3D-printed B4C collimation for neutron pressure cells.

A design for an incident-beam collimator for the Paris-Edinburgh pressure cell is described here. This design can be fabricated from reaction-bonded B4C but also through fast turnaround, inexpensive 3D-printing. 3D-printing thereby also offers the opportunity of composite collimators whereby the tip closest to the sample can exhibit even better neutronic characteristics. Here, we characterize four such collimators: one from reaction-bonded B4C, one 3D-printed and fully infiltrated with cyanoacrylate, a glue, one with a glue-free tip, and one with a tip made from enriched 10B4C. The collimators are evaluated on the Spallation Neutrons and Pressure Diffractometer of the Spallation Neutron Source and the Wide-Angle Neutron Diffractometer at the High Flux Isotope Reactor, both at Oak Ridge National Laboratory. This work clearly shows that 3D-printed collimators perform well and also that composite collimators improve performance even further. Beyond use in the Paris-Edinburgh cell, these findings also open new avenues for collimator designs as clearly more complex shapes are possible through 3D printing. An example of such is shown here with a collimator made for single-crystal samples measured inside a diamond anvil cell. These developments are expected to be highly advantageous for future experimentation in high pressure and other extreme environments and even for the design and deployment of new neutron scattering instruments.

Support of New Triage Protocol among Acute Stroke Care Providers.

OBJECTIVE: We conducted an online survey to gauge the acceptance of sending acute stroke patients with suspected large vessel occlusion (LVO) directly to an endovascular-capable hospital (ECH) even if that means bypassing a closer alteplase-capable hospital (ACH) without endovascular capability. METHODS: The survey was composed of two cases of acute stroke, one with cortical symptoms suggestive of LVO and the other without. In each case, responders were asked to choose between triaging to a closer ACH or an ECH that is further away and to provide an opinion regarding the maximum extra travel time they would tolerate if they chose the ECH. The survey was sent electronically to national groups of neurologists, emergency department (ED) physicians, emergency medical service (EMS) directors, and stroke coordinators. RESULTS: There were 320 responders from 44 states, most of them with 10 years or more of experience. Most of the responders, 72.5%, chose ECH for the LVO case, while 56% chose ACH for the non-LVO case. There were marked differences in responses by specialty: neurology strongly supported ECH for LVO and strongly supported ACH for non-LVO, most ED and EMS chose ECH for both cases, and stroke coordinators were the least supportive of bypassing ACH. Almost all groups agreed on 30 min as the acceptable extra transfer time to ECH. CONCLUSION: Among the survey responders, there is a broad acceptance of the idea of bypassing ACH and going straight to ECH when LVO is suspected; however, there is less agreement on triaging patients with non-LVO stroke.

Microbleeds in the Secondary Prevention of Small Subcortical Strokes Trial: Stroke, mortality, and treatment interactions.

OBJECTIVE: To characterize cerebral microbleeds (CMBs) in lacunar stroke patients in the Secondary Prevention of Small Subcortical Strokes (SPS3) trial and to assess their relationship with recurrent stroke and death, and response to assigned treatment. METHODS: SPS3 is a randomized, clinical trial conducted between 2003 and 2011. Patients with recent magnetic resonance imaging (MRI)-documented lacunar infarcts were randomly assigned in a factorial design to target levels of systolic blood pressure (130-149mmHg vs <130mmHg; open label) and to antiplatelet treatment (aspirin/clopidogrel vs aspirin/placebo; double-blinded). The current analysis involves 1,278 trial participants who had a baseline axial T2*-weighted gradient echo MRI sequence allowing for CMB detection. RESULTS: CMBs were present in 30% of 1,278 patients (mean age = 63 years). Male gender (odds ratio [OR] = 1.7, 95% confidence interval [CI] = 1.3-2.3), history of hypertension (OR = 1.6, 95% CI = 1.2-2.3), increased systolic blood pressure (1.2 per 20mmHg, 95% CI = 1.1-1.4), nondiabetic status (OR = 1.4, 95% CI = 1.1-1.9), multiple old lacunar infarcts (OR = 1.9, 95% CI = 1.5-2.5), and moderate (OR = 1.7, 95% CI = 1.2-2.3) or severe (OR = 4.2, 95% CI = 3.0-5.9) white matter hyperintensities on MRI were independently associated with CMBs. During a mean follow-up of 3.3 years, overall stroke recurrence was 2.5% per patient-year. Patients with CMBs had an adjusted 2-fold increased risk of recurrent stroke (hazard ratio = 2.1, 95% CI = 1.4-3.1). CMBs were not a risk factor for death. There were no statistically significant interactions between CMBs and treatment assignments. INTERPRETATION: Patients with lacunar stroke and CMBs likely harbor a more advanced form of cerebral small vessel disease in need of efficacious therapeutic strategies. Ann Neurol 2017;82:196-207.

