bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract TP222: Improving the Quality of Acute Stroke Care in regional Australia: The Victorian Stroke Telemedicine Program
Authors: Cadilhac Dominique A , Bagot Kathleen L , Kim Joosup , Vu Michelle , Dewey Helen M , Hand Peter J , Mitchell Peter J , Campbell Bruce C , Donnan Geoffrey A , Bladin Christopher F
Published: October 2018

Background:
The Victorian Stroke Telemedicine (VST) program is the largest stroke telemedicine service operating in Australia. Patients and clinicians at 16 regional hospitals in Victoria are provided with 24/7/365 access to a network of on-call metropolitan-based neurologists via telemedicine. The VST program supports rapid differential diagnosis and enhances access to best-practice treatments for acute stroke, including transfer to comprehensive stroke centres for endovascular clot retrieval (ECR).

Method:
A historical-controlled cohort design was used to evaluate the VST Program. At each hospital, consecutive patient-level data were obtained 12 months before the VST program commenced (pre) and during the first 12 months of implementing the program (post). Basic clinical data were collected for patients aged 18 years or more and arriving in the Emergency Department (ED) with suspected stroke. Detailed data collection on the patient journey in hospital was conducted for patients with a confirmed ischemic stroke who arrived within 4.5 hours of symptom onset. Aggregated descriptive statistics using the available data for 16 hospitals are presented.

Results:
Overall, 6099 patients with suspected stroke (2932 pre, 3167 post) have presented up to 28/7/2017. Patients arriving to ED within 4.5 hours of ischemic stroke symptom onset: pre-VST n=358 (54% male; mean age 74 years) and post-VST n=484 (59% male, median age 76 years). The proportion of patients meeting these criteria who received intravenous thrombolysis increased (pre: 30% to post: 38%, p=0.019). The median door-to-needle time was faster (pre: 103 minutes; post: 72 minutes, p<0.001), and more patients received thrombolysis within 60 minutes of arrival (pre: 14%; post: 32%, p<0.001). Symptomatic intracerebral hemorrhage after thrombolysis was reduced (pre: 16%; post: 5%, p=0.002). Since the availability of ECR in May 2015, 25% of cases receiving thrombolysis were transferred for ECR.

Conclusion:
Telemedicine expedites access to optimal stroke care and immediately facilitated access to the newest intervention, ECR, with more patients safely and efficiently treated.
Abstract TP225: Effect of FAST-ED Implementation and Age on Distance Patients Travel From Scene to Comprehensive Stroke Center
Authors: Starosciak Amy K , Ramirez Maygret , Ramos Virginia , Gonzalez Ivis C , Tocre Carrion Camila , Strauss Jayme , De Los Rios La Rosa Felipe
Published: October 2018

Objective:
The Field Assessment Stroke Triage for Emergency Destination (FAST-ED) is a pre-hospital screening tool used to detect large vessel occlusion (LVO) strokes. FAST-ED was implemented by Miami-Dade Fire Rescue (MDFR) in March 2017 with a goal to bring potential LVO patients directly to a Comprehensive Stroke Center (CSC) and activate the endovascular team from the field. In this project, we assessed whether use of the FAST-ED increased the distance patients traveled, assuming some of these patients would bypass a primary or acute stroke ready center to come to a CSC.

Method:
This is a retrospective hospital quality study examining distance traveled by MDFR for acute stroke alerts. Data from three periods were compared: (A) Mar-May 2017 after implementation of FAST-ED, (B) Mar-May 2016, the year before implementation, and (C) Dec 2016-Feb 2017, just before implementation. Distance traveled in miles from scene to our CSC was obtained from MDFR incident reports. Data also were broken down by age (<80 vs. ≥80 years).

Results:
In total, 429 acute stroke alerts brought by MDFR to our CSC were reviewed. There were 138 cases in Period A, 136 in Period B, and 155 in Period C. Out of those cases, 156 were aged ≥80 years; 49/138 (36%) in Period A, 45/136 (33%) in Period B, and 62/155 (40%) in Period C. A two-factor ANOVA was used to determine if there was an effect of FAST-ED implementation and age on distance traveled. Patients ≥80 years traveled statistically significantly shorter distances (7.0 mi) than those <80 (9.0 mi), regardless of time period [F(1,5)=13.70, p<0.001]. There was a marginally significant period x age interaction [F(2,5)=2.35, p=0.09] such that people ≥80 traveled further in Period A compared to Period B (7.8 mi vs. 5.8 mi, p<0.05), whereas people <80 traveled less far in Period A compared to Period C (8.2 mi vs. 10.0 mi, p<0.05). No main effect of period was found.

Conclusion:
Implementation of a FAST-ED EMS initiative to bypass to a CSC did not lead to an overall increase in distance traveled. However, the effect was different depending on whether the patient was over 80 years old or not. These results are interesting because FAST-ED does not have age as a component, but age may contribute to on-the-spot MDFR triaging decisions.
Abstract TP229: Characteristics of Patients With Early Rapid Improvement in NIHSS During Interfacility Transfer
Authors: Zachrison Kori S , Boulouis Gregoire , Lauer Arne , Siddiqui Kwahja A , Charidimou Andreas , Regenhardt Robert W , Viswanathan Anand , Rost Natalia , Leslie-Mazwi Thabele M , Schwamm Lee H
Published: October 2018

Introduction:
Interfacility transfer of patients with suspected large vessel occlusion for endovascular intervention is increasingly common. Eligibility depends on stroke severity (NIHSS), yet changes in NIHSS during transfer have not been well-described.

Objective:
to characterize changes in NIHSS during transfer, and identify factors associated with early rapid improvement.

