bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 137: Efficacy and Safety of a TIA Electronic Support Tool (FASTEST): A Cluster Randomized Controlled Trial
Authors: Ranta Annemarei , Dovey Susan , Gommans John , Weatherall Mark
Published: July 2021

Introduction:
The risk of stroke after a transient ischaemic attack (TIA) is greatest within the first few days of the TIA and then tapers over time. It is known that early initiation of best medical therapy significantly reduces this risk.

Hypothesis:
To test whether a TIA/Stroke Electronic Decision Support (EDS) tool in primary care promotes faster access to optimal TIA management and reduces the risk of recurrent stroke and vascular events.

Methods:
A cluster randomized controlled trial (FASTEST Trial ACTRN12611000792921) with general practitioner (GP) practices randomized to use an EDS tool versus usual care.

Results:
The study period was 28 February 2012 to 15 May 2013 and 46 GP practices (145 GPs) registered 373 patients. Eligibility criteria were met by 291/373 (78%) patients of whom 178 received GP care using the EDS and 113 usual care. Ninety day follow up was completed on 13 August 2013. Stroke occurred in 2/178 (1.1%) of the intervention group and 5/113 (4.4%) in the usual care group; odds ratio (95% CI), unadjusted for cluster randomization, 0.25 (0.05 to 1.29), p=0.073. Any vascular event or death occurred in 7/178 (3.9%) of the EDS group and 14/113 (12.4%) of the control group, unadjusted OR (95% CI) 0.29 (0.11 to 0.74), p=0.007. The time to starting anti-platelet medication, in those not previously using these, was similar in the two groups, median (inter-quartile range) of 0 days (0 to 0) and 0 days (0 to 1) in the EDS and usual care groups. Statin and anti-hypertensive prescription, in those not previously using these, occurred more quickly in the EDS group compared to usual care; median (inter-quartile range) 2 days (0 to 7) versus 3 days (0 to7) for statin and 3 days (0 to 7) versus 5 days (1.5 to 37) for anti-hypertensive prescription.

Conclusion:
The preliminary analysis of this trial supports improved outcomes and process of care with EDS versus usual care for TIA management in primary care. The full analysis, adjusted for the cluster randomization, will be presented at the meeting.
Abstract 138: Assessing Disability Outcome in Acute Stroke Clinical Trials: Increased Study Power with Linear (ALDS) Compared with Ordinal (mRS) Scales
Authors: Chaisinanunkul Napasri N , Starkman Sidney , Gornbein Jeffrey A , Hamilton Scott A , Chatfield Fiona , Conwit Robin A , Saver Jeffrey L
Published: July 2021

Background:
The most common primary endpoint in acute stroke trials is the modified Rankin Scale (mRS) assessment of global disability. However, the mRS lacks granularity (assigns patients among only 7 broad levels) and is ordinal (scale levels unknown distances apart), constraining study power. Instruments that evaluate disability along an interval, continuous scale theoretically should increase study power. The Academic Medical Center linear disability scale (ALDS) is one such scale, assigning patients to scores from 0-100.

Methods:
Consecutive patients undergoing 3 month final outcome visits in the NIH FAST-MAG phase 3 trial were assessed with the mRS and ALDS. Scale scores were compared using splines and linear regression. Model trial power was computed using 4000 random simulations.

Results:
Among 55 patients, mean age was 71.2 (SD±14.2), 67% were male, and entry NIHSS was 10.7 (SD±9.5). At 90d, the median mRS was 3 (IQR 1 - 4, range 0-5, lower better) and median ALDS score 78.8 (IQR 3.3-100, range 0-100, higher better). The mRS and ALDS logit score were highly correlated, r = 0.94. ALDS logit score also correlated strongly with 90d Barthel Index(r=0.92) and 90d NIHSS (r=0.87), as well as modestly with entry NIHSS (r = 0.38). The ALDS showed greater discriminant validity than the mRS, with a mean of only 1.9 (SD±3.2) patients sharing each ALDS logit value versus a mean of 8.0 (SD±3.6) patients sharing each mRS score value, p < 0.001. Over a broad range of treatment effect magnitudes, trial power was 25-30% higher when the ALDS rather than the mRS was used as the primary trial endpoint (Figure).

Conclusion:
Among patients enrolled in an acute neuroprotective stroke trial, the ALDS, a linear disability scale derived using item response theory, showed strong convergent validity and superior discrimination characteristics compared with the modified Rankin Scale, and considerably increased trial power to detect clinically meaningful treatment benefits.
Abstract 143: Evaluation of Interval Times from Onset to Recanalization in Patients Undergoing Endovascular Therapy in the IMS III Trial
Authors: Goyal Mayank , Menon Bijoy , Fan Liqiong , Demchuk Andrew , Yeatts Sharon , Hill Michael , Tomsick Thomas , Khatri Pooja , Zaidat Osama , Jauch Edward , Jovin Tudor G , Broderick Joseph P
Published: July 2021

Background:
There were significant delays in achieving recanalization observed in the IA arm of IMS III. A detailed analysis of the workflow helps to identify factors contributing to overall delay.

Methods:
In 418 subjects randomized to the IA arm, the following time intervals were calculated: stroke onset to ED arrival; ED to CT; CT to start of IV tPA; IV tPA to randomization; randomization to groin puncture; groin puncture to thrombus identification; thrombus identification to start of IA therapy; start of IA therapy to reperfusion. The effects of time of day and general anesthesia (GA) on workflow were evaluated. The change of ED to reperfusion and groin puncture to reperfusion over the study period were also evaluated. All times are reported as medians (with IQR).Kruskal-Wallis test was applied.