Morphological classification of penetrating artery pontine infarcts and association with risk factors and prognosis: The SPS3 trial.

BACKGROUND: Pontine infarcts are common and often attributed to small vessel disease ("small deep infarcts") or basilar branch atherosclerosis ("wedge shaped"). A well-described morphological differentiation using magnetic resonance images has not been reported. Furthermore, whether risk factors and outcomes differ by morphology, or whether infarct morphology should guide secondary prevention strategy, is not well characterized. METHODS: All participants in the Secondary Prevention of Small Subcortical Strokes Study with magnetic resonance imaging -proven pontine infarcts were included. Infarcts were classified as well-circumscribed small deep (small deep infarct, i.e. lacunar), paramedian, atypical paramedian, or other based on diffusion-weighted imaging, T2/fluid-attenuated inversion recovery, and T1-magnetic resonance images. Inter-rater reliability was high (90% agreement, Cohen's kappa = 0.84). Clinical and radiologic features independently associated with small deep infarct versus paramedian infarcts were identified (multivariable logistic regression). Differences in stroke risk and death were assessed using Cox proportional hazards. RESULTS: Of the 3020 patients enrolled, 644 had pontine infarcts; 619 images were available: 302(49%) small deep infarct, 245 (40%) paramedian wedge, 35 (6%) atypical paramedian, and 37 (6%) other. Among vascular risk factors, only smoking (OR 2.1, 95% CI 1.3-3.3) was independently associated with small deep infarct versus paramedian infarcts; on neuroimaging, old lacunes on T1/fluid-attenuated inversion recovery (OR 1.8, 1.3-2.6) and intracranial stenosis (any location) ≥50% (OR 0.62, 0.41-0.96). Small deep infarct versus paramedian was not predictive of either recurrent stroke or death, and there was no interaction with assigned treatment. CONCLUSIONS: Pontine infarcts can be reliably classified based on morphology using clinical magnetic resonance images. Few risk factors differed between small deep infarct and paramedian infarcts with no differences in recurrent stroke or mortality. There was no difference in response to different antiplatelet or blood pressure treatment strategies between these two groups. REGISTRATION: http://www.clinicaltrials.gov/NCT00059306.

A Comparison of Primed Low-frequency Repetitive Transcranial Magnetic Stimulation Treatments in Chronic Stroke.