Methods:
Using prospectively collected data from our institution’s Get with the Guidelines-Stroke registry and telestroke network portal, we identified all stroke patients transferred to our hospital from 01/01/10-01/01/16. We calculated change in NIHSS (arrival score minus telestroke score at transferring outside hospital, OSH). Logistic regression identified factors associated with early rapid improvement, controlling for patient characteristics available on arrival, including tPA use.

Results:
Among the 505 patients included, median NIHSS at OSH was 11 (IQR 5-18) and on arrival was 9 (IQR 3-17); median change of 0 (IQR -3-0). Scores increased by ≥4 points among 7%, and decreased by ≥4 among 19%. In bivariate analysis, early rapid improvement was more likely in patients who were ambulatory at baseline, had higher NIHSS at OSH, and were treated with tPA, and less likely among patients with history of hypertension (Table). In multivariable modeling, early rapid improvement was associated with history of coronary artery disease (CAD) and higher NIHSS at OSH (Table). Patients with early rapid improvement were more likely to be discharged home in bivariate (OR 1.58, 95%CI 1.01-2.50) and multivariable analyses (OR 4.07, 95%CI 1.58-10.49).

Conclusion:
In this cohort of transferred patients, NIHSS scores were frequently unchanged or decreased during transfer. History of CAD and higher baseline NIHSS were associated with early rapid improvement during transfer. If confirmed in a larger sample, these results may be useful for triage and intervention planning for transferred patients.
Abstract TP23: Safety and Outcome of Endovascular Therapy in Patients With Minor Stroke: Florida Puerto Rico Collaboration to Reduce Stroke Disparities Study
Authors: Asdaghi Negar , wang Kefeng , Gutierrez Carolina M M , Marulanda-Londono Erika , Ciliberti-Vargas Maria A , Koch Sebastian , Gardener Hannah E , Dong Chuanhui , Mueller-Kronast Nils , Yavagal Dileep R , Hanel Ricardo , Mehta Brijesh , Rose David Z , Robichaux Mary , Fenelon Kathy , Nobo Ulises , Zevallos Juan Carlos , Rundek Tatjana , Sacco Ralph L , Romano Jose G
Published: October 2018

Background:
Patients with minor ischemic stroke were largely excluded from the randomized trials of endovascular therapy (EVT) in stroke. In the Florida-Puerto Rico Registry we sought to determine the utilization of EVT in this population.

Methods:
From January 2010 to March 2017, 57,750 acute ischemic stroke patients within 24 hours of symptom onset were prospectively included from 88 sites in four Florida regions (south, west central, north and panhandle, east central) and Puerto Rico. Differences between minor (NIHSS ≤ 5) and moderate/severe (NIHSS>5) stroke patients who received EVT were evaluated using multivariable logistic regression with generalized estimating equations.

Results:
Among 2,845 EVT patients (50% women, mean age ±SD 71±14 years), 347 (12%) had NIHSS ≤ 5. As compared to NIHSS>5, minor stroke patients were younger (mean age 67 vs. 71, p<0.01), more men (58% vs. 49%, p=0.01) more privately insured (47% vs. 35%, p<0.01), having more HTN (69% vs. 63%, p=0.03) and prior strokes (25% vs. 20%, p=0.02) but less atrial fibrillation (25% vs. 38%, p<0.01). Minor stroke EVT patients arrived later to the hospital (median 128 vs. 102 min, p=0.02) and during working hours (51% vs. 46%,p=0.09). They were less likely to receive IV tPA (29% vs. 42%, p<0.01), had a longer door to puncture time (median 192 vs. 128 min, p<0.01). In multivariable analysis, young age (OR=1.02, 95%CI 1.01-1.03), early arrival (OR=1.64, 95% CI 1.15-2.33) and FL regions (south vs. west central) (OR=2.67, 95% CI 1.07-6.62) were independently associated with EVT in minor stroke. Symptomatic ICH occurred in 4.6% of minor stroke EVT patients and 6.4% in those with NIHSS>5. Majority of minor stroke patients who received EVT were discharged home or to rehab (75%) while 53% of those with NIHSS>5.

Conclusions:
More than 1 in 10 cases that received EVT had mild neurological symptoms. Many factors including hospital expertise and time of presentation affect the use of this treatment. Further study of EVT in minor stroke is warranted.
Abstract TP230: The Development of a Stroke System of Care in Brazil: Where Are We Now?
Authors: Martins Sheila C , Pontes Neto Octavio M , Martin Kelin , Silva Gisele S , Carvalho João J , Bezerra Daniel , Alves Maramelia A , Oliveira Filho Jamary , Rebello Leticia C , Freitas Gabriel R , Cabral Norberto L
Published: October 2018

Introduction:
The organization of the stroke care in Brazil started in 2002 after the tPA approval. In 2008, was started a task force of stroke neurologists together with the Ministry of Health (MOH) with the objective of supporting the establishment of a nationwide network. Since then, the hospitals have progressively improved their structure. In 2012, was launched the National Stroke Policy, by the MOH, with creation of stroke centers in public health system, reimbursement of tPA, implementation of telemedicine and creation of the Line of Care integrating all stroke assistance. The aim of this study is to compare the structure of stroke care in 2008 and 2017.

Method:
This cross-sectional study compared the structure of stroke centers in 2008 and 2017. The information was collected through online questionnaires sent to the stroke centers and to the vascular neurologists.

Results:
In 2008, 35 stroke centers were active (40% assisting public health patients), only 14% with stroke units and no hospital had telemedicine. The National Emergency Medical Service (EMS) was trained in 4 cities, covering 23% of stroke centers. In 2017, there are 139 stroke centers registered in Brazil. We had answers from 110 hospitals (79%) in 15 out of 26 states (9 states do not have stroke centers). The EMS covers 96% of the stroke centers but only 63% is linked with the local network. The centers are 34% public, 42% private and 24% assist both public and private patients (58% assist public health system). The stroke units are present in 49% of hospitals. Neurologists are available 24h /7 days a week in 82% of the hospitals (33% on duty, 44% on call and 23% by telemedicine). In total, 41% of hospitals are comprehensive stroke centers. As the thrombectomy devices are not paid in the public hospitals, only 2 are comprehensive stroke centers, 8 had structure but not devices and are participating in a clinical trial to approve thrombectomy in public hospitals in Brazil.

