overdiagnosis of stroke. Female gender was associated with misdiagnosis.