BACKGROUND: Preceding low-frequency repetitive transcranial magnetic stimulation (rTMS) with a bout of high-frequency rTMS called priming potentiates the after-effects of the former in healthy adults. The utility of primed rTMS in stroke remains under-explored despite its theoretical benefits in enhancing cortical excitability and motor function. OBJECTIVE: To ascertain the efficacy of priming in chronic stroke by comparing changes in cortical excitability and paretic hand function following three types of primed low-frequency rTMS treatments. METHODS: Eleven individuals with chronic stroke participated in this repeated-measures study receiving three treatments to the contralesional primary motor cortex in randomized order: 6 Hz primed 1 Hz rTMS, 1 Hz primed 1 Hz rTMS, and sham 6 Hz primed active 1 Hz rTMS. Within- and between-treatment differences from baseline in cortical excitability and paretic hand function from baseline were analyzed using mixed effects linear models. RESULTS: 6 Hz primed 1 Hz rTMS produced significant within-treatment differences from baseline in ipsilesional cortical silent period (CSP) duration and short-interval intracortical inhibition. Compared to 1 Hz priming and sham 6 Hz priming of 1 Hz rTMS, active 6 Hz priming generated significantly greater decreases in ipsilesional CSP duration. These heightened effects were not observed for intracortical facilitation or interhemispheric inhibition excitability measures. CONCLUSION: Our findings demonstrate the efficacy of 6 Hz primed 1 Hz rTMS in probing homeostatic plasticity mechanisms in the stroke brain as best demonstrated by differences CSP duration and SICI from baseline. Though 6 Hz priming did not universally enhance cortical excitability across measures, our findings pose important implications in non-invasive brain stimulation application in stroke rehabilitation.

Vertebrobasilar ectasia in patients with lacunar stroke: the secondary prevention of small subcortical strokes trial.

BACKGROUND: The clinical implications of vertebrobasilar ectasia (VBE) in patients with cerebral small-artery disease are not well defined. We investigated whether VBE is associated with recurrent stroke, major hemorrhage, and death in a large cohort of patients with recent lacunar stroke. METHODS: Maximum diameters of the vertebral and basilar arteries were measured by magnetic resonance angiography and computed tomographic angiography in 2621 participants in the Secondary Prevention of Small Subcortical Strokes trial. VBE was defined a priori as basilar artery greater than 4.5 mm and/or vertebral artery greater than 4.0 mm. Patient characteristics and risks of stroke recurrence and mortality during follow-up (median, 3.5 years) were compared between patients with and without VBE. RESULTS: VBE affecting 1 or more arteries was present in 200 (7.6%) patients. Patient features independently associated with VBE were increasing age, male sex, white race ethnicity, hypertension, and higher baseline diastolic blood pressure. Baseline systolic blood pressure was inversely associated with VBE. After adjustment for other risk factors, VBE was not predictive of recurrent stroke (hazard ratio [HR], 1.3; 95% confidence interval [CI], .85-1.9) or major hemorrhage (HR, 1.5; CI, .94-2.6), but was of death (HR, 1.7; CI, 1.1-2.7). CONCLUSIONS: In this large well-characterized cohort of patients with recent lacunar stroke, VBE was predictive of death but not of recurrent stroke or major hemorrhage. In these exploratory analyses, the frequency of VBE was directly related to diastolic blood pressure but inversely related to systolic blood pressure.

Effect of addition of clopidogrel to aspirin on stroke incidence: Meta-analysis of randomized trials.

BACKGROUND: It remains controversial whether dual antiplatelet therapy reduces stroke more than aspirin alone. AIM: We aimed to assess the effects of adding clopidogrel to aspirin on the occurrence of stroke and major haemorrhage in patients with vascular disease. METHODS: Meta-analysis of published randomized trials comparing the combination of clopidogrel and aspirin vs. aspirin alone that reported stroke and major bleeding. RESULTS: Thirteen randomized trials were included with a total of 90 433 participants (mean age 63 years; 63% male) with a mean follow-up of 1·0 years and 2011 strokes. Stroke was reduced 19% by dual antiplatelet therapy (odds ratio = 0·81, 95% confidence interval 0·74-0·89) with no evidence of heterogeneity of effect across different trial populations (I(2) index = 5%, P = 0·4 for heterogeneity). Dual antiplatelet therapy reduced ischemic stroke by 23% (odds ratio = 0·77; 95% confidence interval 0·70-0·85); there was a nonsignificant 12% increase in intracerebral haemorrhage (odds ratio = 1·12, 95% confidence interval 0·86-1·46). Among 1930 participants with recent (<30 days) brain ischemia from four trials, stroke was reduced by 33% (odds ratio = 0·67, 95% confidence interval 0·46-0·97) by dual antiplatelet therapy vs. aspirin alone. The risk of major bleeding was increased by 40% (odds ratio = 1·40, 95% confidence interval 1·26-1·55) by dual antiplatelet therapy. CONCLUSIONS: This meta-analysis demonstrates a substantial relative risk reduction in stroke by clopidogrel plus aspirin vs. aspirin alone that is consistent across different trial cohorts. Major haemorrhage is increased by dual antiplatelet therapy.