Conclusion:
The organization of stroke care in Brazil has improved a lot in recent years. Despite this, we have a lot to improve, since it’s still a small number of hospitals for a huge country, with large part of its population without access to the best treatments.
Abstract TP233: An Analysis of Thrombolysis in a Large Telestroke Program in the Stroke Belt
Authors: Onteddu Sanjeeva , Brown Aliza T , Kovvuru Sukanthi , Chen Yu-ting , Joiner Renee , Morgan Tiffany , Benton Tina , Culp William , Lowery Curtis
Published: October 2018

Background:
Thrombolytic treatment of stroke patients in telestroke can be enhanced by studying critical time interval requirements. We retrospectively examined 12 concurrent months of targeted time interval information from 2016 in a large 48 site telemedicine program. Telemedicine programs with new spoke sites added throughout the year must continually evaluate where improvements can be made to decrease the arrival to treatment time.

Hypothesis:
We hypothesized that referral data analysis would highlight areas for improvement to shorten time to treatment.

Methods:
We analyzed critical time targeted information during 12 months of 247 consecutive telestroke neurology referrals from AR SAVES spoke sites when tissue plasminogen activator (tPA) was given. Measured time intervals of: emergency department (ED) door to CT (ED2CT), ED door to call center (ED2CC) for initiation of consult and ED door to neurology call (ED2NeuroCall), neurology call to camera (NeuroCall2Cam), total consult (Con), ED door to tPA (ED2tPA) were studied.

Results:
Reported median times of door to CT [ED2CT, 8 min, IQR 4-15 min], door to call center [ED2CC, 37 min, IQR 26-53 min], door to neurology call time [ED2NeuroCall, 42 min, IQR 33-57 min], neurology call response time [NeuroCall2Cam, 3 min, IQR 2-5 min], and total time spent in consult [Con, 24 min, IQR 19-32 min] all contributed to a ED2tPA median time of 73 min [IQR 60-90]. Twenty-six percent of referral patients received tPA ≤ 60 min and an overall tPA treatment rate of 33.2% was reported. The largest delay in time were: arrival to neurology call time and in consult time, 27 minutes and 13 minutes respectively. Totaling 40 minutes in variation.

Conclusion:
Focus in either ED2NeuroCall or Con of these time areas, may produce the largest improvements and reduce the door to treatment time. A 20 minute reduction in time would dramatically reduce the door to treatment time and increase the percentage of tPA administration to well within the goal of 60 minutes or less.
Abstract TP235: Prehospital Clinical Deterioration Predicts Further Deterioration in Acute Stroke
Authors: Hill Colin M , Saver Jeffrey L , Liebeskind David S , Starkman Sidney , Shkrikova Kristin , Kim-Tenser May , Hamilton Scott , Sanossian Nerses
Published: October 2018

Background:
Studies of neurologic deterioration in stroke have primarily focused on the acute period 24 hours after arrival. We sought to determine whether prehospital/early ED hyper-acute deterioration portends subsequent deterioration in the 24 hour acute period, as well as other prehospital factors that may predict subsequent deterioration.

Methods:
All subjects were enrolled in the NIH Field Administration of Stroke Therapy-Magnesium (FAST-MAG) trial. Hyper-acute neurologic deterioration was defined as Glasgow Coma Scale (GCS) decreasing ≥2 points from paramedic to ED evaluation, acute neurologic deterioration was defined as ≥4 point increase on the NIH Stroke Scale (NIHSS) from ED evaluation to 24 hours post-arrival. Other prehospital factors investigated included age, race, sex, WBC, serum glucose, arrival NIHSS, systolic blood pressure (SBP), body temperature, intracerebral hemorrhage (ICH), hypertension, smoking, diabetes, and previous stroke.

Results:
Of 1,643 patients, 184 (11.2%) experienced acute 24-hour deterioration. Among deteriorators; 45 % were female and mean age (SD) was 70 (±13.3) years. Median last-known-well time to assessments were: prehospital GCS 25 (IQR 15-46) mins, ED arrival GCS and NIHSS 149 (IQR 120-180) minutes and follow-up (24-hour) NIHSS 26 (IQR 18-30) hours. On multivariate analysis, hyper-acute deterioration increased the odds of subsequent acute neurological deterioration (OR = 2.24, p = 0.010, 95% CI 1.21-4.14). Other factors independently associated with acute 24-hour deterioration were ICH, arrival NIHSS, serum glucose level, SBP and body temperature (see Table 1).

Conclusion:
Hyper-acute deterioration is associated with increased odds of acute neurological deterioration in the subsequent 24-hour period.
Abstract TP236: Emergency Department Arrival Mode Does Not Significantly Impact Door-to-Needle Times for IV tPA in Acute Ischemic Stroke
Authors: Cheng Natalie T , Muller Jonathan , Ortega Albert , Aggarwal Sanket , Donahue Courtney G , Gatton Barbara , Bove Joseph , Salgado Miran
Published: October 2018

Background:
Rapid administration of intravenous alteplase (IV tPA) for acute ischemic stroke leads to improved clinical and functional outcomes. However, several barriers delay or preclude patients from undergoing timely treatment, including delayed triage and evaluation in the emergency department (ED). Patients with acute ischemic stroke who arrive by emergency medical services (EMS) receive a higher level of care, but mode of arrival has not been specifically evaluated as a predictor of IV tPA door-to-needle (DTN) times.

