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Patent foramen ovale (PFO) is a potential conduit for paradoxical embolization to the systemic atrial circulation of a thrombus originating in the venous system. In a selected group of subjects, the prevalence of deep vein thrombosis (DVT) was assessed. Subjects were identified if they underwent magnetic resonance venography (MRV) pelvis and lower extremity doppler (LE-VDU) for assessment of DVT with PFO. The primary outcome measure was to report the number of patients with paradoxical embolization as their suspected etiology of stroke due to the presence of DVT, which then will be considered as determined stroke. Others with determined stroke diagnosis were reported using Treatment of Acute Stroke Trial (TOAST) criteria. At discharge, those without etiology of their stroke were grouped under embolic stroke of undetermined source (ESUS). We further analyzed the prevalence of DVT by age group, ≤ 60 years vs > 60 years to describe if the prevalence is higher with younger age and to evaluate if higher Risk of Paradoxical Embolism (ROPE) score will have higher number of DVTs compared to lower ROPE scores. Of the 293, 19 (7%) were strokes due to paradoxical embolism. At discharge, determined stroke were 54% vs ESUS were 46%. The overall prevalence of DVT was 19 (7%); MRV-pelvis 13 (4%), and LE-VDU was 9 (3%). No significant difference was noted using both modalities. However, in multivariable regression analysis, a trend suggested an association between pelvic thrombi and high ROPE score as the etiology of stroke; OR 3.56 (0.98, 12.93); p = 0.054. Detection of DVT was not associated with PFO, high ROPE scores or young age. Our data indicate an over-reliance of testing for DVT, particularly MRV pelvis with contrast, in patients with PFO. Clinical studies are needed to identify other factors predictive of DVT in patients with ischemic stroke and PFO.

Background and Purpose— Timely access to endovascular thrombectomy (EVT) centers is vital for best acute ischemic stroke outcomes. Methods— US stroke-treating centers were mapped utilizing geo-mapping and stratified into non-EVT or EVT if they reported ≥1 acute ischemic stroke thrombectomy code in 2017 to Center for Medicare and Medicaid Services. Direct EVT-access, defined as the population with the closest facility being an EVT-center, was calculated from validated trauma-models adapted for stroke. Current 15- and 30-minute access were described nationwide and at state-level with emphasis on 4 states (TX, NY, CA, IL). Two optimization models were utilized. Model-A used a greedy algorithm to capture the largest population with direct access when flipping 10% and 20% non-EVT to EVT-centers to maximize access. Model-B used bypassing methodology to directly transport patients to the nearest EVT centers if the drive-time difference from the geo-centroid to hospital was within 15 minutes from the geo-centroid to the closest non-EVT center. Results— Of 1941 stroke-centers, 713 (37%) were EVT. Approximately 61 million (19.8%) Americans have direct EVT access within 15 minutes while 95 million (30.9%) within 30 minutes. There were 65 (43%) EVT centers in TX with 22% of the population currently within 15-minute access. Flipping 10% hospitals with top population density improved access to 30.8%, while bypassing resulted in 45.5% having direct access to EVT centers. Similar results were found in NY (current, 20.9%; flipping, 34.7%; bypassing, 50.4%), CA (current, 25.5%; flipping, 37.3%; bypassing, 53.9%), and IL (current, 15.3%; flipping, 21.9%; bypassing, 34.6%). Nationwide, the current direct access within 15 minutes of 19.8% increased by 7.5% by flipping the top 10% non-EVT to EVT-capable in all states. Bypassing non-EVT centers by 15 minutes resulted in a 16.7% gain in coverage. Conclusions— EVT-access within 15 minutes is limited to less than one-fifth of the US population. Optimization methodologies that increase EVT centers or bypass non-EVT to the closest EVT center both showed enhanced access. Results varied by states based on the population size and density. However, bypass showed more potential for maximizing direct EVT-access. National and state efforts should focus on identifying gaps and tailoring solutions to improve EVT-access.

Background: Systemic administration of bone marrow derived stromal cells (MSCs) releases a broad range of trophic factors mediating stroke recovery. How MSCs release these factors may depend on the state of the circulation after systemic administration. We assessed whether the secretomes of MSCs, upon exposure to peripheral blood monocytes (Mo), differs depending on the temporal course when the Mo were isolated after stroke. Methods: Peripheral blood mononuclear cells (PBMCs) from stroke patients was isolated at 24h (N=10) and day 5-7 (N=7) after stroke, and from healthy controls (N=5) using Ficoll gradient. CD14+ Mo were isolated using indirect magnetic beads labelling. Contact and Trans-well co-culture assays were established using 100,000 CD14+ Mo and MSCs each in a 0.8um transwell system. After 24h, media was collected and analyzed for secretome using multiplex cytokine assay. Subtypes of Mo were evaluated using flow cytometry. Results: There was a significant increase in non-classical (CD14+CD16++) Mo and a significant decrease in classical (CD14++CD16-) Mo at Day5-7 after stroke as compared to 24h after stroke (Fig). When Day5-7 CD14+ Mo were co-cultured with MSCs, we found a significant reduction in inflammatory IL-1β and TNF-α, and a significant increase in anti-inflammatory IL-4 as compared to co-cultures of MSCs with healthy Mo. This effect was more pronounced in transwell (vs contact) co-cultures. Co-cultures of MSCs and Mo from controls or from patients 24h after stroke led to reductions in TNF-α and upregulation in IL-4 compared with Mo alone. There were no differences in effect of MSCs co-cultures with healthy vs 24h stroke Mo. Conclusion: Our study indicates that the immunomodulatory effect of MSCs may be dependent on the phenotype of Mo in the peripheral circulation of stroke patients. Hence, depending on the temporal course after stroke, the systemic circulation of stroke patients may differentially regulate MSCs to release soluble factors.

Introduction: Four Factor Prothrombin Complex Concentrate (4F-PCC) is indicated for reversal of warfarin-induced coagulopathy. In small cohort studies, 4F-PCC has similar hemostatic efficacy rates reversing non-vitamin K anticoagulants (NOACs). There are no comparison studies evaluating 4F-PCC for the reversal of warfarin versus NOACs in the setting of intracerebral hemorrhage (ICH). Methods: A multicenter retrospective cohort study was conducted between 2013-2020 at a comprehensive stroke system in ICH patients who received 4F-PCC for the reversal of warfarin or a NOAC. Patients were included if they were adults with an acute ICH, anticoagulant regimen of warfarin (INR 1.3 or greater) or NOAC, and 2 head CT scans within 24 hours to determine hemostatic efficacy. Hemostatic efficacy was evaluated by the Sarode scale. The chi square and t-test were used as appropriate for demographic and clinical data, with multivariable regression analysis conducted in a forward stepwise manner, retaining variables with significance less than 0.05. Results: One hundred fifty-seven patients were included (baseline characteristics in Table 1). There was no statistically significant difference in effective hemostasis observed between warfarin and NOAC patients (83% vs 75%, p=0.33). Similarly, multivariable analysis did not demonstrate a significant difference in effective hemostasis (OR 0.55, 95% CI: 0.2-1.3, p=0.2). However, due to wide 95% confidence intervals, we cannot exclude a key treatment effect from PCC. After controlling for baseline characteristics, patients treated with NOACs had 53% lower odds of a good clinical outcome compared to those treated with warfarin (Figure 1; OR 0.47, 95% CI: 0.2-1.3, p=0.13). Conclusions: In conclusion, there was no statistically significant difference in hemostatic efficacy or clinical outcomes between warfarin and NOAC patients following reversal with 4F-PCC.