Results:
Time intervals are shown in figure 1. Intubation had no significant effect on the overall workflow time. The time from CT to groin puncture during business hours (Mon-Fri; 0800-1700) was 119 min (n=201; IQR 49 min) and after hours was 141 min (n=203; IQR 54 min, p <0.0001). The time from CT to groin puncture during day time (0800-2100) was 127 min (n=341; IQR: 51 min) and during night time was 142 min (n=63; IQR 60 min, p=0.0012). After adjusting for multiple comparisons (Bonferroni method), the times from ED to reperfusion (316 min in 1st quartile to 246 min in last quartile,p<0.0001), and groin puncture to reperfusion (145 min in 1st quartile to 120 min in last quartile;p=0.0005) decreased over the trial duration.

Conclusion:
In the endovascular arm of the IMS III trial there were significant delays from start of IV tPA to groin puncture. Endovascular techniques used in the trial were quite inefficient in achieving recanalization. Use of GA did not result in additional delays. Endovascular treatment outside of daytime hours did result in slight additional delays. These data may help in designing, optimizing and documenting workflow in current and future endovascular trials.
Abstract 158: Magnetic Resonance Digital Subtraction Angiography Identifies Impaired Drainage in Arteriovenous Malformations With History of Rupture
Authors: Vranic Justin E , Vakil Parmede , Ansari Sameer A , Batjer Hunt H , Bendok Bernard R , Carroll Timothy J
Published: July 2021

BACKGROUND:
Cerebral digital subtraction angiography (DSA) has established impaired hemodynamic drainage of intracranial arteriovenous malformations (iAVM) as a risk factor for iAVM hemorrhage. Unlike conventional DSA, MR-DSA offers a noninvasive means of characterizing iAVM hemodynamics. We hypothesize that MR-DSA will demonstrate impaired drainage in iAVMs with history of rupture when compared to iAVMs without history of rupture.

METHODS:
Consecutive patients with untreated, DSA-confirmed iAVM underwent MR-DSA on a 3T Whole-body MR-scanner. For each iAVM, regions of interest (ROI) were drawn on all feeder arteries and draining veins. Time-density curves were constructed for each ROI. The arteriovenous malformation transit time (ATT) was defined for each ROI as the time between contrast arrival and peak intravascular contrast density on the MR time-density curve. The drainage of each iAVM was characterized by the ratio of the draining vein ATT to the mean feeder artery ATT. The ATT ratio was compared between iAVMs with history of hemorrhage and those without. Statistical analysis was performed using a Student’s unpaired t-test with p <0.05 defined as statistically significant.

RESULTS:
From May 2011 to April 2012, 13 patients (7M:6F, 40.6±13.8 years old) were enrolled in our study, with 3 patients presenting with history of hemorrhage and the remainder presenting with history of seizure, focal neurological deficit, headache, or as an incidental finding. The ATT ratio was significantly higher in iAVMs with history of hemorrhage than in those without (1.17±0.06 vs 0.95±0.02, p <2.9E-7).

CONCLUSION:
MR-DSA identifies impaired drainage in iAVMs with history of rupture without exposing patients to the procedural risks and ionizing radiation associated with cerebral DSA.

FIGURE A:
MR-DSA with feeder artery (red) and draining vein (yellow) labeled.

FIGURE B:
Time-density curves of the artery (red) and vein (yellow) from which vessel ATTs were derived.
Abstract 165: Platelet Derived Growth Factor (pdgf) is Associated With Progression of Symptomatic Intracranial Large Artery Atherosclerosis
Authors: Jeong Sang-Wuk
Published: July 2021

Background and Purpose:
Studies on the molecular pathways involved in the progression of intracranial large artery atherosclerosis are rare. We aimed to study the relationship between biomarkers and the risk of progression of symptomatic intracranial large artery atherosclerosis.

Methods:
Of 409 patients in Trial of cilostazol in symptomatic intracranial stenosis-2 (TOSS-2) study, 52 patients showed progression of symptomatic intracranial large artery atherosclerosis on MRA after 7 months. We selected 20 patients with progression and 40 age- and sex- matched control patients. We collected blood sample initially, one month and 7 month after infarction, and multiplex analysis of biomarkers including interleukin-1,2,6,8,10, soluble CD40ligand, TNF alpha, PDGF, soluble ICAM, E-selectin and VCAM , MMP-2,3,9, SOD1,2,3 and adipokines, were performed.

Results:
Demographic features such as age, sex, hypertension, diabetes and smoking history were not different between both groups. On univariate analysis, 7 month PDGF-AA (3053 ± 2896 pg/ml, vs 1444±1548 pg/ml), PDGF-AB/BB (15304.0±15634 pg/ml vs 5627±8656 pg/ml) level and MPO(25.7±33.9vs 9.9±8.7ng/ml) were higher in progression group. On multivariate analysis using logistic model, 7 month PDGF AA is independent prognostic factor for progression of intracranial large artery atherosclerosis (p=0.012).