Hypothesis:
Patients with acute ischemic stroke who arrive by EMS to the ED will be treated more quickly than patients who arrive by other means.

Methods:
This was a retrospective cohort study evaluating all adult patients presenting with suspected acute ischemic stroke to the ED of an academic hospital and New York State Department of Health-designated stroke center in Brooklyn, NY, who received IV tPA from June 2011 to June 2017. Using Get With the Guidelines - Stroke Program data, a stroke coordinator abstracted data on patient age, sex, NIHSS, arrival mode, emergency severity index (ESI), DTN time, and discharge disposition.

Results:
A total of 156 patients received IV tPA for suspected acute ischemic stroke in the ED during the study period. Baseline characteristics of the sample were mean age of 66 (SD 14.4) years, 48.5% were female, and mean DTN time 46 minutes. The majority of these patients (79.5%) arrived by EMS. The median DTN time in the EMS arrival group was 42.5 (IQR 34-54) minutes compared to 51.5 (IQR 44-58) minutes in the non-EMS arrival group (
P
< 0.05). There was a trend toward more severe strokes in the EMS arrival group but this was not statistically significant (median NIHSS 10 [IQR 6-19] for EMS vs. 4 [IQR 3-5.25] for non-EMS,
P
= 0.05). While arrival mode was not a significant predictor of DTN time (χ
2
[2,
N
= 156] = 59.2,
P
= 0.32), NIHSS was significantly negatively correlated with DTN time (r = -0.20,
P
= 0.01). This may be due to less diagnostic uncertainty and faster clinical decision-making with more severe strokes.

Conclusions:
Arrival by ambulance to the ED is not associated with a significantly shorter DTN times in patients with acute ischemic stroke. However, there is a significant inverse correlation between NIHSS and DTN time.
Abstract TP240: Determinants of Functional Outcomes in Patients Treated With Intravenous Tissue Plasminogen Activator in Telestroke
Authors: Girotra Tarun , Ajinkya Shaun , Kohli Disha , Debenham Ellen , Holmstedt Christine , Banerjee Chirantan
Published: October 2018

Background:
Intravenous thrombolysis in acute ischemic stroke patients (AIS) via telestroke (TS) is safe and effective, with comparable functional outcomes to patients treated at academic stroke centers. However, the association between demographic, clinical and TS logistic factors and functional outcome at 3 months in TS patients has not been studied. Identification of TS specific predictors of good outcome may guide future strategies of care delivery.

Aim:
To determine demographic, clinical, and TS logistic variables associated with 90-day functional outcome in AIS patients treated with IV tPA via TS.

Methods:
We retrospectively analyzed all TS consults treated with IV tPA between January 2016-July 2017 in our state-wide telestroke network. Patients who underwent endovascular intervention were excluded. Fisher exact and χ
2
test for categorical and Student
t
test for continuous variables with a significance level of <0.05 were used. Stepwise logistic regression model was used to identify predictors for favorable outcome (mRS 0-2) at 3 months

Results:
tPA was given to 400 AIS patients via TS. Functional outcome at 90 days was obtained in 94.3% patients. Mean age was 66.8 years and 62% patients were Caucasian. Median NIHSS on presentation was 7. Medical history included hypertension (72%), diabetes (36%), hyperlipidemia (25%), atrial fibrillation (AF) (11%), and CHF (5%). Mean “onset to needle” time was 138.4 minutes(min) and mean “door to needle time” was 61.4 min. Mean “door to login” time was 26.2 min, and mean “login to tPA” time was 19.7 min. Symptomatic ICH and asymptomatic ICH occurred in 15 (5.98%) and 28(11.3%) respectively. Younger age, lower NIHSS at presentation, lower door to login time, and absence of AF and CHF were associated with higher odds of good functional outcome at 90 days in univariate analyses. In multivariate logistic regression, age (OR 0.75, 95% CI 0.67-0.84) and NIHSS at presentation (OR 0.85, 95% CI 0.82-0.89) remained independent predictors.

Discussion:
Younger patients and patients with low NIHSS at presentation are more likely to have good outcome post IV tPA treatment via TS. Larger studies powered to measure the impact of TS delivery variables on functional outcome are needed.
Abstract TP244: The Clinical Prediction Rules to Classify Type of Stroke at Prehospital
Authors: Uchida Kazutaka , Yoshimura Shinichi , Hiyama Nagayasu , Oki Yoshiharu , Matsumoto Tsuyoshi , Tokuda Ryou , Yamaura Ikuya , Saito Shin , Takeuchi Masataka , Shigeta Keigo , Araki Hayato , Morimoto Takeshi
Published: October 2018

Introduction:
The effectiveness of endovascular thrombectomy for acute cerebral large vessel occlusion (LVO) was proved, but many patients did not received such interventions because capable operators were not placed at all hospitals. If the type of stroke [large vessel occlusion, subarachnoid hemorrhage (SAH), intracranial hemorrhage (ICH), other cerebral infarction (CI)] was predicted at prehospital, better access to appropriate interventions were capable. We, thus, developed the clinical prediction rules to classify the type of stroke who were suspected to suffer acute stroke at prehospital, and validated them.

Methods:
We analyzed consecutive 1,229 patients who were suspected to suffer acute stroke from June, 2015 to March 2016. We obtained the history and physical signs at prehospital from paramedics and final diagnosis from hospital transferred. We constructed multivariate logistic regression models for 1) LVO, 2) SAH, 3) ICH, 4) CI, and developed the clinical prediction rules for each type. We prospectively validated the rules with another consecutive patients from August 2016 to July 2017 using mobile application.

