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Objective: Agonism of protease-activated receptor (PAR) 1 by activated protein C (APC) provides neuro- and vasculoprotection in experimental neuroinjury models. The pleiotropic PAR1 agonist, 3K3A-APC, reduces neurological injury and promotes vascular integrity; 3K3A-APC proved safe in human volunteers. We performed a randomized, controlled, blinded trial to determine the maximally tolerated dose (MTD) of 3K3A-APC in ischemic stroke patients., Methods: The NeuroNEXT trial, RHAPSODY, used a novel continual reassessment method to determine the MTD using tiers of 120, 240, 360, and 540 μg/kg of 3K3A-APC. After intravenous tissue plasminogen activator, intra-arterial mechanical thrombectomy, or both, patients were randomized to 1 of the 4 doses or placebo. Vasculoprotection was assessed as microbleed and intracranial hemorrhage (ICH) rates., Results: Between January 2015 and July 2017, we treated 110 patients. Demographics resembled a typical stroke population. The MTD was the highest-dose 3K3A-APC tested, 540 μg/kg, with an estimated toxicity rate of 7%. There was no difference in prespecified ICH rates. In exploratory analyses, 3K3A-APC reduced ICH rates compared to placebo from 86.5% to 67.4% in the combined treatment arms (p = 0.046) and total hemorrhage volume from an average of 2.1 ± 5.8 ml in placebo to 0.8 ± 2.1 ml in the combined treatment arms (p = 0.066)., Interpretation: RHAPSODY is the first trial of a neuroprotectant for acute ischemic stroke in a trial design allowing thrombectomy, thrombolysis, or both. The MTD was 540 μg/kg for the PAR1 active cytoprotectant, 3K3A-APC. A trend toward lower hemorrhage rate in an exploratory analysis requires confirmation., Clinical Trial Registration: Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT02222714. ANN NEUROL 2019;85:125-136., (© 2018 American Neurological Association.)

Background and Purpose: To assess the effect of optimal medical management including atherosclerotic risk factor control on ischemic stroke (IS), transient ischemic attack (TIA), carotid revascularization (CRV), and progression of severity of carotid stenosis (PSCS) in patients with asymptomatic carotid artery stenosis (ACAS)., Methods: We conducted a retrospective analysis of patients with ACAS (who had at least 3 serial carotid duplex ultrasounds) for incidence of IS, TIA, and PSCS., Results: Eight hundred sixty-four patients with a mean follow-up duration of 79 ± 36 months were included. IS/TIA and CRV occurred in 12.2% of the patients and PCSS was observed in 21.5% vessels. On univariate analysis it was found that low-density lipoprotein (LDL) levels >100 mg/dL, no statin or low-potency statins, average systolic blood pressure (SBP) ≥140 mm Hg and/or diastolic blood pressure (DBP) ≥90 mm Hg and history of smoking were predictors of the combined endpoint of IS/TIA/CRV and PSCS. On multivariate analysis, it was found that LDL >100 mg/dL, no statin or low-potency statin, SBP ≥140 mm Hg and/or DBP ≥90 mm Hg, and Hx of smoking were independent predictors of PSCS. Similarly no statin or low-potency statin, SBP ≥140 mm Hg and/or DBP ≥90 mm Hg, Hx of atrial fibrillation/flutter, Hx of chronic kidney disease, and PSCS were independent predictors of IS/TIA. No statin or low-potency statin, SBP ≥140 mm Hg and/or DBP ≥90 mm Hg, diabetes mellitus, baseline carotid artery stenosis ≥70%, and PSCS were found to be independent predictors of combined endpoint IS/TIA and CRV., Conclusion: Intensive medical therapy in the patients with ACAS results in lower incidence of IS/TIA, CRV, and PSCS with a significant incremental beneficial effect., (© 2017 S. Karger AG, Basel.)

Background and Purpose: The advent of intra-arterial neurothrombectomy (IAT) for acute ischemic stroke opens a potentially transformative opportunity to improve neuroprotection studies. Combining a putative neuroprotectant with recanalization could produce more powerful trials but could introduce heterogeneity and adverse event possibilities. We sought to demonstrate feasibility of IAT in neuroprotectant trials by defining IAT selection criteria for an ongoing neuroprotectant clinical trial., Methods: The study drug, 3K3A-APC, is a pleiotropic cytoprotectant and may reduce thrombolysis-associated hemorrhage. The NeuroNEXT trial NN104 (RHAPSODY) is designed to establish a maximally tolerated dose of 3K3A-APC. Each trial site provided their IAT selection criteria. An expert panel reviewed site criteria and published evidence. Finally, the trial leadership designed IAT selection criteria., Results: Derived selection criteria reflected consistency among the sites and comparability to published IAT trials. A protocol amendment allowing IAT (and relaxed age, National Institutes of Health Stroke Scale, and time limits) in the RHAPSODY trial was implemented on June 15, 2015. Recruitment before and after the amendment improved from 8 enrolled patients (601 screened, 1.3%) to 51 patients (821 screened, 6.2%; odds ratio [95% confidence limit] of 4.9 [2.3-10.4]; P<0.001). Gross recruitment was 0.11 patients per site month versus 0.43 patients per site per month, respectively, before and after the amendment., Conclusions: It is feasible to include IAT in a neuroprotectant trial for acute ischemic stroke. Criteria are presented for including such patients in a manner that is consistent with published evidence for IAT while still preserving the ability to test the role of the putative neuroprotectant., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02222714., (© 2016 American Heart Association, Inc.)