Conclusion:
PDGF-AB/BB level is associated with progression of symptomatic intracranial large artery atherosclerosis.
Abstract 174: Roles of Pericyte NADPH Oxidase 4 in Acute Brain Ischemia
Authors: Nishimura Ataru , Ago Tetsuro , Tachibana Masaki , Makihara Noriko , Matsuo Ryu , Wakisaka Yoshinobu , Kuroda Junya , Kitazono Takanari
Published: July 2021

Pericytes exist abundantly in the brain and compose the neurovascular unit. It has been elucidated that pericytes play a key role in the formation and maintenance of the blood-brain barrier (BBB), thus being considered to play significant roles in brain ischemia. The NADPH oxidase (Nox) family proteins are a major source of reactive oxygen species (ROS). We have reported previously that Nox4 is abundantly expressed in pericytes among the Nox family. Our goal was to elucidate the roles of Nox4 in brain pericytes during acute brain ischemia. We confirmed by quantitative PCR that Nox4 was abundantly expressed in human cultured brain microvascular pericytes (HBMPC) and was significantly upregulated by hypoxia. We produced a mouse middle cerebral artery occlusion (MCAO) stroke model and examined the expression of Nox4 in the brain. Immunofluorescent double labeling demonstrated that Nox4 expression was upregulated in microvessels particularly in peri-infarct areas and was co-stained with PDGFRβ, a pericyte marker. In order to elucidate the role of Nox4 in brain pericyte during brain ischemia, we generated mice with human Nox4 overexpression using a promoter of SM22α, a pericyte/smooth muscle cell marker (Tg-Nox4). We confirmed that SM22α was expressed in mouse brain pericytes by co-immunostaining with PDGFRβ. We isolated microvessels from Tg-Nox4 brain and confirmed that human Nox4 mRNA was highly expressed. In MCAO model, the infarct volume was significantly larger in Tg-Nox4 than in littermate controls. Confocal microscopy demonstrated that IgG leakage in peri-infarct areas was significantly increased in Tg-Nox4, suggesting that Nox4 overexpression in pericytes enhanced BBB breakdown during acute brain ischemia. To elucidate the mechanisms, we induced adenovirus-mediated overexpression of Nox4 in HBMPC. We demonstrated that Nox4 overexpression increased NFκB phosphorylation and MMP9 expression in the cells.In conclusion, Nox4 may be a major source of ROS in brain pericytes and is upregulated directly by hypoxia in peri-infarct areas during acute brain ischemia. Pericyte Nox4 may enhance BBB breakdown through the activation of NFκB-MMP9 signaling during acute brain ischemia.
Abstract 182: "Spot" Sign vs "Dot" Sign as Predictor of Hemorrhagic Stroke Outcomes
Authors: Brag Katherine O , Jones Erica , Monlezun Dominique , George Alex , Halstead Michael , Martin-Schild Sheryl , El Khoury Ramy
Published: July 2021

Introduction:
Hematoma expansion (HE) is an established predictor of mortality and poor functional outcome after intracerebral hemorrhage (ICH). The computed tomography angiography (CTA) “spot” sign predicts HE and deterioration. The “dot” sign on delayed post-contrast CT (PCCT) has undetermined clinical significance but is thought to represent a slower rate of bleeding than the “spot” sign. We aimed to compare the sensitivity of a “dot” sign with the “spot” sign and establish the clinical significance of the “dot” sign.

Methods:
Patients with ICH presenting to our center July 2008-May 2013 were identified from our stroke registry. Only patients with baseline CT, CTA and PCCT and follow-up CT 6-36 hours later were included. Patients with clot evacuation between baseline and follow-up CT were excluded. HE was defined as 1) any ≥ 1cc increase and 2) significant ≥ 12.5cc increase or >33% increase in volume. Differences in cohort characteristics were assessed using appropriate statistical tests and sensitivity was calculated from 2x2 tables. Unadjusted logistic regression models were used to investigate the relation of “spot” and “dot” signs with HE and poor functional outcome (discharge mRS 4-6).

Results:
Of the 210 ICH patients included in the analyses (median age 61, 44.7% female, 66.2% black), 39 (18.5%) patients had a PCCT “dot” sign and 19 (9%) had a CTA “spot” sign. Significant HE occurred in 15% with “dot” sign and 8% with “spot” sign. The PCCT “dot” sign had a sensitivity of 0.52 in predicting significant HE and a sensitivity of 0.69 in predicting discharge mRS 4-6 (compared with 0.24 and 0.30 for “spot” sign, respectively). Patients with a “dot” sign, but without a “spot” sign, had significantly increased odds of any HE (OR 5.7, 95% CI 1.9-17.8, p=0.003), mRS 4-6 (OR 8.1, 95% CI 1.03-64.6, p=0.048), and death (OR 8.1, 95% CI 1.4-48.4, p=0.02), but not significant HE (OR 2.2, 95% CI 0.7-6.7, p=0.15).

Conclusions:
The PCCT “dot” sign was more sensitive in predicting hematoma expansion than the CTA “spot” sign and predicted hematoma expansion and poor functional outcome even in the absence of the “spot sign.” The utility of PCCT imaging in acute evaluation of ICH patients requires validation, but our study supports clinical relevance of the “dot” sign.
Abstract 192: Bone Marrow Mononuclear Cells May Enhance Recovery After Stroke By Modulating the Microglial Response
Authors: Yang Bing , Parsha Kaushik , Migliati Elton , Savitz Sean
Published: July 2021

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
<0.05); 2)Compared to saline, MNCs significantly reduced the total number of CD11b

+

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
<0.05).