Results:
In the derivation cohort, 104 LVO, 57 SAH, 169 ICH, and 183 CI were observed. The area under the receiver operating curve (AUC) of the rules were 0.90 for LVO, 0.90 for SAH, 0.85 for ICH, and 0.65 for CI. The validation cohort of 932 patients showed the sensitivity and specificity of the rules were 0.53 and 0.95 for LVO, 0.73 and 0.96 for SAH, 0.52 and 0.85 for ICH, 0.63 and 0.70 for CI. The AUCs of LVO, SAH, ICH, and CI were 0.85, 0.96, 0.77, and 0.67, respectively.

Conclusions:
The clinical prediction rule calculated by paramedics at prehospital can easily classify the patients who suspected to have stroke into LVO, SAH, ICH, and CI with excellent performance. By applying the rules, more patients would receive appropriate interventions without unnecessary delay. 
Abstract TP25: Impact of Get With the Guideline on Reducing Door-to-Reperfusion Time and Promote Good Clinical Outcome for Mechanical Endovascular Reperfusion Therapy
Authors: Suzuki Shuichi , Meng Jason , Abcede Linda , Mohammad Shafie , Yu Wengui , Stradling Dana , Patel Ravi , Lin Li-Mei , Golshani Kiarash , Hsu Frank
Published: October 2018

Background:
Reducing the Door to Revascularization (DTR) time is an essential factor to promise good clinical outcomes in the mechanical endovascular therapy of large vessel occlusion (LVO) of anterior circulation acute ischemic stroke. Thus, it is imperative to know the critical steps, in which we can reduce the DTR time in the acute stroke intervention.

Objectives:
The object of this study is to identify the critical steps that cause the delay in DTR by utilizing the Get with the Guideline (GWTG) Stroke Reporting Measures. This study further evaluates the implementation of GWTG to develop an optimal workflow to improve DTR time in acute stroke intervention.

Methods:
Retrospective cohort analysis was performed over a three-year-period in anterior- circulation LVO acute ischemic stroke with mechanical thrombectomy. DTR was collected and subdivided into various interval time measures including Door to Puncture (DTP) Time, Picture to Puncture (PTP) Time, and Puncture to Revascularization (PTR) Time. GWTG Stroke Reporting Measuring system was implemented to detect the delay of each interval. The impact of GWTG system was evaluated by comparing each interval time of pre- vs. post-GWTG cohort. The Angiographic outcomes in Thrombolysis in Cerebral Infarction (TICI) perfusion scale, and clinical outcomes as measured by modified Rankin Scale (mRS) at 90 days were also compared between pre-vs. post-GWTG cohort.

Results:
Data of a total 38 patients pre-GWTG, and 52 patients post- GWTG cohort were analyzed. In the Pre-GWTG, the greatest delay was observed in the PTP with median 94 minutes. Implementation of GWTG significantly shortened PTP (pre-GWTG vs. Post-GWTG: 94 vs. 35 min), resulted in significant reduction in DTR (214 vs. 125 min). There was no significant difference in the PTR or in the proportion of the good angiographic outcomes of TICI IIB and III between pre- vs. post-GWTG cohort. The proportions of good clinical outcome in mRS 0-2 were significantly higher in post-GWTG (50% vs. 64%).

Conclusion:
GWTG implementation with Stroke Reporting Measures substantially achieved reduction in various interval time of DTR, especially in the PTR, which lead better clinical outcome.
Abstract TP251: Release of IL-6 After Stroke Contributes to Impaired Cerebral Autoregulation and Hippocampal Neuronal Necrosis Through NMDA Receptor Activation and Upregulation of ET-1 and JNK
Authors: Armstead William M , Hekierski Hugh , Pastor Philip , Yarovoi Serge , Higazi Abd Al Roof , Cines Douglas
Published: October 2018

Introduction:
The sole FDA approved drug treatment for acute stroke is tissue type plasminogen activator (tPA). However, its brief therapeutic window and post-treatment complications markedly constrain its use. Upregulation of JNK MAPK and ET-1 by exogenous tPA after thrombotic stroke contributes to impaired cerebrovascular autoregulation, which exacerbates ischemic injury. Wild type (wt) tPA can bind to either the lipoprotein-related receptor (LRP), which mediates vasodilation, or NMDA-receptors (NMDA-Rs), exacerbating vasoconstriction and ischemia. tPA-A
296-299
, a variant that is fibrinolytic and binds to LRP but not to NMDA-Rs, does not induce upregulation of ET-1 and JNK and thereby does not exacerbate loss of autoregulation and the resultant histopathology after stroke. Elevations in IL-6, a marker of the inflammation that accompanies ischemic stroke, is reported to be an adverse prognostic factor.

Hypothesis:
We hypothesized that IL-6 released after stroke by wt tPA through activation of NMDA-Rs and upregulation of ET-1 and JNK contributes to impairment of cerebral autoregulation and increased histopathology.

Methods:
Pial artery diameter, CSF ET-1, JNK, and IL-6 measured and histopathology assessed in anesthetized pigs. Stroke was induced by photothrombosis.

Results:
IL-6 was increased post-stroke, which was increased further by wt tPA. Co-administration of the IL-6 antagonist LMT-28 with wt tPA prevented impairment of cerebral autoregulation and necrosis of hippocampal CA1, CA3 cells. Isoproterenol dilation was unchanged by stroke. tPA-A
296-299
, wt tPA co-administered with the JNK inhibitor SP 600125 and the ET-1 antagonist BQ 123 blocked stroke induced elevation of IL-6. Co-administration of LMT-28 with wt tPA blocked the augmentation of JNK and ET-1 post-stroke.