Background: Acute ischemic strokes outcomes may be less favorable in elderly patients. Whether transferring octogenarians with large vessel occlusion (LVO) for endovascular thrombectomy (EVT) results in similar outcomes to younger patients is uncertain. Methods: A pooled cohort from 6 centers (Europe, US) from 1/2014 to 5/2020 of pts with (ICA, M1, M2) LVO transferred for EVT ≤ 24 hrs from LKW. Patients were stratified into < 80 vs ≥ 80 years old. We compared 90 day functional independence and safety outcomes and assessed for predictors of good outcome (mRS 0-2) and profound disability (mRS 5-6). Results: Of 1176 pts received EVT as transfers, 216 (18%) were octogenarians. Baseline NIHSS was higher in octogenarians [19 (14, 22) vs 17 (12, 21), p Milder strokes (aOR 0.88, 95%CI 0.86-0.91, p Conclusion: EVT may be associated with lower independence rates in transferred octogenarians with LVO. Milder stroke severity, earlier presentation and IV thrombolysis increased the odds of good outcomes in octogenarians. Severe strokes and later treatment were associated with profound disability. Optimized selection and workflow is warranted in transferring elderly patients for EVT.

Introduction: Little is known on the impact of telestroke in addressing disparities in acute ischemic stroke care. Methods: We conducted a retrospective review of acute ischemic stroke patients evaluated over our 17-hospital telestroke network in Texas from 2015-2018. Patients were described as Non-Hispanic White (NHW) male or female, Non-Hispanic Black (NHB) male or female, or Hispanic (HIS) male or female. Single imputation using fully conditional specification was conducted to impute missing values in NIHSS (N=103). We compared frequency of tPA and mechanical thrombectomy (MT) utilization, door-to-consultation times, door-to-tPA times, and time-to-transfer for patients who went on to MT evaluation at the hub after having been screened for suspected large vessel occlusion at the spoke. Results: Among 3873 patients (including 1146 NHW male (30%) and 1134 NHW female (29%), 405 NHB male (10%) and 491 NHB female (13%), and 358 HIS male (9%) and 339 HIS female (9%) patients) (Table 1), we did not find any differences in door-to consultation time, door-to-tPA time, time-to-transfer, frequency of tPA administration or incidence of MT utilization (Table 1 & 2). Conclusion: There was a lack of racial, ethnic, and sex disparities in ischemic stroke care metrics within our telestroke network. In order to fully understand how telestroke alleviates disparities in stroke care beyond our single-network review, collaboration among networks is needed to formulate a multicenter telestroke database similar to the Get-With-The Guidelines.

Background: Direct To Angio (DTA) for transferred large vessel occlusions (LVO) lowers time to endovascular thrombectomy (EVT), reperfusion and potentially improves outcomes. Safety and efficacy of DTA in late time window and on-call hours is unknown. Methods: Pooled cohort from 6 centers (EU, US) from 1/14-5/20 (ICA, M1, M2) LVO pts transferred for EVT≤24 hrs from LKW. Pts stratified into with repeat imaging (RI) (CT+/- CTA/CTP) and without RI (DTA). We compared time metrics, good outcome (90 day mRS 0-2), safety (sICH, mortality) and assessed the impact of arrival for EVT; regular (M-F, 8am-5pm) vs on-call hrs. Propensity matched analysis was done. Results: Of 1178 EVT transfers, 334 (28%) were DTA. DTA pts had more tPA (61% vs 51%, p=0.002), trended to lower NIHSS 17 (12, 20) vs 17 (13, 21), p=0.07 and lower LKW to arrival 268 (190, 430) min vs 280 (190, 518), p=0.097. Groin puncture (GP) was faster with DTA (p6-24, p=0.88 for interaction). In propensity matched 75 pairs, DTA had shorter time to EVT (19 min vs 52, p Conclusion: In pooled, non-randomized data DTA may result in faster treatment, safe and better functional outcomes, during all hours and treatment windows. Repeat imaging may be reasonable with prolonged transfer times. Optimal EVT workflow in transfers may result in faster, safe reperfusion with higher good outcomes.

Introduction Differences in access to stroke care and compliance with standard of care stroke management among patients of varying racial and ethnic backgrounds and sex are well-characterized. However, little is known on the impact of telestroke in addressing disparities in acute ischemic stroke care. Methods We conducted a retrospective review of acute ischemic stroke patients evaluated over our 17-hospital telestroke network in Texas from 2015-2018. Patients were described as Non-Hispanic White (NHW) male or female, Non-Hispanic Black (NHB) male or female, or Hispanic (HIS) male or female. We compared frequency of tPA and mechanical thrombectomy (MT) utilization, door-to-consultation times, door-to-tPA times, and time-to-transfer for patients who went on to MT evaluation at the hub after having been screened for suspected large vessel occlusion at the spoke. Results Among 3873 patients (including 1146 NHW male (30%) and 1134 NHW female (29%), 405 NHB male (10%) and 491 NHB female (13%), and 358 HIS male (9%) and 339 HIS female (9%) patients), we did not find any differences in door-to consultation time, door-to-tPA time, time-to-transfer, frequency of tPA administration, or incidence of MT utilization. Conclusion We did not find racial, ethnic, and sex disparities in ischemic stroke care metrics within our telestroke network. In order to fully understand how telestroke alleviates disparities in stroke care, collaboration among networks is needed to formulate a multicenter telestroke database similar to the Get-With-The Guidelines.

Background: The effect of anesthesia choice on endovascular thrombectomy (EVT) outcomes is unclear. Methods: In the prospective multicenter cohort study of imaging selection for EVT (SELECT), patients were stratified based on their anesthesia type into general anesthesia (GA) and conscious sedation (CS). EVT times and outcomes were compared. Further we assessed the impact of ischemic core size (rCBF Results: Of 361 enrolled, 285 received EVT. 129 (45%%) received GA and 156 (54%) CS. The baseline characteristics were similar, except for presentation NIHSS (GA 17(13-21), CS 15(11-20), p=0.027) and ischemic core volume (GA 14.1 cc (0-38) vs CS 6.3(0-26.1), p=0.034). GA was associated with numerically longer arrival to GP times 92 (68—115) vs. 85(60-117) mins, p=0.58. After adjustment for baseline imbalances, patients who received CS had a shift toward better outcome (adj cOR 1.72, 95% CI=1.08-2.75, p=0.022) with higher functional independence rates 56.8% vs 48.8%, p=0.75. Furthermore, GA was associated with higher mortality rates (19% vs 9%, p=0.017), figure 1A. In patients with core volume ≥ 50 cc, there was a trend for a shift towards better outcomes (adj cOR=5.84, 95%CI= 0.90-38.00, P=0.065), figure 1B while there was no difference in patients with core volume < 50 cc (adj cOR=1.01 (95%CI 0.53-1.94, P=0.96), figure 1C. There was an interaction between core volume size and anesthesia type on functional outcome (p=0.042). For every 10cc increase in the core volume, the odds of attaining better functional outcome decreased by 29% (adjusted cOR: 0.71, 95% CI=0.61-0.83, p Conclusion: Conscious sedation was associated with a shift towards better EVT outcomes. This effect was driven by patients with larger ischemic core volumes and has implications for randomized trials of conscious sedation vs general anesthesia.