Conclusions:
MNCs may enhance recovery after stroke by altering monocyte trafficking and changing microglial polarization into a healing phenotype.
Abstract 195: Simvastatin Rescues Impaired Angiogenesis Potential of Cerebrovascular Endothelial Cells by AGEs : The Role of Autophagy
Authors: Hou Xuwei , Hu Zhaohui , Wang Ningfu
Published: July 2021

Background:
Statin therapy is beneficial for ischemic stroke (IS) partly due to its pro-angiogenic effect. In diabetes patients, the accumulations of advanced glycation end products (AGEs) impair the angiogenic potential of endothelial cells (ECs), comprising collateral circulation in ischemic area. Autophagy affects endothelial function. The effect of statins on EC autophagy remains largely unknown. This study was to: 1.investigate the effect of Statin on the angiogenesis ability of ECs impaired by AGEs; 2. explore the autophagy of ECs in this process.

Methods:
primary cerebromicrovascular endothelial cells (CMVECs) were isolated from Wistar rats and cultured in medium. CMVECs were treated with AGEs. Subsequently, Simvastatin was added to cells. The angiogenic potential was evaluated by tube formation in vitro. Two autophagy marker, Beclin1 and LC3 protein expression were detected by western blot assay. The autophagosome quantitative analysis was evaluated by GFP-LC3-II assay.

Results:
AGEs (25mg/L, 50mg/L and 100mg/L) reduced the number of tube like structures in a dose dependant manner, accompanied by dramatically enhanced cellular autophagy level indicated by the increased GFP-LC3-II puncta number/cell and increased Beclin1 and LC3 expressions. Autophagy inhibitor 3-MA reversed the AGEs impaired angiogenic ability of CMVES. Simvastatin administration (10μmol/L) markedly increased the angiogenic potential of CMVES evaluated by tube formation ability, together with decreased Beclin1 and LC3, as well as decreased GFP-LC3-II puncta number/cell. AGEs significantly inhibits the PI3K/Akt/mTOR, while Simvastatin re-activate this pathway. More interestingly, the addition of mTOR inhibitor, rapamycin, which enhance the cellular autophagy, abolished the rescue effect of Simvastatin on the angiogenic potential of CMVECs impaired by AGEs.

Conclusion:
This study provides evidence that AGEs impair the angiogenesis ability via triggering high level of autophagy of CMVECs. Simvastatin rescue the angiogenic ability of CMVECs by surprising autophagy level via activation of PI3K/Akt/mTOR pathway.
Abstract 214: The Field Administration of Stroke Therapy - Magnesium (FAST-MAG) Phase 3 Trial: Primary Results
Authors: Saver Jeffrey L , Eckstein Marc , Stratton Samuel , Pratt Frank , Hamilton Scott , Conwit Robin , Liebeskind David , Lyden Patrick , Sanossian Nerses , Sung Gene , Kramer Ian , Moreau Gary , Goldweber Robert , Starkman Sidney ,   the FAST-MAG Investigators and Coordinators
Published: July 2021

BACKGROUND:
Magnesium is neuroprotective in preclinical models of stroke and has been safe and shown signals of potential efficacy when delivered early after onset of human cerebral ischemia. Delayed initiation of neuroprotective agents has hindered past neuroprotective agent trials. We performed a multicenter, randomized, double-blind, placebo-controlled phase 3, trial to test whether paramedic initiation of intravenous magnesium sulfate within 2 hours of symptom onset improves the longterm functional outcome of hyperacute stroke patients.

METHODS:
Inclusion criteria were: 1) likely stroke as identified by the Los Angeles Prehospital Stroke Screen (LAPSS), 2) age 40-95, 3) symptom onset within 2 hours of treatment initiation, 4) deficit present ≥ 15 minutes. Trial sites included 315 ambulances, 40 EMS agencies, and 60 receiving hospitals throughout Los Angeles and Orange Counties, with 2988 paramedics trained in study procedures. From Jan 2005 - Dec 2012, paramedics in the field administered a loading dose (4 grams over 15 minutes) of magnesium sulfate (Mg) or matched saline placebo. Upon arrival in an ED, a maintenance infusion followed: 16 grams Mg or matched placebo over 24 hours. The primary endpoint was the modified Rankin Scale measure of global disability at 90 days.

RESULTS:
Among the 1700 enrolled patients, mean age was 69 (SD 13.6), 42.7% were female, median pretreatment stroke severity on the Los Angeles Motor Scale (LAMS) was 4.0, and median early post-treatment NIHSS stroke severity on ED arrival was 9.0. Final diagnosis of the presenting event was acute cerebral ischemia in 73.0%, acute hemorrhagic stroke in 23.2%, and stroke-mimicking condition in 3.8%. The median time from last known well to start of study infusion was 48 minutes (IQR 37 - 68). The proportion of patients receiving study infusion within the first hour after last known well was 74.1%.

CONCLUSION:
Prehospital initiation of neuroprotective agents can be performed in a large phase 3 acute stroke trial, permitting rapid drug start, with treatment in the first, “golden” hour in three-quarters of patients. The study blind will be broken in late fall and the first public presentation of trial efficacy results presented at the ISC meeting.
Abstract 24: Predictors of Occult Atrial Fibrillation in Cryptogenic Stroke
Authors: Ingala Erin , Jara Jenny , Fessler Emily , Cucchiara Brett L , Messe Steven R , Mullen Michael T , Prasad Allyson , Hutchinson Mathew , Kasner Scott E
Published: July 2021

Background and Purpose:
Prolonged cardiac monitoring may identify paroxysmal atrial fibrillation (AF) in patients with cryptogenic stroke. We aimed to identify clinical, echocardiographic, and neuroimaging features which may increase the efficiency of detecting AF on cardiac monitoring.