Conclusions:
IL-6 released after stroke, which is enhanced by wt tPA through activation of NMDA-Rs and upregulation of ET-1 and JNK, impairs cerebral autoregulation and increased histopathology. Strategies that promote fibrinolysis while limiting activation of NMDA-Rs and release of IL-6, such as tPA-A
296-299
, may improve the benefit/risk ratio compared to wt tPA in treatment of stroke.
Abstract TP253: Double Negative T Cells With FasL Mutation Promote M2-Microglial Polarization By Inhibiting PTPN2/TNF-α Pathway in Experimental Stroke
Authors: Meng Hailan , Zhao Haoran , Cao Xiang , Weng Leihua , He Dongsheng , Xu Yun
Published: October 2018

Instructions:
The crosstalk between T lymphocytes and microglia plays an important role in modulating neuroinflammation after ischemic stroke. We have demonstrated FasL mutant (
gld
) mice attenuated brain inflammation after ischemic injury, with a dramatic accumulation of double negative (DN) T cells in brain. However, the effects of DN T lymphocytes in modulating pro-inflammatory (M1) or anti-inflammatory (M2) microglial polarization are not fully understood.

Methods:
Middle cerebral artery occlusion (MCAO) was induced for 60 min followed by 24 h and 72 h reperfusion in both
gld
and C57BL/6J mice. DN T lymphocytes isolated from
gld
and C57BL/6J mice after MCAO were cocultured with primary microglia for 24 h. The subtypes of T lymphocytes and microglial polarizations in ischemic brain were measured by flow cytometry, real-time PCR and immunofluorescence.Oxygen glucose deprivation (OGD)-induced neurons were treated by the coculture supernatant for 24 h, followed by propidium iodide and calcein AM staining. In inhibition study, DN T cells were pretreated with ethyl-3,4-dephostatin, a inhibitor of protein tyrosine phosphatases nonreceptor type 2 (PTPN2), for 24 h.

Results:
In vivo
, compared to C57BL/6J mice, DN T cells were significantly accumulated in ischemic cerebral hemisphere in
gld
mice 72 h after MCAO, accompanied by increased M2 microglial polarization.
In vitro
, microglia underwent M1 polarization when cocultured with DN T cells from C57BL/6J mice, whereas shifted to M2 phenotype when cocultured with
gld
-derived DN T cells. In addition, the coculture supernatant from
gld
mice attenuated OGD-induced neuronal death and neurotoxicity. Furthermore, DN T lymphocytes from
gld
mice exhibited a profound downregulation of PTPN2 in protein levels, which was accompanied by an enhanced protein level of TNF-α. In contrast, inhibition of PTPN2 abolished the decreased expression of TNF-α in DN T cells from
gld
mice, and simultaneously reduced the M2-microlgial polarization.

Conclusions:
DN T cells with FasL mutation drives M2-microglial polarization and attenuated neuroinflammation in experimental stroke. The underlying mechanisms may involve the abolishment of FasL/PTPN2 pathway in inhibiting TNF-α expression in DN T cells with FasL mutation.
Abstract TP254: Effects of Inducible Nitric Oxide Synthase on Behavior and Functional Outcomes in a Novel “Humanized” Transgenic Mouse Model of Ischemic Stroke
Authors: Brichacek Allison L , Jun Sujung , Povroznik Jessica M , Nwafor Divine C , Benkovic Stanley A , Wang Wei , Quintana Dominic D , Hu Heng , Ren Xuefang , Engler-Chiurazzi Elizabeth B , Brown Candice M
Published: October 2018

Introduction:
Inducible nitric oxide synthase (iNOS) is a critical regulator of brain and systemic inflammatory responses in many neurological disorders. Intriguingly,
iNOS
null mice have produced equivocal outcomes in mouse models of ischemic stroke, a result that may be due, in part, to species-specific differences between the mouse and human
iNOS
genes. Due to numerous differences at the gene regulatory level, mouse
iNOS
naturally produces much higher levels of nitric oxide (NO) than the human gene. To resolve the functional differences between mouse and human iNOS in ischemic stroke, we employed a novel mouse that expresses human
iNOS
on a mouse
iNOS
null genetic background, termed the HN mouse. Our study objective was to compare functional and behavioral outcomes following ischemic stroke between wildtype (WT) and HN mice.

Hypothesis:
We hypothesized that post-stroke functional outcomes would be more severe in HN male mice than in WT mice.

Methods:
Male C57BL/6J (WT) and HN mice (4-6 months) were subjected to 60 minutes of transient middle cerebral artery occlusion (tMCAO) followed by reperfusion and behavioral assessments at seven-day intervals for 30 days. Laser-Doppler flowmetry pre- and post-tMCAO was used to assess the effect of iNOS on blood flow. A comprehensive neurological battery was used to assess sensorimotor ability, reflexes, and balance, followed by open field, wire hang, and rotarod testing to evaluate locomotor activity, limb strength, and coordination.

Results and Conclusion:
Blood flow was significantly decreased in the ipsilateral hemisphere of both WT and HN mice following acute ischemic stroke; however, HN mice exhibited a sustained global decrease in blood flow following reperfusion. HN mice also demonstrated decreased locomotor activity and coordination, as well as greater neurological deficits compared to WT mice. Overall, these results suggest that the HN mouse model recapitulates more neurological deficits associated with human ischemic stroke than WT mice. Thus, the HN mouse may represent a more “humanized” model of ischemic stroke than more commonly used mouse models that express the mouse
iNOS
gene.
Abstract TP256: Interactions Between Activated Microglia and Macrophages on Polarization and Chemotaxis Effect After Ischemic Stroke
Authors: Huang Meiying , Kim Jong Youl , Park Joohyun , Lee Jong Eun
Published: October 2018

The inflammatory response following acute ischemic stroke is a well-known and widely studied phenomenon, but the mechanism is still unclear. After ischemic stroke, microglia and recruited macrophages play major roles in neuroinflammation after ischemic stroke. To characterize these roles, we explored how these cells affect counterpart’s differentiation, polarization and infiltration or migration.