Introduction: Whether reperfusion therapy is safe and efficacious in acute ischemic strokes (AIS) due to posterior circulation large vessel occlusions (PCLVO) beyond 4.5 hrs is unknown. Methods: A retrospective analysis of AIS due to PCLVO presenting to a comprehensive stroke center up to 24 hrs from last known well. Patients were stratified based on the treatment received into reperfusion therapy (IV-tPA and/or endovascular thrombectomy) and no reperfusion therapy. All patients received CT/CTA and CT perfusion with RAPID mismatch determination. Functional independence (90 day mRS 0-2) and sICH were primary and secondary outcomes. The two groups were compared in the overall cohort in an ordinal logistic regression and in a propensity matched analyses. Results: Between 8/2017 and 5/2019, 52 patients were included [reperfusion = 23(44%) vs no-reperfusion=29(56%)]. Reperfusion rate beyond 4.5 hours was 26% (6/23). The two groups were similar at baseline except for larger perfusion delays (Tmax>6s) volume [median (IQR), 16 (0, 46) vs. 0 (0, 25) cc, p=0.03], and higher presentation NIHSS [median (IQR), 10 (5, 21) vs. 4 (1, 8), p=0.004] in the reperfusion group. Reperfusion was associated with higher functional independence rates 10 (43%) vs. 8 (28%), p=0.23 (fig 1), and a trend for a shift towards better outcomes adj cOR 1.89, 95% CI=0.59-6.13, p=0.29. There was no difference in sICH rates 9% vs. 0%, P=0.19. In a propensity matched analysis on NIHSS and perfusion deficit of 14 pairs, reperfusion was associated with statistically significant higher mRS 0-2 rates 9 (64%) vs. 1 (7%), p=0.004 (fig 2). Functional independence rates did not differ in the reperfusion group in relation to time (47% Conclusion: PCLVOs with more severe strokes and large perfusion deficits were more likely to receive reperfusion which was associated with a shift towards better outcomes both earlier and beyond 4.5 hours without worsening safety outcomes.

Background: Whether IV tPA has adjunctive benefit to endovascular thrombectomy (EVT) is unclear. Methods: In a prospective multicenter cohort study of imaging selection for EVT (SELECT), patients who received IV tPA vs. no IV tPA were compared stratified by stroke severity and ischemic core size (rCBF Results: Of 361 enrolled, 285 received EVT; 226 presented within 4.5 hrs, 162 (72%) received IV tPA. IV tPA patients had lower median ASPECTS (8 vs 9, p=0.007) and larger ischemic core size (11.4 (1.5-37) vs 3.9 (0-32.15), p=0.042, otherwise similar at baseline. There were no delays in EVT delivery associated with tPA: median time (IQR) from arrival to groin puncture 95.0 min (66.0, 118.0) tPA vs 81.5 (63.5, 107.5) no tPA, p=0.21. IV tPA use was associated with higher mRS 0-2 rates (57% vs 44%), aOR 2.02 (95% CI 1.01-4.03, p=0.046) after adjustment for baseline differences with a shift towards better outcomes on all mRS levels (cOR 2.06, 95% CI 1.18-3.59, p=0.01) with lower mortality (11% vs 22%, p=0.026) and similar sICH rates (and 6% vs 6%, p=1.0). In patients with NIHSS Conclusion: IV tPA did not result in thrombectomy delivery delays and may result in better outcomes. Patients with less severe strokes and smaller infarct size had a stronger association between the use of IV tPA and favorable outcomes.

Introduction: Functional outcomes and length of stay (LOS) are common outcome measures in stroke patients at Inpatient Rehabilitation Facilities (IRF). Aim: To examine trends in functional outcomes among patients with hemorrhagic versus ischemic stroke in IRF. Methods: Using a prospectively collected database of stroke patients admitted in our health system of 5 IRFs in Houston, we reviewed patients with either ischemic or hemorrhagic stroke between 1/18 to 6/19. The main outcome measure was the FIM scores. The relationship between LOS and FIM score improvement were analyzed using a third order polynomial regression model. Results: Among 88 patients, 43% were female and 60% had an ischemic stroke. The median LOS was 21 days (IQR14, 26) for all patients; 22 (IQR16, 30) in patients with hemorrhagic stroke; 20.5 (IQR14, 25) in patients with ischemic stroke (P: 0.24). Based on change in FIM, stroke patients benefited the most from IRF in the first 17 days (P Conclusion: Stroke patients in our IRF network benefit the most on FIM in the first 17 days. Further studies are needed to identify factors that could maximize functional gains in IRF.

Background: Whether Endovascular Thrombectomy (EVT) may improve clinical outcomes in patientswith Pre-Stroke disability as compared to medical management only (MM) is unknown. Methods: A retrospective analyses of anterior circulation LVOs (ICA, MCA M1/M2) with mRS 2-4presenting 0-24 hrs from last-known-well to a single comprehensive stroke center was performed.Patients were stratified based on the treatment received into EVT and MM. The primary outcome was90-day mRS. Safety (sICH and mortality) was a secondary outcome. Ordinal analysis compared the twogroup for a shift towards less severe disability with EVT and identified variables independentlycorrelated with better and worse outcomes in both EVT and MM. Results: From Jan 2012 - Aug 2019, 101 patients were identified (EVT=42, MM=59). Baselinecharacteristics were similar in the two groups. EVT resulted in higher rates of mRS 2 and 3 (15% vs 4%,P=0.064) and a shift towards better outcomes (adj cOR 1.142; 95% CI1.050-1.369, p=0.039) as comparedto MM only (Figure 1). There was no significant difference in the composite outcome of sICH andmortality (aOR=0.47, 95% CI 0.307 - 1.810, p=0.167). Higher ASPECTS was associated with betteroutcomes in EVT (adj cOR 1.312 for each point, 95%CI 1.021 - 3.859, p-0.027) while higher NIHSS (adjcOR 0.886 for each point increment in NIHSS, 95%CI 0.793-0.951, p-0.034), left hemispheric strokes (adjcOR 1.615; CI 1.24 - 4.5; p = 0.04) independently correlated with worse outcomes in MM. Conclusions: EVT may result in better outcomes and avoid worsening disability in patients with Prestrokeimpairment without increasing safety concerns. Those with more severe and left hemisphericstrokes were more likely to have devastating outcomes if not treated with EVT.

Introduction: Many cell-based therapies attenuate secondary degeneration after initial ischemic injury and enhance repair. We serially compared over time the integrity of the corticospinal tract (CST) in ischemic stroke (IS) patients treated with autologous bone marrow cells versus a prospectively collected, comparable stroke patient population not treated with cells (controls). Methods: We imaged 37 IS patients (17=treated, 20=control) at 1, 3, and 12 mo after stroke on a 3T MRI. A maximum of 10 million cells/kg were administered IV within 72 hrs of stroke. 3D anatomical and DTI images were obtained. CST integrity was assessed by relative (ipsilesional/contralesional) rFA in the rostral pons (RP). A mixed model was used for statistical analysis. Results: Infarct size of controls was 26.4 ±27 mL and the treated group was 64.7 ± 40.3 mL. The rFA in the rostral pons (RP) of controls decreased from 0.91 ± 0.1 to 0.86 ± 0.1 over 12 months. In the cell treated group, rFA in the RP decreased initially from 0.73 ±0.1 to 0.69 ±0.1 between 1 and 3 months but then increased to 0.76 ± 0.1 at 12 months. Qualitative and quantitative results are summarized (fig). The rFA in the RP was significantly correlated (p Conclusion: Despite smaller infarct size in controls, CST integrity continued to degenerate and showed no improvement by 12 months after stroke. In contrast, the cell treated patients with initial larger infarcts showed initial degeneration of the CST but then had improved CST integrity by 12 months after stroke. The temporal decrease in rFA in controls and increase in rFA in treated patients suggest a potential treatment effect from the cells. Although the results are generated from a non-randomized trial, the significant correlation between mRS and rFA suggests rFA could be used as a surrogate marker of treatment effect.