Methods:
We studied a retrospective cohort of 227 subjects with cryptogenic ischemic stroke referred for 28 day mobile cardiac outpatient telemetry (MCOT). Patients with large artery disease or high risk sources of cardioembolism were excluded. We reviewed medical records, brain images, and echocardiograms, blinded to MCOT results. Acute and/or chronic infarctions were characterized by size, location, and as cortical, subcortical, or both; wedge-shaped; lacunar; borderzone; and/or multiple territories. Cardiac features included left atrial (LA) size, ejection fraction, aortic arch atheroma, and PFO. Variables were tested in univariate analyses and further incorporated in a multivariate logistic regression model to determine independent predictors of detecting AF.

Results:
The cohort age was 62.9±2.9 years, 42% were men, and 53% were white. Median CHADS was 3 and CHADS2Vasc was 5. Infarcts were >1.5 cm in 62% of subjects, predominantly cortical in 47%, subcortical in 39%. Only 9% were single, deep, and <1.5 cm. LA size was 3.6±0.7 cm and ejection fraction was 61±9%. MCOT detected AF in 30 (13%) patients. In multivariate analysis, AF was only associated with age>60 (OR 3.6 [1.2-10.4], p=0.02) and prior (chronic) cortical or cerebellar infarction (OR 3.3 [1.3-8.6], p=0.013) (C-statistic 0.72). There was no association with any other clinical, echocardiographic, or radiographic parameter. AF was detected in 32% of patients with age >60 and the presence of prior cortical or cerebellar infarction, compared to 4% with neither of these factors.

Conclusion:
Atrial fibrillation is detected on MCOT in a substantial minority of cryptogenic stroke patients. Age>60 and the presence of prior cortical or cerebellar strokes are predictive of detecting AF in these patients. Other brain and cardiac characteristics were not found to be helpful. These data may aid in the selection of patients for prolonged arrhythmia monitoring.
Abstract 40: The Impact of an Institutional Acute Stroke Protocol on Time to Treatment of Childhood Stroke
Authors: Shack Melissa , Andrade Andrea , Shroff Manohar , Moharir Mahendranath , Yau Ivanna , Askalan Rand , MacGregor Daune , Rafay Mubeen F , Paterson Julie , deVeber Gabrielle A
Published: July 2021

Introduction:
In pediatric stroke, reported median delays from symptom onset to imaging diagnosis are 16-24hrs. This results in delayed treatment initiation. The impact of an Acute Stroke Protocol in pediatric hospitals has not been reported. Such a program was implemented at SickKids in 2005. The current study measured the impact of this protocol on delays to diagnosis and initiation of antithrombotic agents.

Methods:
We compared time to diagnosis and treatment in children (age 1mo-18yrs) with acute AIS diagnosed after stroke protocol implementation (‘post-protocol’ from 2005-2012), to 209 children diagnosed ‘pre-protocol’ 1992-2004. Focused health record reviews abstracted intervals from symptom onset to diagnosis and to initiation of first antithrombotic treatment. We statistically compared time intervals in pre and post-protocol cohorts.

Results:
Among 118 children diagnosed post-protocol (75 outpatient and 43 inpatient strokes), median age was 5.8 years with 65 males. Median delay from symptom onset to diagnosis in post-protocol children was similar to pre-protocol children, for all strokes (19.9hrs vs 22.7hrs respectively; p=0.24), outpatient (22.4hrs vs 29.1hrs; p=0.12) and inpatient strokes (12.8hrs vs 14.6hrs; p=0.92). The main contributors to diagnosis beyond 6 hrs were delays in initial neuroimaging (25% of delays) and false-negative neuroimaging results (19% of delays) in CT scan as first test. The interval from diagnosis to antithrombotic treatment was more frequently within 24 hours for children treated post-protocol (55.1% vs 18.7% pre-protocol;p<0.0001) and in post-protocol children this interval was median 4.5 hrs (IQR 1.9-16.6). Also children with inpatient strokes more frequently received antithrombotic agents post-protocol (58% vs 35% pre-protocol;p=0.031). The types of antithrombotic treatments were similar (p=0.337).

Conclusions:
The implementation of an Acute Stroke Protocol in our children’s hospital reduced the time to initiation of antithrombotic treatment. As thrombolysis and other hyper-acute treatments become available, the implementation of institutional Acute Stroke Protocols in children’s hospitals will be an important strategy to increase access to these therapies for children with AIS.
Abstract 41: Care Seeking Behaviours in Childhood Arterial Ischemic Stroke
Authors: MacKay Mark T , Stojanovski Belinda , Donnan Geoffrey A , Churilov Leonid , Mosely Ian , Hocking Grant , Monagle Paul T
Published: July 2021

Objective:
Taking appropriate action in the pre-hospital setting is important for rapid stroke diagnosis in adults but data are lacking for children. Our objectives were to describe help seeking behaviour and pathways to hospital in pediatric arterial ischemic stroke.

Methods:
A structured interview was performed to determine carer actions and pathway to hospital. Event driven process modeling techniques were used to develop questions with fundamental objectives being timely and correct recognition of stroke in the pre-hospital setting.

Results:
Parents of 28 children (61% female) were interviewed. 27 children (96%) were awake at stroke ictus and 26 (93%) had sudden onset symptoms. Child’s location at stroke onset included home 19 (68%), school 3 (11%) or other setting 6 (21%). Carers present included parent 21 (75%), teacher 2 (7%), other adult 4 (14%) or alone 1 (4%). 24 (89%) parents thought symptoms were serious but only 10 (36%) considered the possibility of stroke. Symptoms of most concern to parents included face weakness 14 (54%), speech disturbance 9 (32%), incoordination or difficulty walking 6 (21%), headache 5 (18%) and weakness 4 (14%).
Initial
actions included calling 911 in 10 (36%), wait and see 6 (21%), calling family member 1 (4%), private transport to emergency room (ER) 7 (25%) or family physician 4 (14%). 22 (85%) carers thought urgent action was required but only 14 (54%) ultimately called 911. First heath professional contact included paramedic 13 (46%), ER physician 8 (29%) or family physician 7 (25%). Median time from onset to ER arrival was 1.8 hours (IQR 0.75-7).