Methods:
BV2 (microglia cell line) were treated with lipopolysaccharides (LPS; 10ng/mL) or interleukin-4 (IL-4; 25ng/mL), and the supernatant was collected as M1 or M2 conditioned media of BV2. The supernatant of PMA differentiated THP-1 (monocyte cell line) followed by LPS (20ng/mL) treatment or interleukin-13 (IL-13; 25ng/mL) & IL-4(25ng/mL) co-treatment was collected as M1 or M2 conditioned media of THP-1. After BV2 or THP-1 cultured in conditioned media, the activation and polarization were assessed by ICC and confocal microscopy for CD11b, CD86 and CD206. Transwell inserts of 3 and 8 μm pore membrane were used for THP-1 infiltration and BV2 migration assay. M1/M2 conditioned media of BV2 and THP-1 and the brain tissue of ischemic mouse model were assessed by proteome profiler array (PPA) to find target cytokine and chemokine.

Results:
THP-1 and BV2 expressed CD206 in M2 conditioned media of BV2 or THP-1. M2 conditioned media of BV2 increased the infiltratory ability of THP-1 while M1 conditioned media of THP-1 enhanced BV2 migration. MIP-2 was significantly expressed in the M1 conditioned media of BV2 and MIP-1a was high in the M2 conditioned media of BV2. MIF and CCL5 were highly expressed in M1 and M2 conditioned media of THP-1, particularly in M1. After ischemic stroke, chemokines were significantly expressed at 3 days than at 7 days in the PPA and several spots were match to the conditioned media of BV2.

Conclusion:
Our study suggests a new insight into the interaction of microglia and monocyte through their ability to expression of cytokine and chemokine after ischemic stroke. Modulation of microglial and monocyte by key cytokine and chemokine represents huge potential for new therapeutic strategies in acute brain injury.
Abstract TP258: Activation Of JAK/STAT3 Restores Nature Killer Cell Function and Improves Immune Defense After Brain Ischemia
Authors: Jin Wei-Na , Liu Qiang , Shi Samuel , Gonzales Rayna , Shi Fu-Dong
Published: October 2018

Background:
Stroke-induced immune suppression predisposes the host to infections, and can contribute to high morbidity and mortality in stroke patients worldwide. Since ischemic stroke has a profound effect on the systemic immune response which may explain the increased susceptibility of stroke patients to infection, an urgent need persists for a better understanding of mechanisms associated with immune suppression so that new and effective treatments for stroke can be identified. Natural killer (NK) cells play a key role in early host defense against pathogens by killing infected cells and/or producing cytokines such as interferon-γ. As the phenotype and function of peripheral NK cells have been widely investigated in ischemic stroke, in this study we comprehensively analyzed molecular signature of NK cells after ischemic brain injury.

Methods:
The nCounter Mouse Inflammation gene expression kit containing 561 inflammation related genes was used to analyze gene expression changes in splenic NK cells over the time course of experimental ischemic stroke. In order to investigate the effect of STAT3 activation on NK cell phenotype and function after stroke, splenic NK cells isolated from wildtype C57 mice targeting STAT3 was established by introducing STAT3 CRISPR activation plasmid.

Results:
We observed that different splenic NK cell phenotypes and functional properties across the time course of MCAO was reflected in distinct gene expression profiles. Functional analysis revealed that the most overrepresented NK cell biologic processes are those related to NK cell mediated immune response and functions. Based on gene expression and pathway-network analysis, we observed that STAT3 exhibited lower expression levels after transient middle cerebral artery occlusion (MCAO) compared with sham controls. Genetic activation of STAT3 by introducing STAT3 CRISPR plasmid prevented the loss of NK cell derived interferon-γ production after MCAO, together with reduced bacteria burden and mortality.

Conclusion:
Our data suggest that brain ischemia impairs NK cell-mediated immune defense in periphery at least in part through JAK-STAT3 pathway, which can be re-addressed by modulating STAT3 activation status.
Abstract TP259: Tryptophan Metabolism Affects the Intestinal Immune Response After Stroke
Authors: Benakis Corinne , Sadler Rebecca , Singh Vikramjeet , Roth Stefan , Liesz Arthur
Published: October 2018

Introduction:
The gut microbiota influences the severity of brain injury through regulation of intestinal immune homeostasis. However, molecular cues involved in microbiota-immune interaction after stroke are unknown. Metabolites have a pivotal role in connecting commensals to the immune response. Specifically, bacteria-derived metabolites of tryptophan catabolism activate the transcription factor aryl hydrocarbon receptor (AhR) which regulates T cell polarization directly or via tolerogenic function of dendritic cells (DCs).

Hypothesis:
Since adaptive immune cells are involved in stroke, we hypothesize that modulation of tryptophan metabolism–orchestrated by bacteria–modifies T cell differentiation and influences stroke outcome.

Methods:
Stroke is induced by the occlusion of the middle cerebral artery (MCAO) in C57BL6 mice. Blood and the distal small intestine are sampled for the detection of tryptophan metabolites and quantified by metagenomics or mRNA expression. Immune cells are isolated from the intestine and analyzed by flow cytometry. Stroke outcome is measured by infarct volumetry and behaviour tests.

Results:
Tryptophan catabolism was augmented in mice subjected to stroke-induced dysbiosis–shown by a) an increase of the most proximal metabolite kynurenine and a concomitant decrease of tryptophan and b) an upregulation of mRNA expression of the rate-limiting enzyme involved in tryptophan’s breakdown. This was paralleled by an increase of AhR mRNA in the ileum after MCAO. To test the implication of AhR on the tolerogenic function of DCs, we used AhR-DCs knock-out mice. We found that CD103+CD11b+ DCs lacking AhR were downregulated after stroke compared to wild-type (WT) mice. Interestingly, polarization state of T cells was modified in DCs lacking AhR (regulatory versus Th17 cell ratio). This could influence the central nervous system immune response and induce protection after stroke, as suggested by a reduction of infarct volume observed 3 days after stroke in AhR-DCs knock-out mice compared to WT mice.