Effects of long-term blood pressure lowering and dual antiplatelet treatment on cognitive function in patients with recent lacunar stroke: a secondary analysis from the SPS3 randomised trial.

BACKGROUND: The primary outcome results for the SPS3 trial suggested that a lower systolic target blood pressure (<130 mm Hg) might be beneficial for reducing the risk of recurrent stroke compared with a higher target (130-149 mm Hg), but that the addition of clopidogrel to aspirin was not beneficial compared with aspirin plus placebo. In this prespecified secondary outcome analysis of the SPS3 trial, we aimed to assess whether blood pressure reduction and dual antiplatelet treatment affect changes in cognitive function over time in patients with cerebral small vessel disease. METHODS: In the SPS3 trial, patients with recent (within 6 months) symptomatic lacunar infarcts from 81 centres in North America, Latin America, and Spain were randomly assigned, in a two-by-two factorial design, to target levels of systolic blood pressure (1:1; 130-149 mm Hg vs <130 mm Hg; open-label) and to a once-daily antiplatelet treatment (1:1; aspirin 325 mg plus clopidogrel 75 mg vs aspirin 325 mg plus placebo; double-blind). For this analysis, the main cognitive outcome was change in Cognitive Abilities Screening Instrument (CASI) during follow-up. Patients were tested annually for up to 5 years, during which time the mean difference in systolic blood pressure was 11 mm Hg (SD 16) between the two targets (138 mm Hg vs 127 mm Hg at 1 year). We used linear mixed models to compare changes in CASI Z scores over time. The SPS3 trial is registered with ClinicalTrials.gov, number NCT00059306. FINDINGS: The study took place between March 23, 2003, and April 30, 2012. 2916 of 3020 SPS3 participants (mean age 63 years [SD 11]) with CASI scores at study entry were included in the analysis, with a median follow-up of 3·0 years (IQR 1·0-4·9). Mean changes in CASI Z scores from study entry to assessment at years 1 (n=2472), 2 (n=1968), 3 (n=1521), 4 (n=1135), and 5 (n=803) were 0·12 (SD 0·83), 0·15 (0·84), 0·16 (0·95), 0·19 (0·99), and 0·14 (1·09), respectively. Changes in CASI Z scores over time did not differ between assigned antiplatelet groups (p=0·858) or between assigned blood pressure target groups (p=0·520). There was no interaction between assigned antiplatelet groups and assigned blood pressure target groups and change over time (p=0·196). INTERPRETATION: Cognitive function is not affected by short-term dual antiplatelet treatment or blood pressure reduction in fairly young patients with recent lacunar stroke. Future studies of cognitive function after stroke should be of longer duration or focus on patients with higher rates of cognitive decline. FUNDING: US National Institute of Neurological Disorders and Stroke.

Clinical correlates of infarct shape and volume in lacunar strokes: the Secondary Prevention of Small Subcortical Strokes trial.