Conclusions:
Only one-third of carers considered stroke as a possible cause for their child’s neurological symptoms and less than half called 911. Initiatives are required to educate parents about taking appropriate action to improve access to time critical interventions.
Abstract 46: Leukoaraiosis Evolves Through Discrete Acute Ischemic Injuries: Weekly Diffusion Tensor Imaging and T2 Relaxometry at 16 Time Points
Authors: Conklin John , Silver Frank L , Mikulis David J , Mandell Daniel M
Published: July 2021

INTRODUCTION:
Leukoaraiosis, the presence of “incidental” white matter lesions in the aging brain, is increasingly recognized as a predictor for dementia, ischemic stroke, intracerebral hemorrhage and vascular death. The pathogenesis of leukoaraiosis remains controversial, with abnormalities of small arterioles hypothesized to play an important role. To investigate this hypothesis, we sought to characterize the temporal evolution of the individual lesions making up leukoaraiosis.

HYPOTHESIS:
Discrete occlusive events at the level of small arterioles play a key role in the pathogenesis of leukoaraiosis.

METHODS:
Participants were prospectively recruited through an outpatient neurology clinic (inclusion criteria: age > 60 years, Fazekas grade 3 leukoaraiosis burden; exclusion criteria: cortical infarct, cardioembolic disease, dissection, carotid stenosis > 50%). Subjects underwent an identical MRI protocol in each of 16 consecutive weeks, including diffusion tensor imaging (DTI) and multi-echo T2-weighted imaging. Parametric maps of the apparent diffusion coefficient (ADC), fractional anisotropy (FA) and T2 relaxation time were constructed and coregistered (Analysis of Functional NeuroImages, NIH; 3D Slicer, www.slicer.org; Matlab, The MathWorks). Images were reviewed for new diffusion restricting lesions, and such lesions were manually segmented. Plots of lesion ADC, FA and T2 were generated and temporally aligned to the onset of acute diffusion restriction.

RESULTS:
Five subjects (mean age 69 ± 8 years) met criteria and completed all 16 MRI scans. There were no lacunar or large artery infarcts during the study period. A total of 9 new diffusion restricting white matter lesions were identified (mean volume 0.06 ± 0.03 cc). Evolution of these lesions showed striking similarity to that of cerebral infarction, with acute reduction in ADC, followed by gradual rise in ADC and T2, and corresponding decline in FA. At 8 weeks, new lesions were indistinguishable from pre-existing white matter disease.

CONCLUSION:
Leukoaraiosis evolves through temporally and spatially discrete acute ischemic injuries. This supports the hypothesized role of small vessel arteriolar pathology as a key pathogenetic mechanism.
Abstract 47: Proteomic Profiling of Acute Stroke Patients Highlights the Importance of vWF and vWF-Cleaving Protease (ADAMTS13) in Thrombolysis
Authors: Ning MingMing , Van Cott Elizabeth , Lopez Mary , Sarracino Dave , Wickham Thomas , McMullin David , Wang Xiaoying , Zhao Bingqiao , Buonanno Ferdinando , Lo Eng H
Published: July 2021

Introduction:
Recent animal studies show rADAMTS13 (vWF cleaving protease) to block tPA-induced BBB opening, reducing tPA-related hemorrhage and augmenting tPA’s thrombolytic effect. From proteomic screening, we found ADAMTS13/vWF to be an important pathway in tPA responders. Thus, the vWF/ADAMTS13 (vWF cleaving protease) axis may be an important modifier of tPA response in the clinical setting. But the effect of tPA on the ADAMTS13/vWF balance has not been studied directly in stroke patients post-tPA. Here we measured vWF and ADAMTS13 in acute ischemic stroke patients post IV tPA to investigate their clinical utility to follow tPA response.

Methods:
Quantitative Mass Spectrometry (MS), latex immuno-turbidimetric assay, and ELISA were performed in acute ischemic stroke plasma over time, with clinical outcome measured at 3 months. Response was defined per NINDS trial as mRankins<=2 and >= 4 points improvement on NIHSS.

Results:
Post tPA (up to 72 hours), ADAMTS13 is persistently and significantly higher in tPA responders than in non-responders (Figure 1A). Conversely, within 72 hrs post tPA, the ratio of vWF/ADAMTS13 (a measure of clot burden vs clot lysis) is significantly higher in tPA patients who did not improve compared to those who did. tPA patients also had lower vWF/ADAMTS13 ratios than non-tPA strokes (Figure 1B).