Background: National guidelines endorse recombinant tissue-type plasminogen activator (r-tPA) in eligible patients with acute ischemic stroke to improve patients' functional recovery. However, 23% to 40% of ideal candidates with acute ischemic stroke for reperfusion are not treated, perhaps because of the difficulty in explaining the benefits and risks of r-tPA within the frenetic pace of emergency department care. To support better knowledge transfer and creation of a shared decision-making tool, we conducted qualitative interviews to define the information needs and preferred presentation format for stroke survivors, caregivers, and clinicians considering r-tPA treatment., Methods and Results: A multidisciplinary team used qualitative research methods to identify informational needs and strategies for describing the benefits and risks of r-tPA in a clinical setting. Through focus groups (n=10) of stroke survivors (n=39) and caregivers (n=24) and individual interviews with emergency physicians (n=23) and advanced practice nurses (n=20), several themes emerged. Survivors and caregivers preferred a broader definition of a good outcome (independence, rather than no significant disability), simpler graphs as compared with detailed pictographs, and presentation of both population and individualized benefits (framed positively) and risk of receiving r-tPA. Some physicians expressed skepticism with the data and the ability to present risk/benefit information emergently, whereas other physicians and most advanced practice nurses thought such information would improve care. Physicians stressed the importance of presenting the risk of thrombolytic-related intracranial hemorrhage., Conclusions: This study suggests that a positively framed risk-benefit tool with graphical presentations of general and patient-specific risk estimates could support patients and providers in considering r-tPA for acute ischemic stroke., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01864928., (© 2015 American Heart Association, Inc.)

Background and Purpose: High revascularization rates in large-vessel occlusion strokes treated by mechanical thrombectomy are not always associated with good clinical outcomes. We evaluated predictors of functional dependence despite successful revascularization among patients with acute ischemic stroke treated with thrombectomy., Methods: We analyzed the pooled data from the Multi Mechanical Embolus Removal in Cerebral Ischemia (MERCI), Thrombectomy Revascularization of Large Vessel Occlusions in Acute Ischemic Stroke (TREVO), and TREVO 2 trials. Successful revascularization was defined as thrombolysis in cerebral infarction score 2b or 3. Functional dependence was defined as a score of 3 to 6 on the modified Rankin Scale at 3 months. We assessed relationship of demographic, clinical, angiographic characteristics, and hemorrhage with functional dependence despite successful revascularization., Results: Two hundred and twenty-eight patients with successful revascularization had clinical outcome follow-up. The rates of functional dependence with endovascular success were 48.6% for Trevo thrombectomy and 58.0% for Merci thrombectomy. Age (odds ratio, 1.04; 95% confidence interval, 1.02-1.06 per 1-year increase), National Institutes of Health Stroke Scale score (odds ratio, 1.08; 95% confidence interval, 1.02-1.15 per 1-point increase), and symptom onset to endovascular treatment time (odds ratio, 1.11; 95% confidence interval, 1.01-1.22 per 30-minute delay) were predictors of functional dependence despite successful revascularization. Symptom onset to reperfusion time beyond 5 hours was associated with functional dependence. All subjects with symptomatic intracranial hemorrhage had functional dependence., Conclusions: One half of patients with successful mechanical thrombectomy do not have good outcomes. Age, severe neurological deficits, and delayed endovascular treatment were associated with functional dependence despite successful revascularization. Our data support efforts to minimize delays to endovascular therapy in patients with acute ischemic stroke to improve outcomes., Clinical Trial Registration Url: http://www.clinicaltrials.gov. Unique identifier: NCT00318071, NCT01088672, and NCT01270867., (© 2014 American Heart Association, Inc.)