BACKGROUND AND PURPOSE: Infarct size and location are thought to correlate with different mechanisms of lacunar infarcts. We examined the relationship between the size and shape of lacunar infarcts and vascular risk factors and outcomes. METHODS: We studied 1679 participants in the Secondary Prevention of Small Subcortical Stroke trial with a lacunar infarct visualized on diffusion-weighted imaging. Infarct volume was measured planimetrically, and shape was classified based on visual analysis after 3-dimensional reconstruction of axial MRI slices. RESULTS: Infarct shape was ovoid/spheroid in 63%, slab in 12%, stick in 7%, and multicomponent in 17%. Median infarct volume was smallest in ovoid/spheroid relative to other shapes: 0.46, 0.65, 0.54, and 0.90 mL, respectively (P<0.001). Distributions of vascular risk factors were similar across the 4 groups except that patients in the ovoid/spheroid and stick groups were more often diabetic and those with multicomponent had significantly higher blood pressure at study entry. Intracranial stenosis did not differ among groups (P=0.2). Infarct volume was not associated with vascular risk factors. Increased volume was associated with worse functional status at baseline and 3 months. Overall, 162 recurrent strokes occurred during an average of 3.4 years of follow-up with no difference in recurrent ischemic stroke rate by shape or volume. CONCLUSIONS: In patients with recent lacunar stroke, vascular risk factor profile was similar among the different infarct shapes and sizes. Infarct size correlated with worse short-term functional outcome. Neither shape nor volume was predictive of stroke recurrence. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00059306.

Predictors of mortality in patients with lacunar stroke in the secondary prevention of small subcortical strokes trial.

BACKGROUND AND PURPOSE: The Secondary Prevention of Small Subcortical Stroke trial (SPS3) recruited participants meeting clinical and radiological criteria for symptomatic lacunes. Individuals randomized to dual antiplatelet therapy with clopidogrel and aspirin had an unanticipated increase in all-cause mortality compared with those assigned to aspirin. We investigated the factors associated with mortality in this well-characterized population. METHODS: We identified independent predictors of mortality among baseline demographic and clinical factors by Cox regression analysis in participants of the SPS3 trial. Separately, we examined the effect on mortality of nonfatal bleeding during the trial. RESULTS: During a mean follow-up of 3.6 years, the mortality rate was 1.78% per year for the 3020 participants (mean age, 63 years). Significant independent predictors of mortality at study entry were age, diabetes mellitus, history of hypertension, systolic blood pressure (hazard ratio [HR], 1.3 per 20 mm Hg increase), serum hemoglobin<13 g/dL (HR, 1.6), renal function (HR, 1.3 per estimated glomerular filtration rate decrease of 20 mL/min), and body mass index (HR, 1.8 per 10 kg/m2 decrease). Participants with ischemic heart disease (P=0.01 for interaction) and normotensive/prehypertensive participants (P=0.03 for interaction) were at increased risk if assigned to dual antiplatelet therapy. Nonfatal major hemorrhage increased mortality in both treatment arms (HR, 4.5; 95% confidence interval, 3.1-6.6; P<0.001). CONCLUSIONS: Unexpected interactions between assigned antiplatelet therapy and each of ischemic heart disease and normal/prehypertensive status accounted for increased mortality among patients with recent lacunar stroke given dual antiplatelet therapy. Despite extensive exploratory analyses, the mechanisms underlying these interactions are uncertain. CLINICAL TRIAL REGISTRATION URL: http://www.SPS3ClinicalTrials.gov. Unique identifier: NCT00059306.

Trends in 10-year survival of patients with stroke hospitalized between 1980 and 2000: the Minnesota stroke survey.