Introduction: White matter tract (WMT) injury occurs in patients with acute cerebrovascular disorders. In this study, we elucidate longitudinal differences in mechanism of injury and repair between ischemic stroke (ISC) and intracerebral hemorrhage (ICH). Methods: Twenty patients (10 ISC and ICH) were prospectively imaged at 1, 3, and 12 months of onset on a 3T MRI. 3D anatomical and DTI images were obtained and integrity of the corticospinal tract (CST) assessed at the ipsi and contralesional posterior limb of internal capsule (PLIC). Fractional anisotropy (FA), mean diffusivity (MD) and pixel volume were recorded. A linear regression model was applied for statistical analysis. Results: ISC group had 4 men, 6 women whereas ICH group had 7 men, 3 women, both with average age 52. Baseline NIHSS in ISC was 11 (IQR=4.5-20) and ICH 6 (IQR=2-13). All lesions were unilateral, hemispheric, completely subcortical or with a significant subcortical component. The average lesion and hematoma volume at 1 month was 37 and 39 cc in ISC and ICH, respectively. The MD in the PLIC of the ISC increased from 1 to 3m (P Conclusions: ISC and ICH display unique patterns of WMT changes over one year in which ICH injury reflects a compression of the CST that resolves over time, while in ISC our data show degeneration and microstructural injury. These changes reflect different mechanisms of injury and remodeling on a cellular level. A better understanding of these changes could improve recovery therapies. Larger studies are needed to better characterize long term WMT changes in IS and ICH.

Background: The efficacy of endovascular thrombectomy (EVT) in M2 occlusions is uncertain. Methods: In a prospective multicenter cohort study of imaging selection (SELECT), EVT outcomes were compared to medical managment (MM) in M2 occlusions. Further, we assessed for potential treatment benefit in patients with higher stroke severity (NIHSS) and a larger perfusion deficit on CTP (Tmax > 6 sec - ischemic core volume)The primary outcome was excellent outcome (mRS 0-1). Results: of 361 patients enrolled in SELECT, 87 had isolated M2 occlusion (EVT 59, MM 28). Baseline NIHSS median (IQR) (EVT 14 (10-20), MM 15 (9.5-19.5), p=0.72) and infarct volume rCBF10 had better outcomes with EVT (46%) vs MM (10%), aOR=11.39, 95% CI=1.80-72.11, p=0.01 as shown in figure 1. As perfusion deficit lesion size increased, the odds of achieving excellent outcomes was reduced (for each 10cc by 11%, aOR: 0.89, 95% CI=0.79-1.00, p=0.05). Excellent outcomes declined in patients with MM as perfusion deficit lesion size increased, yet in the EVT they were maintained as shown in figure 2. Similar results were obtained for mRS 0-2. Conclusion: EVT may result in better rates of excellent outcomes in isolated M2 occlusions, especially those with more severe strokes and larger perfusion deficits who are more likely to have worse outcomes without emergent reperfusion.

Background: Whether Endovascular Thrombectomy (EVT) is cost-effective in large ischemic core infarcts is unknown. Methods: In the prospective multicenter cohort study of imaging selection study (SELECT), large core was defined as CT ASPECTS < 6 or CTP ischemic core volume (rCBF Results: Of 361 enrolled, 105 had large core on CT or CTP (EVT 62, MM 43). 19 (31%) EVT patients achieved mRS 0-2 vs 6 (14%) MM (aOR: 3.27, 95% CI: 1.11-9.62; P = .03) with a shift towards better mRS (adj cOR: 2.12, 95% CI: 1.05-4.31, P = .04). Over 20 years EVT was associated with $26589 (C.I. $8672- $43978) incremental costs and a gain of 1.18 QALYs (C.I. 0.091- 2.2) per patient. EVT could avert 75 deaths over a theoretical cohort of 1000 patients (MM 861 vs EVT 786) thus the ICER of EVT compared to MM was $22400 per QALY (CI. $10109 - $66140), which is EVT has a higher NMB compared to MM at the lower and upper WTP thresholds (EVT $86,3 and 271,4 million vs MM $53,6-$179,3 million), Tab 2. The PSA confirmed the results (fig 1). The CEAC showed 94% and 97% cost-effectiveness probability of EVT at the lower and upper values respectively of the maximum WTP, fig 2. EVT ICER in SELECT large core ($22400/QALY) was higher but still comparable to those in HERMES ($16882/QALY), DAWN ($7335/QALY) and DEFUSE3 ($14673/QALY), Tab 3. Conclusion: EVT may result in better outcomes and more lives saved in large core patients with higher QALYs, NMB and an acceptable ICER. The results were comparable to other EVT RCTs.

Introduction: Cryptogenic stroke may result from paradoxical embolism through a patent foramen ovale (PFO). However, the association between deep vein thrombosis (DVT) and cryptogenic stroke has not been proven. The objective of our study is to compare the incidence of DVT in young and old patients who presented with acute ischemic stroke and were found to have a PFO. Method: We conducted a single-centre retrospective study from January 2014-December 2018. Patients over the age of 18 with ischemic stroke and PFO, who underwent magnetic resonance venography (MRV) of the pelvis and venous doppler ultrasonography (VDU) for assessment of DVT were included. Primary endpoint was the incidence of DVT in patients that were age ≤ 60 (young group) compared to those age > 60 (old group). We further analyzed the incidence of DVT in cryptogenic stroke vs determined origin; and based on the Risk of Paradoxical Embolism (ROPE) score. Results: We included 327 patients: 200 were young (Y) and 127 were old (O). Incidence of DVT was similar for patients in Y versus those in O group (7% vs 8%). A significantly higher ROPE score ≥ 6 was seen in the Y group (71% vs 9%; p Conclusions: Detection of DVT was not associated with PFO, high ROPE scores or cryptogenic strokes. Our data indicate an over-reliance of testing for DVT, particularly MRV pelvis with contrast, in patients with PFO. Clinical studies are needed to identify other factors predictive of DVT in patients with ischemic stroke and PFO.

Background Unregulated inflammatory and thrombotic responses have been proposed to be important causes of early brain injury and worse clinical outcomes after subarachnoid hemorrhage (SAH). Objective We hypothesize that SAH is characterized by an increased inflammatory and thrombotic state and disruption of associations between these states. Methods This is a retrospective cohort study of 60 patients with SAH. 23 patients with unruptured aneurysms (UA) and 77 patients with traumatic brain injury (TBI) were chosen as controls. Plasma cytokine levels were measured using a 41-plex human immunoassay kit, and cytokine patterns associated with SAH, UA and TBI were identified using statistical and informatics methods. Results SAH was characterized by an increase in several cytokines and chemokines, platelet-derived factors, and growth factors. Cluster analysis identified several cytokine clusters common in SAH, UA and TBI groups – generally grouped as platelet-derived, vascular and pro-inflammatory clusters. In the UA group, the platelet-derived cluster had an inverse relationship with the inflammatory cluster which was absent in SAH. Additionally, a cluster comprising of growth and colony stimulating factors was unique to SAH. Conclusions A cluster of cytokines involved in growth and colony stimulation was unique to SAH. Negative associations between the thrombotic and inflammatory molecules were observed in UA but not in SAH. Further studies to examine the pathophysiology behind the cluster unique to SAH and the associations between the thrombotic and inflammatory cytokines are required.

BACKGROUND: Animal models have demonstrated the deleterious contribution of splenic immunocytes on secondary brain injury after stroke. While previous work has demonstrated splenic contraction (SC) in patients with acute ischemic stroke (AIS) and intracranial hemorrhage (ICH), no clinical studies have examined the relationship between the systemic inflammatory response syndrome (SIRS) with SC in stroke patients. METHODS: This is a retrospective analysis of a previous prospective observational study where daily spleen sizes were evaluated in 178 acute stroke patients. Spleen contraction was based on previously established normograms of healthy volunteers from the same study. SC from the first 24 hrs of stroke onset was evaluated against criteria for SIRS for the first 5 days of admission after AIS. RESULTS: 91patients had verified AIS without concurrent infection at admission. SIRS was not associated with SC at admission. African American patients with early SIRS had higher odds of having SC. Older patients with persistent SIRS at 72 hrs had lower odds of SC. At 48 hrs, there was significantly higher lymphocytosis and lower neutrophils present in patients with SC. Patients with SIRS at 72 hrs were more likely to have worse discharge mRS. CONCLUSION: This study provides evidence for an association among SC and SIRS in African American patients suggesting that spleen changes could be a biomarker for detecting SIRS in this population. Our data also indicate a counter association between SC and a lack of SIRS in patients older than 75. Further studies are needed to ascertain how age affects this association.