We aimed to investigate stroke etiology in our cohort of patients with mild ischemic stroke (MIS) and to study the effect of stroke etiology on patient outcome. We also studied the effect of intravenous (IV) recombinant tissue plasminogen activator (rt-PA) in this cohort. We analyzed patients with MIS who were eligible for IV rt-PA presenting within 3 hours of symptom onset with a National Institutes of Health Stroke Scale (NIHSS) score ≤ 5 admitted from March 2006 through June 2009. Stroke etiology was determined using the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification. Primary outcome was the discharge NIHSS score. We identified 110 patients with MIS with a male-to-female ratio of: 1.4:1 and a mean age of 69 ± 13 years. The mean admission NIHSS score was 2 ± 3. The stroke risk factors were identified as: hypertension, 82 patients (75%); previous stroke/transient ischemic attack, 36 patients (33%); and atrial fibrillation, 28 patients (26%). Stroke etiology was identified as: large vessel atherosclerosis (31 patients, 28%), cardioembolism (29, 26%), small vessel occlusion (seven, 6%) and those with other or undetermined conditions (43, 39%). IV rt-PA was administered to 25 patients (23%). Despite the use of IV rt-PA in only one patient with small vessel occlusion, patients in our study with this stroke etiology tended to have better outcomes compared to those with other stroke subtypes, although the difference was not statistically significant. The discharge NIHSS score did not show any statistically significant difference between the treated and untreated patients with MIS. Our study shows that MIS may be caused by non small vessel occlusion in more patients than previously reported and this subgroup of patients with MIS should not be excluded from trials of intravenous and endovascular therapies., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background and Purpose: Current selection criteria for intra-arterial therapies in the anterior circulation use time windows of 8 hours. Modern neuroimaging techniques have identified individuals with salvageable penumbra who present beyond this timeframe. We sought to assess safety, procedural, and clinical outcomes of MRI or CT perfusion imaging-based endovascular therapy in patients with anterior circulation stroke treated beyond 8 hours from time last seen well., Methods: We conducted a multicenter retrospective review of consecutive patients meeting the following criteria: (1) acute proximal intracranial anterior circulation occlusion; (2) endovascular treatment initiated >8 hours from time last seen well; and (3) treatment selection based on MRI or CT perfusion imaging., Results: Two hundred thirty-seven patients were identified (mean age, 63.8 ± 16 years; mean baseline National Institutes of Health Stroke Scale, 15 ± 5.5; mean time last seen well to treatment, 15 ± 11.2 hours; male gender, 46%). Successful revascularization was achieved in 175 of 237 (73.84%) patients. Parenchymal hematoma occurred in 21 of 237 (8.86%) patients. The 90-day mortality rate was 21.5% (51 of 237). The rate of good outcomes was 45% (100 of 223) in the 223 patients with available modified Rankin Scale data at 90 days or time of hospital discharge. In multivariate analyses, age (OR, 0.96; 95% CI, 0.94 to 0.98; P=0.002), admission National Institutes of Health Stroke Scale (OR, 0.93; 0.87 to 0.98; P=0.016), and successful revascularization (OR, 4.32; 1.99 to 9.39; P<0.0001) were identified as independent predictors of good outcomes., Conclusions: Endovascular therapy can be instituted with acceptable safety beyond 8 hours from time last seen well when selection is based on advanced neuroimaging. Successful revascularization is significantly associated with higher rates of good outcomes. The benefit of this approach compared with standard medical therapy should be assessed in a prospective randomized trial.

Background and Purpose: We hypothesized that transcranial laser therapy (TLT) can use near-infrared laser technology to treat acute ischemic stroke. The NeuroThera Effectiveness and Safety Trial-2 (NEST-2) tested the safety and efficacy of TLT in acute ischemic stroke., Methods: This double-blind, randomized study compared TLT treatment to sham control. Patients receiving tissue plasminogen activator and patients with evidence of hemorrhagic infarct were excluded. The primary efficacy end point was a favorable 90-day score of 0 to 2 assessed by the modified Rankin Scale. Other 90-day end points included the overall shift in modified Rankin Scale and assessments of change in the National Institutes of Health Stroke Scale score., Results: We randomized 660 patients: 331 received TLT and 327 received sham; 120 (36.3%) in the TLT group achieved favorable outcome versus 101 (30.9%), in the sham group (P=0.094), odds ratio 1.38 (95% CI, 0.95 to 2.00). Comparable results were seen for the other outcome measures. Although no prespecified test achieved significance, a post hoc analysis of patients with a baseline National Institutes of Health Stroke Scale score of <16 showed a favorable outcome at 90 days on the primary end point (P<0.044). Mortality rates and serious adverse events did not differ between groups with 17.5% and 17.4% mortality, 37.8% and 41.8% serious adverse events for TLT and sham, respectively., Conclusions: TLT within 24 hours from stroke onset demonstrated safety but did not meet formal statistical significance for efficacy. However, all predefined analyses showed a favorable trend, consistent with the previous clinical trial (NEST-1). Both studies indicate that mortality and adverse event rates were not adversely affected by TLT. A definitive trial with refined baseline National Institutes of Health Stroke Scale exclusion criteria is planned.

It has been known for many years that immune system alterations occur with Parkinson's disease (PD). Changes in lymphocyte populations in cerebrospinal fluid and blood, immunoglobulin synthesis, and cytokine and acute phase protein production have been observed in patients with PD. Hence, there is evidence for inflammation. In this report we demonstrate that cyclic exercise over months results in a significant increase in the rise of plasma anti-inflammatory signal molecules, such as interleukin-10 and adrenocorticotropin. Additionally, endogenous plasma morphine levels increase with the duration of the cyclic exercise protocol. Morphine is identified and quantified by high performance liquid chromatography coupled to electrochemical detection and nano electro-spray ionization double quadrupole orthogonal acceleration time of flight mass spectrometry. Proinflammatory cytokine, i.e., interleukin-1, interleukin-6, plasma levels did not increase. These results matched with those reported previously, demonstrating enhanced motor skills and mood elevation with this cyclic exercise protocol, suggest that this protocol induces the formation of anti-inflammatory signal molecules, which appear to be associated with alleviation of some of the clinical characteristics of PD.