BACKGROUND AND PURPOSE: We report on trends in poststroke survival, both in the early period after stroke and over the long term. We examine these trends by stroke subtype. METHODS: The Minnesota Stroke Survey is a study of all hospitalized patients with acute stroke aged 30 to 74 years in the Minneapolis-St Paul metropolis. Validated stroke events were sampled for survey years 1980, 1985, 1990, 1995, and 2000 and subtyped as ischemic or hemorrhagic by neuroimaging for survey years 1990, 1995, and 2000. Survival was obtained by linkage to vital statistics data through the year 2010. RESULTS: There were 3773 acute stroke events. Age-adjusted 10-year survival improved from 1980 to 2000 (men 29.5% and 46.5%; P<0.0001; women 32.6% and 50.5%; P<0.0001). Ten-year ischemic stroke survival (n=1667) improved from 1990 to 2000 (men 35.3% and 50%; P=0.0001; women 38% and 55.3%; P<0.0001). Ten-year hemorrhagic stroke survival showed a trend toward improvement, but this (n=489) did not reach statistical significance, perhaps because of their smaller number (men 29.7% and 45.8%; P=0.06; women 39.2% and 49.6%; P=0.2). Markers of stroke severity including unconsciousness or major neurological deficits at admission declined from 1980 to 2000 while neuroimaging use increased. CONCLUSIONS: These poststroke survival trends are likely because of multiple factors, including more sensitive case ascertainment shifting the case mix toward less severe strokes, improved stroke care and risk factor management, and overall improvements in population health and longevity.

ASA failure: does the combination ASA/clopidogrel confer better long-term vascular protection?

OBJECTIVE: To assess whether adding clopidogrel to acetylsalicylic acid (ASA) has a long-term protective vascular effect in patients with lacunar stroke while taking ASA. METHODS: Post hoc analysis of 838 patients with ASA failure and recent lacunar stroke from the Secondary Prevention of Small Subcortical Strokes Trial (SPS3) cohort randomly allocated to aspirin (325 mg/day) and clopidogrel (75 mg/day) or placebo. Primary efficacy outcome was stroke recurrence (ischemic and intracranial hemorrhage) and main safety outcome was major extracranial hemorrhage. Patients were followed for a mean period of 3.5 years. RESULTS: The ASA failure group had a significantly higher risk of vascular events including ischemic stroke when compared with the non-ASA failure group (n = 2,151) in SPS3 (p = 0.03). Mean age was 65.6 years and 65% were men. The risk of recurrent stroke was not reduced in the dual antiplatelet group, 3.1% per year, compared to the aspirin-only group, 3.3% per year (hazard ratio [HR] 0.91; 95% confidence interval [CI] 0.61-1.37). There was also no difference between groups for ischemic stroke (HR 0.90; 95% CI 0.59-1.38). The risk of gastrointestinal bleeding was higher in the dual antiplatelet group (HR 2.7; 95% CI 1.1-6.9); however, the risk of intracranial hemorrhage was not different. CONCLUSIONS: In patients with a recent lacunar stroke while taking ASA, the addition of clopidogrel did not result in reduction of vascular events vs continuing ASA only. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with recent lacunar stroke while taking ASA, adding clopidogrel as compared to continuing ASA alone does not reduce the risk of recurrent stroke.

Serial treatments of primed low-frequency rTMS in stroke: characteristics of responders vs. nonresponders.

PURPOSE: This study analyzed the characteristics of responders vs. nonresponders in people with stroke receiving a novel form of repetitive transcranial magnetic stimulation (rTMS) to improve hand function. METHODS: Twelve people with stroke received five treatments of 6-Hz primed low-frequency rTMS to the contralesional primary motor area. We compared demographic factors, clinical features, and the ipsilesional/contralesional volume ratio of selected brain regions in those who improved hand performance (N = 7) on the single-hand component of the Test Évaluant la performance des Membres supérieurs des Personnes Âgées (TEMPA) and those who showed no improvement (N = 5). RESULTS: Responders showed significantly greater baseline paretic hand function on the TEMPA, greater preservation volume of the ipsilesional posterior limb of the internal capsule (PLIC), and lower scores (i.e., less depression) on the Beck Depression Inventory than nonresponders. There were no differences in age, sex, stroke duration, paretic side, stroke hemisphere, baseline resting motor threshold for ipsilesional primary motor area (M1), NIH Stroke Scale, Upper Extremity Fugl-Meyer, Mini-Mental State Examination, or preservation volume of M1, primary somatosensory area, premotor cortex, or supplementary motor area. CONCLUSION: Our results support that preserved PLIC volume is an important influential factor affecting responsiveness to rTMS.