Background Inflammatory mechanism has been implicated in delayed cerebral ischemia (DCI) and poor functional outcomes after subarachnoid hemorrhage (SAH). Identification of cytokine patterns associated with inflammation in acute SAH will provide insights into underlying biological processes of DCI and poor outcomes that may be amenable to interventions. Methods Serum samples were collected from a prospective cohort of 60 patients with acute non-traumatic SAH at four time periods ( Results Of the 60 patients enrolled in the study, 14 (23.3%) developed DCI and 16 (26.7%) had poor functional outcomes at 3 months. DCI was associated with increased levels of PDGF-ABBB and CCL5 and decreased levels of IP-10 and MIP-1α. Poor functional outcome was associated with increased levels of IL-6 and MCP-1α. Network analysis identified distinct cytokine clusters associated with DCI and functional outcomes. Conclusions Serum cytokine patterns in early SAH are associated with poor functional outcomes and DCI. The significant cytokines primarily modulate the inflammatory response. This supports earlier SAH studies linking inflammation and poor outcomes. In particular, this study identifies novel cytokine patterns over time that may indicate impending DCI.

OBJECTIVE The primary imaging modalities used to select patients for endovascular thrombectomy (EVT) are noncontrast computed tomography (CT) and CT perfusion (CTP). However, their relative utility is uncertain. We prospectively assessed CT and CTP concordance/discordance and correlated the imaging profiles on both with EVT treatment decisions and clinical outcomes. METHODS A phase 2, multicenter, prospective cohort study of large-vessel occlusions presented up to 24 hours from last known well was conducted. Patients received a unified prespecified imaging evaluation (CT, CT angiography, and CTP with Rapid Processing of Perfusion and Diffusion software mismatch determination). The treatment decision, EVT versus medical management, was nonrandomized and at the treating physicians' discretion. An independent, blinded, neuroimaging core laboratory adjudicated favorable profiles based on predefined criteria (CT:Alberta Stroke Program Early CT Score ≥ 6, CTP:regional cerebral blood flow (

Introduction: Recent studies show rising incidence of stroke in the young, for which risk factors are not well characterized. There is evidence of increased risk in certain race and ethnic groups. We sought to assess racial differences in risk factors, stroke etiology, and outcomes among young stroke patients. Methods: Using data from our inpatient registry for ischemic stroke, we reviewed patients aged 18-50 who were admitted 01/2013 to 04/2018. Race/ethnicity were characterized as non-Hispanic White (NHW), non-Hispanic Black(NHB), Hispanic(HIS) and other groups were excluded given small numbers ( Results: Among 862 patients admitted in the study period, mean age was 40.9 (SD 7.8), 57.3% were male, and 36.4% NHW, 42.8% NHB, 20.8% HIS. History of hypertension (HTN), type II diabetes (DM II), smoking, heart failure (CHF), prior stroke, end stage renal disease, and triglycerides varied significantly by race (Table 1). Compared to NHW, NHB had higher odds of HTN (OR 2.2, CI 1.6-3.0), CHF (OR 2.3, CI 1.1-4.6), and DMII (OR 1.81, CI 1.2-2.7) while HIS had higher odds of DMII (OR 2.26, CI 1.4-3.6) and lower odds of smoking (OR 0.5, 0.3-0.8). Arrival NIHSS was higher in NHB, but etiology and rates of tpA treatment and thrombectomy did not vary by race. Compared to NHW patients, NHB (OR 0.5, CI 0.3-0.9 ) and HIS (OR 0.4 CI 0.2-0.9) were less likely to have good functional outcome (mRS Conclusions: In this study, there was a higher prevalence of several modifiable risk factors in NHB and HIS young stroke patients and early functional outcome was worse in these groups. This suggests a need for targeted prevention efforts for younger populations at highest risk. The findings regarding outcomes deserve further study.

Background aims Extensive animal data indicate that mesenchymal stromal cells (MSCs) improve outcome in stroke models. Intra-arterial (IA) injection is a promising route of delivery for MSCs. Therapeutic effect of MSCs in stroke is likely based on the broad repertoire of secreted trophic and immunomodulatory cytokines produced by MSCs. We determined the differential effects of exposing MSCs to different types of clinically relevant vehicles, and/or different additives and passage through a catheter relevant to IA injections. Methods MSCs derived from human bone marrow were tested in the following vehicles: 5% albumin (ALB), 6% Hextend (HEX) and 40% dextran (DEX). Each solution was tested (i) alone, (ii) with low-dose heparin, (iii) with 10% Omnipaque, or (iv) a combination of heparin and Omnipaque. Cells in vehicles were collected directly or passed through an IA catheter, and MSC viability and cytokine release profiles were assessed. Results Cell viability remained above 90% under all tested conditions with albumin being the highest at 97%. Viability was slightly reduced after catheter passage or exposure to heparin or Omnipaque. Catheter passage had little effect on MSC cytokine secretion. ALB led to increased release of angiogenic factors such as vascular endothelial growth factor compared with other vehicles, while HEX and DEX led to suppression of pro-inflammatory cytokines such as interleukin-6. However, when these three vehicles were subjected to catheter passage and/or exposure to additives, the cytokine release profile varied depending on the combination of conditions to which MSCs were exposed. Discussion Exposure of MSCs to certain types of vehicles or additives changes the profile of cytokine secretion. The activation phenotype of MSCs may therefore be affected by the vehicles used for these cells or the exposure to the adjuvants used in their administration.

Cell-based therapies including bone-marrow derived mononuclear cells (MNCs) are now widely being studied because of their pleotropic effects and promising results to improve recovery after stroke in animal models. Unlike other types of cell therapies, MNCs is a mixture of lymphoid, myeloid, erythroid, and stem cell populations. Which cell population(s) accounts for the beneficial effects of MNCs in stroke recovery is unclear. In this paper, we employed a mouse stroke model with middle cerebral artery occlusion (MCAo), and used positively and negatively sorted autologous MNCs by MACs to determine which fractions of the MNCs contribute to their beneficial effects. We evaluated the benefits of neurofunctional recovery produced by individual cell lineages within MNCs in a long-term observation study up to 28 days after stroke. Mortality and modulation of inflammation were also compared among different sub-populations. We further studied the impact of neurotoxicity posed by activated microglia in the presence of different cell lineages within MNCs. We concluded that myeloid cell lineage and stem cell/progenitors appeared to be important components within MNCs that contribute to improved outcomes after stroke.