Conclusion:
Through dynamic changes detected in the vWF/ADAMTS13 pathway, our data suggest the balance of clot burden vs lysis is crucial in tPA response as measured in patient plasma in real time. More vWF degradation in tPA patients via ADAMTS13 is correlated to better clinical outcome within the first 72 hours, and conversely, increased clot burden was found in tPA non-responders. Studying endogenous ADAMTS13 activity in tPA response is an initial step to obtain evidence for its potential clinical utility. And vWF/ADAMTS13 ratio may be a biologically relevant and potentially clinically useful marker of clotting/lytic status in early thrombolysis.
Abstract 51: Effects of Vascular Risk Factors on Microstructural White Matter: A Voxel-Based Longitudinal Diffusion Tensor Imaging Study
Authors: Maillard Pauline , Fletcher Evan , Carmichael Owen , Mungas Dan , Reed Bruce , DeCarli Charles
Published: July 2021

Background:
Diabetes mellitus type II (DMT2) and hypertension (HTN) have been reported as increasing the risk of dementia. Because recent cross-sectional diffusion tensor imaging (DTI) studies have identified association between vascular risk factors (VRF) and microstructural white matter (WM) abnormalities in elderly, longitudinal DTI studies are needed to determine whether VRF may be associated with accelerated WM degeneration over time.

Methods:
114 cognitively normal participants from University of California, Davis Alzheimer’s Disease Center, aged 73.9±6.7, received a comprehensive clinical evaluation and brain MRI including T1-weighted and DTI sequences on two dates (mean delay: 3.3 years). Baseline and follow-up FA maps were calculated, aligned, and subtracted to provide FA change ([[Unable to Display Character: ∆]]FA) maps and warped to a common template (MDT). Coregistration of baseline and follow-up T1 maps to MDT enabled computation of Jacobian images (i.e. the local contraction factor). VRF score (VRFS) was computed as the sum of DMT2, HTN and hyperlipidemia (HYP) incidence based on the subject’s medical history. We then used voxel-based linear regressions to relate annual [[Unable to Display Character: ∆]]FA and Jacobian determinants to VRFS, adjusting for potential confounders. Resulting T maps were corrected for multiple comparisons.

Results:
Poorer VRF score was associated with higher rate of [[Unable to Display Character: ∆]]FA loss and of GM atrophy with regions most heavily implicated including the corpus callosum and the frontal GM (see Figure1).

Conclusions:
This is one of very few studies of longitudinal DTI change in the elderly. DMT2, HTH and HYP are associated with accelerated WM degeneration and GM atrophy in areas whose integrity is known to be reduced in mild cognitive impairment and dementia. Future work should clarify the independent role of these vascular risk factors in accelerating brain aging.
Abstract 67: HsCRP Predicts Recurrent Stroke and Vascular Events among Patients with Lacunar Stroke: The Levels of Inflammatory Markers in the Treatment of Stroke (LIMITS) Study
Authors: Elkind Mitchell S , Zhang Yu , McClure Leslie A , Coffey Christopher S , White Carole , Roldan Ana , Del Brutto Oscar H , Pretell Edwin J , Pettigrew L. C , Tapia Jorge , Meyer Brett C , Luna Jorge , Spitalnik Steve L , Wang Hangli , Benavente Oscar ,   LIMITS Investigators
Published: July 2021

Objective:
To determine whether high sensitivity C-reactive protein (hsCRP) predicts recurrent stroke and other vascular events among recent lacunar stroke patients.

Background:
Inflammatory markers have been associated with risk of first stroke. Their role in predicting recurrence is unclear.

Methods:
The Levels of Inflammatory Markers in the Treatment of Stroke study is an international prospective study of inflammatory markers among recent lacunar stroke patients enrolled in the NIH-funded randomized Secondary Prevention of Small Subcortical Strokes trial. Patients had blood samples drawn, saved at -80 degrees C, and run at a central lab for hsCRP using nephelometry. Cox proportional hazard models were used to estimate hazard ratios and 95% confidence intervals (HR, 95% CI) for associations of hsCRP with recurrence risk before and after adjusting for demographics, comorbidities, and statin use.

Results:
Among 1244 lacunar stroke patients (mean 63.3 ± 10.8 years), median hsCRP was 2.16 mg/L (interquartile range 0.93-4.86), and levels differed by age, sex, smoking, and LDL. Median time between stroke and hsCRP measurement was 60 days, and levels were inversely and weakly correlated with proximity to stroke date (r=-0.06, p=0.039). There were 83 recurrent ischemic strokes (45 lacunes), 16 hemorrhages, and 115 major vascular events (stroke, MI, vascular death). Compared to the bottom quartile, those in the top quartile of hsCRP (>4.86 mg/dl) were at increased risk of recurrent ischemic stroke (unadjusted HR 2.54, 95% CI 1.30-4.96), and the risk persisted after adjusting for age, sex, race, region, hypertension, smoking, prior history of stroke, diabetes, lipid levels, and statin use (adjusted HR 2.28, 95% CI 1.14-4.57). HsCRP was associated with an increased risk of major vascular events (top quartile adjusted HR 1.98, 95% CI 1.11-3.54). Results were similar using clinical thresholds of high risk hsCRP (> 3 mg/dl). There was no interaction of randomized antiplatelet treatment with hsCRP levels for stroke risk.

Conclusions:
Among recent lacunar stroke patients, elevated hsCRP levels predict increased risk of recurrent strokes and other vascular events. Levels of inflammatory markers did not predict a response to dual antiplatelet treatment.
Abstract 86: Methodological Issues in Telephone Interventions for Stroke Survivors and Family Caregivers
Authors: Kirkness Catherine J , Buzaitis Ann , Habermann Barbara , Jessup Nanette M , McClennon Susan M , McKenzie Sylvia , Weaver Micheal T , Weisman Pamela , Mitchell Pamela H , Bakas Tamilyn
Published: July 2021

Background:
Post-stroke follow-up interventions are increasingly delivered by telephone. Though many studies report comparable outcomes for phone and in-person delivery, little is reported regarding the feasibility of using this technology in stroke.