Conclusion:
These findings suggest that stroke-induced dysbiosis leads to an increase of tryptophan catabolism, and that AhR depletion in DCs influences immune cell polarization and stroke outcome.
Abstract TP260: A Novel Neurogenic-Stem Cell Stimulating Curcumin Analog to Treat Acute Ischemic Stroke
Authors: Lapchak Paul A , Boitano Paul D , Schubert David , Lyden Patrick D
Published: October 2018

While nerve cells rapidly die in stroke, and patients do initiate a neurogenic response to replace these cells, there has been no attempt to develop pleiotropic cytoprotective compounds to further promote neurogenesis in stroke patients, and there are no neurogenic or cytoprotective drugs approved by the FDA. In this study, we focused on the parent compound J-147, a curcumin derivative that is a 5-LOX inhibitor, and has potent neuroprotective and neurogenic activities. J-147 rescues HT22 cells from iodoacetic acid challenge (EC
50
50 nM), and oxytosis (EC
50
115 nM). J-147 is neuroprotective against glutamate excitotoxcity in E18 cortical neuron culture (EC
50
27 nM), and prevents cell death in an embryonic cortical cell trophic factor withdrawal assay (EC
50
25 nM). J-147 can rescue a clone of the hippocampal nerve cell line HT22 expressing TrkB, from serum starvation under conditions where the cells can be protected by BDNF (EC
50
50 nM). In mice, J-147 is neurogenic and can stimulate cell division in germinal regions of the brain (increase BrdU
+
DCX
+
labeled cells), enhances endogenous neurotrophic factors and energy metabolism. With this basis, we tested J-147 in 2 translational stroke models. First, using a rodent intraluminal suture model, in combination with a quantal analysis method to determine the effect of increasing ischemia duration (5-90 minutes) on behavioral deficits, IV J-147 treatment (10 mg/kg) administered 5 minutes following the end of occlusion (5-90 minutes), significantly (P=0.045) reduced stroke-induced behavioral deficits and increased the P
50
value to 36.37 ± 1.72 (n=19) minutes from P
50
= 20.1 ± 4.07 minutes (n=19) for the control group. J-147 also reduced infarct volume following IV administration (p<0.05). Second, using the standardized rabbit small clot embolic stroke model, IV J-147 treatment (10mg/kg) administered 1 hour post-embolization increased the P
50
value (behavior) to 1.88 ± 0.10 mg (n=20) compared to P
50
= 1.07 ± 0.07 (n=19) for control(p<0.05). Additional studies showed that J-147 was not mitogenic, or cytotoxic using the CeeTox assay (Raking 90μM) and had a good IV PK profile in rabbits/rats (t
1/2
5.89-8.56 hours). These data support the development of J-147 and neurogenic analogs as a novel class of drug to treat stroke.
Abstract TP263: Activation of Endothelial p21-Activated Kinase 1 Provides Neuroprotection After Stroke
Authors: Liu Lin , Sun Ping , Yi Yanhua , Spahr Zachary R , McCullough Louise , Li Jun
Published: October 2018

Stroke is a major cause of death and long-term disability. Pak1 is implicated in many neurological disorders as it has been suggested to promote neuronal survival. However, its function and mechanisms have not been investigated in stroke. We assessed the hypothesis that Pak1 provides neuroprotection in stroke by stimulating the secretion of brain-derived neurotrophic factor (BDNF) in endothelial cells.

Transient focal ischemia was induced by middle cerebral artery occlusion (MCAO, 90 mins) in young WT male mice. Two doses of IPA3, a Pak1 specific inhibitor, were injected (i.p.) at 30 minutes prior to stroke and 1.5 hours after stroke. For mechanism studies, lentivirus (LV) encoding Pak1 or IPA3 was used to overexpress or pharmacologically inhibit Pak1 in mouse primary brain microvascular endothelial culture. Then the cells were subjected to OGD (16h) with 48 h re-oxygenation and conditioned media (Endo-CM) were collected subsequently. Mouse primary cortical neuron culture was treated with Endo-CM after OGD (90 mins) and neuronal death was assessed 24 hours later.

Pak1 activation (phosphorylated Pak1) was observed in the ischemic hemispheres 6 and 72 hours after MCAO (p-Pak1: sham 94.5± 4.7% versus 6-hour stroke 192.5 ± 10.4% ; sham 94.5± 4.7% versus 72-hour stroke 254.4 ± 32.3%, n = 4 p/g, p<0.05 for both). Administration of IPA3 increased brain infarct size assessed 24 hours after MCAO stroke. In endothelial cultures, overexpression of Pak1 increased BDNF secretion in Endo-CM after OGD (LV-GFP 22.7 ± 2.8 versus LV-Pak1 48.6± 5.5, n = 4 p/g, p<0.05). Accordingly, inhibition of Pak1 attenuated levels of BDNF in Endo-CM (Vehicle 24.5 ± 1.5 versus IPA3 9.4± 0.7, n = 3 p/g, p<0.05). Finally, treatment with Endo-CM collected from Pak1 overexpressing culture reduced neuronal death after OGD (LV-GFP 36 ± 2% versus LV-Pak1 10± 1%, n = 3 p/g, p<0.05), while Endo-CM from cells treated with Pak1 inhibitor increased neuronal mortality (Vehicle 24± 7% versus IPA3 43± 2%, n = 3 p/g, p<0.05).

Taken together, we demonstrated that endothelial Pak1 provides neuroprotection after ischemia. Mechanically, our data revealed that activation of Pak1 stimulates endothelial production of a well-known potent neuroprotectant, BDNF.