Background and purpose Recent studies show rising incidence of stroke in the young, for which risk factors are not well characterized. There is evidence of increased risk in certain racial and ethnic groups. We assessed racial differences in risk factors, stroke etiology, and outcomes among young stroke patients. Methods Using data from our inpatient registry for ischemic stroke, we reviewed patients aged 18–50 who were admitted 01/2013 to 04/2018. Race/ethnicity were characterized as non-Hispanic White (NHW), non-Hispanic Black (NHB), Hispanic (HIS). For univariate comparisons Chi-square and Kruskal–Wallis tests were performed as appropriate. Multivariable logistic regression was used to assess impact of race on day seven modified Rankin score (mRS). Results Among 810 patients with race and outcome data who were admitted in the study period, median age was 43, 57.1% were male, and 36.5% NHW, 43.2% NHB, 20.2% HIS. History of hypertension (HTN), type II diabetes (DM II), smoking, heart failure (CHF), prior stroke, and end-stage renal disease varied significantly by race. Compared to NHW, NHB had higher odds of HTN (OR 2.28, 1.65–3.15), CHF (OR 2.17, 1.06–4.46), and DM II 1.92 (1.25–2.94) while HIS had higher odds of DM II (OR 2.52, 1.55–4.10) and lower odds of smoking (OR 0.56, 0.35–0.90). Arrival NIHSS was higher in NHB, but etiology and rates of tpA treatment and thrombectomy did not vary by race. Compared to NHW patients, NHB (OR 0.50 CI (0.31–0.78)) and HIS (OR 0.37 CI (0.21–0.67)) were less likely to have good functional outcome (mRS Conclusions In this study, there was a higher prevalence of several modifiable risk factors in NHB and HIS young stroke patients and early functional outcome was worse in these groups. Our study suggests a need for targeted prevention efforts for younger populations at highest risk for stroke.

Background Endovascular thrombectomy RCTs used different imaging selection modalities and criteria. Early window (0–6 hours) trials mostly used simple CT, while DAWN and DEFUSE3 utilized advanced perfusion images (CTP/MRP) beyond 6 hours. Thus, optimal imaging selection criteria for thrombectomy is unknown. Method In this multicenter prospective cohort study, consecutive anterior-circulation large vessel occlusion patients up-to-24 hours from last-known-normal were enrolled in 9 centers (January/16–February/18). All patients received CT and CTP with mismatch determination using RAPID software. Treating physicians documented imaging selection modality prior to thrombectomy. Patients were divided based on selection modality into CT versus CTP groups. A blinded independent core-lab adjudicated imaging profiles defined a priori (Good CT=ASPECTS≥6, Good CTP=core vol 1.2). The primary outcome (90 day mRS=0–2) was compared between the CT and CTP groups and for different CT and CTP profiles. Results Of 445 patients enrolled, 341 received thrombectomy (figure 1). Median/IQR age=66/57–77, NIHSS=17/12–21, LSN-to-GP=3.8 hours/2.6–5.7 (range=1.2–17.6). 20% had ICA occlusions, 62% M1, and 18% M2. Selection modality was CT in 42% and CTP in 58%, with similar good outcome (CT=53.3% vs 54.3%=CTP, aOR=0.6,95% CI: 0.3 to 1.5, p=0.3, figure 2a). There was no interaction with time, early vs late window, p=0.1. 87% had good CT and 89.6% had good CTP with comparable good outcome (CT=55.7% vs CTP=57.3, aOR=2.2, 95% CI: 0.5 to 10.9, p=0.3, figure 2b). In early window, the good outcome rates were 54.9% for good CT and 58% for good CTP; for late window, they were 58.7% and 57.1%, respectively. There was no interaction with time (p=0.5). 16.8% would have been excluded from thrombectomy based on either CT or CTP only; 40.5% of them had good outcome. Of patients potentially excluded by CT but qualified by CTP, 50% had good outcomes with thrombectomy and 33% with medical management only. Similarly, of those excluded by CTP but treated by CT, 27.8% had good outcomes with and 0% without thrombectomy, respectively (table 1). Furthermore, discordant profiles patients (Good CT-Poor CTP and Poor CT-Good CTP) with good reperfusion (mTICI ≥2b) had higher good outcome rates, compared to mTICI Thrombectomy did not confer good outcomes in patients with Poor CT-Poor CTP. Conclusion Good outcome rates were comparable in patients selected for thrombectomy by CT versus CTP and those with good imaging profiles on either CT or CTP irrespective of the treatment time window, early or late. However, both imaging modalities excluded a similar number of patients who may benefit from the intervention. Our results will be validated in a randomized trial (SELECT2). Disclosures A. Sarraj: 1; C; Principal Investigator of the SELECT and SELECT 2 trials – unrestricted grant from Stryker Neurovascular to UT McGovern-Houston. 2; C; Consultant and Speaker for Stryker Neurovascular, Advisory Board – Stryker Neurovascular. 6; C; UT-Memorial Hermann Center PI for the Trevo Registry and DEFUSE 3 TRIAL, Steering Committee –ASSIST Registry. A. Hassan: None. R. Gupta: None. C. Sitton: None. J. Grotta: None. C. Cai: None. G. Cutter: None. B. Imam: None. S. Reddy: None. K. Parsha: None. N. Vora: None. M. Abraham: None. R. Edgell:None. F. Hellinger: None. D. Haussen: None. H. Kamal: None. L. McCullough: None. M. Lansberg: None. S. Savitz: None. G. Albers: None.

Autologous bone marrow-derived mononuclear cells (MNCs) are a potential therapy for ischemic stroke. However, the effect of MNCs in intracerebral hemorrhage (ICH) has not been fully studied. In this study, we investigated the effects of autologous MNCs in experimental ICH. ICH was induced by infusion of autologous blood into the left striatum in young and aged male Long Evans rats. Twenty-four hours after ICH, rats were randomized to receive an intravenous administration of autologous MNCs (1 × 10(7) cells/kg) or saline. We examined brain water content, various markers related to the integrity of the neurovascular unit and inflammation, neurological deficit, neuroregeneration, and brain atrophy. We found that MNC-treated young rats showed a reduction in the neurotrophil infiltration, the number of inducible nitric oxide synthase-positive cells, and the expression of inflammatory-related signalings such as the high-mobility group protein box-1, S100 calcium binding protein B, matrix metalloproteinase-9, and aquaporin 4. Ultimately, MNCs reduced brain edema in the perihematomal area compared with saline-treated animals at 3 days after ICH. Moreover, MNCs increased vessel density and migration of doublecortin-positive cells, improved motor functional recovery, spatial learning, and memory impairment, and reduced brain atrophy compared with saline-treated animals at 28 days after ICH. We also found that MNCs reduced brain edema and brain atrophy and improved spatial learning and memory in aged rats after ICH. We conclude that autologous MNCs can be safely harvested and intravenously reinfused in rodent ICH and may improve long-term structural and functional recovery after ICH. The results of this study may be applicable when considering future clinical trials testing MNCs for ICH.

Animal models provide evidence of spleen mediated post-stroke activation of the peripheral immune system. Translation of these findings to stroke patients requires estimation of pre-stroke spleen volume along with quantification of its day-to-day variation. We enrolled a cohort of 158 healthy volunteers and measured their spleen volume over the course of five consecutive days. We also enrolled a concurrent cohort of 158 stroke patients, measured initial spleen volume within 24 h of stroke symptom onset followed by daily assessments. Blood samples for cytokine analysis were collected from a subset of patients. Using data from healthy volunteers, we fit longitudinal quantile regression models to construct gender and body surface area based normograms of spleen volume. We quantified day-to-day variation and defined splenic contraction. Based on our criteria, approximately 40% of stroke patients experienced substantial post-stroke reduction in splenic volume. African Americans, older patients, and patients with past history of stroke have significantly higher odds of post-stroke splenic contraction. All measured cytokine levels were elevated in patients with splenic contraction, with significant differences for interferon gamma, interleukin 6, 10, 12, and 13. Our work provides reference standards for further work, validation of pre-clinical findings, and characterization of patients with post-stroke splenic contraction.