Purpose:
We report positive and negative aspects of phone interventions in two ongoing stroke studies, including strategies to overcome limitations

Methods:
Study A is comparing a tailored phone intervention with an active listening phone intervention for 254 stroke family caregivers. Study B is comparing tailored in-person versus phone interventions in 100 stroke survivors. Researchers in both studies identified facilitators and barriers to using the telephone.

Results:
Advantages of phone delivery included ease of access for both caregivers and survivors, less time commitment, and no pressure to present a good appearance (of the home or self). Study A sessions averaged 30 minutes for the tailored intervention versus 16 minutes for active listening. Caregiver rapport was easily established with both interventions. Nurses expressed relief that the study was conducted by phone given the number of rescheduled appointments. Study B phone sessions were shorter than in-person (25 minutes vs. 35-40). There were particular challenges for survivors who had expressive language difficulty, and motor deficits made it hard for some to hold the phone. Hearing deficits posed difficulty, as well as background noise and the lack of ability to “see” nonverbal cues. Investigators used speaker phones when possible for persons with limitations and also recorded conversations to further interpret responses.

Conclusions:
Though telephone delivery poses some challenges, these can be overcome. For stroke caregivers, advantages clearly outweigh the disadvantages, though for stroke survivors, speakerphones and/or videoconferencing may improve quality. Further research using telephone technologies needs to be conducted, particularly in today’s cost-sensitive health care environment where in-person delivery methods are increasingly under scrutiny.
Abstract 97: The Impact of “Traditional” Risk Factors for Incident Versus Recurrent Stroke
Authors: Howard George , Kissela Brett , Kleindorfer Dawn O , Safford Monika M , Cushman Mary , Soliman Elsayed Z , Judd Suzanne E , Moy Claudia S , Lackland Daniel T , McClure Leslie A , Howard Virginia J ,   for the REasons for Geographic And Racial Differences in Stroke (REGARDS) Study
Published: July 2021

Introduction:
Risk factors for incident stroke have been shown to also be associated with risk for recurrent stroke; however, to our knowledge there has not been a cohort with risk factors measured in a sufficient number of stroke-free and prevalent stroke cases to contrast the impact of the risk factors between incident and recurrent stroke.

Methods:
REGARDS recruited 30,239 participants between 2003 and 2007. Participants were stratified into those reporting and not reporting a physician-diagnosed stroke at baseline. Proportional hazards analysis was used to assess the role of risk factors for stroke.

Results:
Over 6.2 years of follow-up, there were 825 strokes among 25,849 (3.2%) participants without stroke/TIA at baseline, and 310 strokes among 3,101 (10.0%) with stroke/TIA at baseline. In those stroke-free at baseline, there was an age-by-race interaction (p = 0.0003) with a substantially higher risk among blacks than whites at age 45 (HR = 2.69; 95% CI: 1.85 - 3.91), but with increasing age to age 85 this disparity disappeared (HR = 0.95; 95% CI: 0.74 - 1.23). However, there was a constant (p = 0.98) 21% non-significantly higher risk among blacks over the entire age range. For both blacks and whites, the impact of increasing age had a substantially smaller impact on recurrent than incident stroke. The traditional risk factors had a generally smaller impact for recurrent than incident stroke (significantly for atrial fibrillation and heart disease), however, they remained significantly associated with increased risk for recurrent stroke (see table).

Discussion:
The role of race and age differed for incident versus recurrent stroke, while the traditional risk factors persisted as indicators of higher risk for recurrent stroke. The smaller impact of stroke risk factors on recurrent stroke should be interpreted with caution, as the higher event rate in this group could imply that the risk factors still have a powerful effect on absolute risk.
Abstract T MP100: Improving Encounter Frequency, Physician Prescribing, or Patient Adherence - What Works Best for Controlling Blood Pressure? Results From a Validated Micro-Simulation Model
Authors: Fontil Valy , Bibbins-Domingo Kirsten , Kazi Dhruv , Coxson Pamela , Sidney Steve , Khanna Raman , Victor Ronald G , Pletcher Mark
Published: July 2021

Background:
Only half of hypertensive adults achieve blood pressure (BP) control in the United States.

Methods:
We developed the BP Control Model to simulate physician- and patient-level processes relevant in achieving BP control. We validated the model by simulating the intervention arm of a recent multicenter clinical trial and used the validated model to examine the effects of isolated improvements in three modifiable processes on BP control. Data from national surveys, cohort studies, and trials were used to parameterize the model. We simulated 5,000 hypothetical adult patients with uncontrolled hypertension (systolic BP≥ 140) using probability sampling of participants from the 2009-2010 National Health and Nutrition Examination Survey. We modeled 50% improvements and ideal scenarios for each process parameter.

Outcome:
We reported outcomes in terms of BP control (% with SBP < 140 mmHg), and average change in BP at 52 weeks.

Results:
In our validation analysis, the model-predicted BP control was similar to what was achieved in the VIPER-BP clinical trial (63.5% vs. 63.8%). In our base case scenario, 24% of the NHANES-derived cohort achieved BP control at 52 weeks. In scenarios with 50% improvements, the model predicted small increases in BP control, but substantially larger and more variable effects when processes were idealized (Table). Control was reached in 77% with ideal treatment intensification, 44% with ideal encounter frequency, only 32% with ideal adherence, and 97% when all three processes were idealized.

Conclusion:
While improving patient adherence to medications would improve BP control, healthcare systems can achieve similar or greater success by focusing on increasing the frequency of clinical encounters and improving physicians’ prescribing behavior. The BP Control Model can be used to predict how much improvement to expect from such interventions.