Early brain injury (EBI) after aneurysmal subarachnoid hemorrhage (aSAH) is defined as brain injury occurring within 72 h of aneurysmal rupture. Although EBI is the most significant predictor of outcomes after aSAH, its underlying pathophysiology is not well understood. We hypothesize that EBI after aSAH is associated with an increase in peripheral inflammation measured by cytokine expression levels and changes in associations between cytokines. aSAH patients were enrolled into a prospective observational study and were assessed for markers of EBI: global cerebral edema (GCE), subarachnoid hemorrhage early brain edema score (SEBES), and Hunt–Hess grade. Serum samples collected at ≤ 48 h of admission were analyzed using multiplex bead-based assays to determine levels of 13 pro- and anti-inflammatory cytokines. Pairwise correlation coefficients between cytokines were represented as networks. Cytokine levels and differences in correlation networks were compared between EBI groups. Of the 71 patients enrolled in the study, 17 (24%) subjects had GCE, 31 (44%) subjects had SEBES ≥ 3, and 21 (29%) had HH ≥ 4. IL-6 was elevated in groups with GCE, SEBES ≥ 3, and HH ≥ 4. MIP1β was independently associated with high-grade SEBES. Correlation network analysis suggests higher systematic inflammation in subjects with SEBES ≥ 3. EBI after SAH is associated with increased levels of specific cytokines. Peripheral levels of IL-10, IL-6, and MIP1β may be important markers of EBI. Investigating systematic correlations in addition to expression levels of individual cytokines may offer deeper insight into the underlying mechanisms related to EBI.

Objective:To investigate inflammatory processes after aneurysmal subarachnoid hemorrhage (aSAH) with network models.Methods:This is a retrospective observational study of serum samples from 45 participants with aSAH analyzed at multiple predetermined time points: Results:Network models revealed that systematic inflammatory activity peaks at 24 to 48 hours after the bleed. Individual cytokine levels changed significantly over time, exhibiting increasing, decreasing, and peaking trends. Platelet-derived growth factor (PDGF)-AA, PDGF-AB/BB, soluble CD40 ligand, and tumor necrosis factor-α (TNF-α) increased over time. Colony-stimulating factor (CSF) 3, interleukin (IL)-13, and FMS-like tyrosine kinase 3 ligand decreased over time. IL-6, IL-5, and IL-15 peaked and decreased. Some cytokines with insignificant trends show high correlations with other cytokines and vice versa. Many correlated cytokine clusters, including a platelet-derived factor cluster and an endothelial growth factor cluster, were observed at all times. Participants with higher clinical severity at admission had elevated levels of several proinflammatory and anti-inflammatory cytokines, including IL-6, CCL2, CCL11, CSF3, IL-8, IL-10, CX3CL1, and TNF-α, compared to those with lower clinical severity.Conclusions:Combining reductionist and systematic techniques may lead to a better understanding of the underlying complexities of the inflammatory reaction after aSAH.

Background: Some types of cell-based therapies may reduce secondary brain injury after stroke by modulating immune responses from the spleen. Here, we hypothesized that fractalkine (FKN; CX3CL1) derived from the spleen mediates cross-talk between the spleen and brain, and that upregulation of FKN in the spleen by bone marrow mononuclear cells (MNCs) is an important mechanism underlying how MNCs enhance recovery after stroke. Methods: To model ischemic stroke, we employed rat and mouse middle cerebral artery occlusion (MCAo) models. 24 hours after MCAo, animals received autologous MNCs IV or saline as vehicle controls. Brains and spleens were harvested and serum was collected at various time points after MCAo. FKN gene expression and protein levels were measured. Functional testing was evaluated for up to 28d after MCAo. In parallel experiments, mice were subjected to splenectomy two weeks prior to MCAo and the same experiments were repeated in animals without a spleen. In another experiment, antibody neutralizing FKN receptor (anti-CX3CR1) was injected ICV at 1 hour after MNC to evaluate the impact of blocking the FKN receptor in the brain. Results: MNC treatment significantly increased FKN levels in the spleen, serum and brain starting 1 day after MNC treatment, as compared to the vehicle-treated group. Splenectomy significantly attenuated FKN upregulation in response to MNC administration, and also attenuated the treatment-mediated effects on functional recovery. ICV injection of anti-CX3CR1 also abolished the MNCs-mediated beneficial effect on stroke recovery. In cell culture experiment, MNCs increased soluble FKN release by spenocytes and this process required physical MNC-splenocyte interaction and was dependent on the presence of IFN-γ. Conclusion: MNCs enhance stroke recovery through mechanisms involving the spleen; FKN may be one of the important signals mediating the cross-talk between the spleen and the brain.

IMPORTANCE: The efficacy and safety of endovascular thrombectomy (EVT) in patients with large ischemic cores remains unknown, to our knowledge. OBJECTIVE: To compare outcomes in patients with large ischemic cores treated with EVT and medical management vs medical management alone. DESIGN, SETTING, AND PARTICIPANTS: This prespecified analysis of the Optimizing Patient’s Selection for Endovascular Treatment in Acute Ischemic Stroke (SELECT) trial, a prospective cohort study of imaging selection that was conducted in 9 US comprehensive stroke centers, enrolled patients between January 2016 and February 2018, and followed them up for 90 days. Patients with moderate to severe stroke and anterior circulation large-vessel occlusion presenting up to 24 hours from the time they were last known to be well were eligible for the cohort. Of these, patients with large ischemic cores on computed tomography (CT) (Alberta Stroke Program Early CT Score

Background In animal models, the spleen contracts after acute ischemic stroke, followed by release of inflammatory cells leading to secondary brain injury. Aims We aim to characterize splenic responses in patients with acute ischemic stroke. Methods In this prospective observational study, we measured daily spleen sizes with abdominal ultrasound in 30 patients with suspected acute ischemic stroke. Splenic ultrasounds were also performed in 20 healthy individuals. Results A generalized estimating equation, longitudinal regression model for adjusted spleen measurements showed the difference between baseline spleen volume (within six-hours of stroke onset) and the volume at the last measured time point (up to seven-days) to be statistically significant (volume difference of 51·9 cm3, P = 0·04). Healthy controls had significantly smaller day-to-day variations; the maximum observed difference in mean spleen volume between any two time points was 9·5 cm3, with the average change over the period of observation being 1·24 cm3. A statistically significant negative association was also observed between the pattern of change of total white blood cell count and spleen volume ( P = 0·01). An analysis of individual cases demonstrated possible associations between daily spleen volume changes and clinical course. Conclusions We hypothesize that the spleen may initially contract after ischemic stroke followed by a re-expansion and that it contributes to ischemic brain injury mediated via cellular components. Characterization of the splenic response after stroke and its contribution to cerebral ischemic injury has the potential to provide new opportunities for the development of novel stroke therapies.

The systemic administration of autologous bone marrow (BM) derived mononuclear cells (MNCs) is under investigation as a novel therapeutic modality for the treatment of ischemic stroke. Autologous applications raise the possibility that MNCs could potentially be stored as a banked source. There have been no studies that investigate the effects of cryopreservation of BM-MNCs on their functional abilities in stroke models. In the present study, C57BL/6 mice were subjected to middle cerebral artery occlusion (MCAo) for 60 minutes and then divided into two treatment groups: fresh MNCs versus cryopreserved MNCs. BM-MNCs were collected at 22 hours after MCAo and were stored in liquid nitrogen for 12 months in cryopreserved MNCs group. BM-MNCs cellular viability, composition, and phenotype of the various subpopulations of mice BM-MNCs were evaluated by flow cytometry, and the behavioral recovery of stroke animals was tested with freshly harvested MNCs versus cryopreserved MNCs by corner test and ladder rung test. We found that long-term cryopreservation negatively impacts the cellular viability of bone marrow MNCs. Cryopreservation also alters the cellular composition of various subpopulations within the MNCs. However, despite the changes observed in cryopreserved cells, both fresh and frozen MNCs have similar beneficial effect on behavioral and histological outcomes.

Multiple studies have been performed to evaluate the effects of mesenchymal stem cells (MSCs) in animal models of Parkinson's disease (PD). We performed a meta-analysis to estimate the treatment effect of unmodified MSCs on behavioral outcomes in preclinical studies of PD. We performed a systematic literature search to identify studies that used behavioral testing to evaluate the treatment effect of unmodified MSCs in PD models. Meta-analysis was used to determine pooled effect size for rotational behavior and limb function, and meta-regression was performed to explore sources of heterogeneity. Twenty-five studies, including three delivery routes, a wide range of doses, and multiple PD models, were examined. Significant improvement was seen in the pooled standardized mean difference (SMD) for both rotational behavior [SMD: 1.24, 95% confidence interval (95% CI): 0.84, 1.64] and limb function (SMD: 0.84, 95% CI: 0.01, 1.66). Using meta-regression, intravenous administration and higher dose had a larger effect on limb function. Treatment with MSCs improves behavioral outcomes in PD models. Our analyses suggest that MSCs could be considered for early-stage clinical trials in the treatment of PD.

Objectives: Animal models have shown that the spleen contracts and contributes to post-ischemic inflammation that may exacerbate brain injury and impair recovery. Translation of these findings in patients is challenging because of a lack of normative spleen volume (SV) data. We created normograms of SV for an adult at-risk population, quantified splenic contraction (SC) in stroke patients, and characterized patients with SC. Methods: We enrolled 158 healthy volunteers (HV) with matching age and gender distribution with that of our stroke center registry. Spleen ultrasounds were performed on 5 consecutive days. We used quantile regression models to identify predictors of SV for HV. Gender and body surface area (BSA) were used to construct percentile based normograms of SV, and the expected pre-stroke SV were calculated, from which SC was quantified. We also enrolled a cohort of 170 patients with acute stroke and intracerebral hemorrhage within 24 hours of symptom onset and performed serial spleen ultrasound measurements during hospitalization. Logistic regression was used to determine factors associated with SC. Results: Normograms for SV in healthy males and females based on BSA were created (Figure 1). Over a 5-day consecutive period of daily spleen measurements, the maximum day to day variation was 10.6 cm3. Based on these findings, stroke patients with a normalized SV below 20 cm3 of their expected SV, were classified as having SC. Excluding stroke mimics, 158 patients were included in the analyses, of which 64 (40.5%) had SC detected within 24 hrs of symptom onset. African-American race, older age, and history of previous stroke were significantly associated with SC (Table 1). Conclusion: The spleen does appear to reduce in size after stroke in some specific subgroups of patients with acute stroke and brain hemorrhage. The biological relevance of SC to the inflammatory response and functional outcomes of stroke patients are currently being studied in our study cohorts.

Background The use of bone marrow–derived mesenchymal stromal cells (MSCs) as a cellular therapy for various diseases, such as graft-versus-host disease, diabetes, ischemic cardiomyopathy and Crohn's disease, has produced promising results in early-phase clinical trials. However, for widespread application and use in later phase studies, manufacture of these cells must be cost-effective, safe and reproducible. Current methods of manufacturing in flasks or cell factories are labor-intensive, involve a large number of open procedures and require prolonged culture times. Methods We evaluated the Quantum Cell Expansion System for the expansion of large numbers of MSCs from unprocessed bone marrow in a functionally closed system and compared the results with a flask-based method currently in clinical trials. Results After only two passages, we were able to expand a mean of 6.6 × 10 8 MSCs from 25 mL of bone marrow reproducibly. The mean expansion time was 21 days, and cells obtained were able to differentiate into all three lineages: chondrocytes, osteoblasts and adipocytes. The Quantum was able to generate the target cell number of 2.0 × 10 8 cells in an average of 9 fewer days and in half the number of passages required during flask-based expansion. We estimated that the Quantum would involve 133 open procedures versus 54,400 in flasks when manufacturing for a clinical trial. Quantum-expanded MSCs infused into an ischemic stroke rat model were therapeutically active. Conclusions The Quantum is a novel method of generating high numbers of MSCs in less time and at lower passages when compared with flasks. In the Quantum, the risk of contamination is substantially reduced because of the substantial decrease in open procedures.

Background: Autologous bone marrow mononuclear cells (MNCs) have been shown in multiple labs to improve stroke recovery in animal models but the mechanisms remain unclear. We assessed whether MNCs modulate macrophage-microglia responses in acute stroke. Methods: C57/BL mice were subjected to middle cerebral artery occlusion (MCAo) for 60 minutes or sham surgery. 24 hours later, they were randomized to receive saline infusion IV or 1x 10 6 autologous MNCs IV. At various time points after stroke, 1ml peripheral blood was collected and brains were harvested up to day14. Peripheral blood was labeled with anti-mouse CD45, CD115, F4/80 or Gr-1 antibodies and then assessed by flow cytometry. Microglia were isolated from brains by Optiprep gradient and stained with anti-mouse CD11b, CD45, and CD86 antibodies for evaluation by flow cytometry. For gene expression analyses by RT-PCR, microglia-macrophages were further sorted by magnetic activated-cells sorting using CD11b antibody. Results: 1) At day 2 after stroke, the percentage of CD115 + monocytes and CD115 + /Gr-1 low cells were significantly decreased in whole peripheral blood but F4/80 + macrophages were increased. MNCs increased the abundance of CD115 + /Gr-1 low cells and decreased the abundance of F4/80 + macrophages in peripheral blood compared to saline control at day 2 after stroke (n=5, p + microglia-macrophages in the stroke-affected hemisphere at day 2 to day 6. MNCs significantly decreased the proportion of CD11b + /CD45 high among CD11b + cells at day 2 and day 4 and CD86 + cells among CD11b + cells at day 2. Among CD11b + microglia-macrophages isolated from the ipsilateral hemisphere of MNC treated mice, compared to saline treated controls, iNOS and IL-1β genes expression were down-regulated at day 2. At day 6, iNOS remained down-regulated while now IL-10, Arganase-1 and CD206 genes expression (markers for the “healing” macrophage phenotype) were up-regulated (n=3 to 5, p Conclusions: MNCs may enhance recovery after stroke by altering monocyte trafficking and changing microglial polarization into a healing phenotype.

Background: Systemic administration of marrow stromal cells (MSCs) leads to the release of a broad panel of cytokines and growth factors that may stimulate repair after stroke. However, the activation of MSCs may differ depending on the external environment they encounter after systemic injection. We explored the question whether the secretomes of MSCs, once exposed to systemic blood, differs depending on whether blood is from stroke patients versus healthy controls. Methods: Clinical grade bone marrow MSCs from a healthy donor at passage 2 were thawed and re-suspended in PBS. Peripheral blood from healthy subjects (n=4) and stroke patients (n=3) was collected. Blood from stroke patients was collected at 24 hrs after symptom onset. Whole blood or plasma was added to wells. PBS was then added with or without 200,000 MSCs. At various time points, aliquots were collected and probed for cytokines using a MAGPIX reader. Results: Placing MSCs in blood from healthy or stroke patients led to a differential release of cytokines (Fig 1). There were no changes in cytokines levels over time from wells that contained MSCs plus blood derived from healthy controls. However, there were significant increases in IL-8, IL-10 and VEGF levels in wells that contained MSCs plus blood from stroke patients (Fig 1). The increase in TNF-α in wells that contained blood alone from stroke patients was reduced by the addition of MSCs. In wells that contained MSCs plus plasma derived from stroke patients, there were very similar cytokine changes compared with wells that contained MSCs plus plasma derived from healthy controls (data not shown). Conclusion: The components of circulatory blood in stroke patients may be important to activate MSCs to release soluble factors that could modify brain recovery after stroke. Upon systemic administration, the exposure of MSCs to the microenvironment of blood might lead to different activation patterns depending on the health status of the individual.