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There is a critical need to elucidate molecular mechanisms underlying brain injury, repair, and recovery following ischemic stroke—a global health problem with major social and economic impact. Despite 5 decades of intensive research, there are no widely accepted neuroprotective drugs that mitigate ischemic brain injury, or neuroreparative drugs, or personalized approaches that guide therapies to enhance recovery. We here explore novel reverse translational approaches that will complement traditional forward translational methods in identifying mechanisms relevant to human stroke outcome. Although genome-wide association studies have yielded over 30 genetic loci that influence ischemic stroke risk, only a few genome-wide association studies have been performed for stroke outcome. We discuss important considerations for genetic studies of ischemic stroke outcome—including carefully designed phenotypes that capture injury/recovery mechanisms, anchored in time to stroke onset. We also address recent genome-wide association studies that provide insight into mechanisms underlying brain injury and repair. There are several ongoing initiatives exploring genomic associations with novel phenotypes related to stroke outcome. To improve the understanding of the genetic architecture of ischemic stroke outcome, larger studies using standardized phenotypes, preferably embedded in standard-of-care measures, are needed. Novel techniques beyond genome-wide association studies—including exploiting informatics, multi-omics, and novel analytics—promise to uncover genetic and molecular pathways from which drug targets and other new interventions may be identified.

ObjectiveTo determine the patient- and tissue-based relationships between cerebral hemodynamic and oxygen metabolic stress, microstructural injury, and infarct location in adults with sickle cell disease (SCD).MethodsControl participants and patients with SCD underwent brain MRI to quantify cerebral blood flow (CBF), oxygen extraction fraction (OEF), mean diffusivity (MD), and fractional anisotropy (FA) within normal-appearing white matter (NAWM) and infarcts on fluid-attenuated inversion recovery. Multivariable linear regression examined the patient- and voxel-based associations between hemodynamic and metabolic stress (defined as elevated CBF and OEF, respectively), white matter microstructure, and infarct location.ResultsOf 83 control participants and patients with SCD, adults with SCD demonstrated increased CBF (50.9 vs 38.8 mL/min/100 g,p <0.001), increased OEF (0.35 vs 0.25,p <0.001), increased MD (0.76 vs 0.72 × 10−3mm2s−1,p= 0.005), and decreased FA (0.40 vs 0.42,p= 0.021) within NAWM compared to controls. In multivariable analysis, increased OEF (β = 0.19,p= 0.035), but not CBF (β = 0.00,p= 0.340), independently predicted increased MD in the SCD cohort; neither were predictors in controls. On voxel-wise regression, the SCD cohort demonstrated widespread OEF elevation, encompassing deep white matter regions of elevated MD and reduced FA, which spatially extended beyond high-density infarct locations from the SCD cohort.ConclusionElevated OEF, a putative index of cerebral oxygen metabolic stress, may provide a metric of ischemic vulnerability that could enable individualization of therapeutic strategies in SCD. The patient- and tissue-based relationships between elevated OEF, elevated MD, and cerebral infarcts suggest that oxygen metabolic stress may underlie microstructural injury prior to the development of cerebral infarcts in SCD.

Objectives This systematic review aimed to evaluate the efficacy and safety of Tao-Hong Siwu Tang (TST) for the treatment of primary dysmenorrhea. Methods We searched four English databases (MEDLINE, EMBASE, Allied and Complementary Medicine Database, and Cochrane Central Register of Controlled Trials [CENTRAL, Cochrane Library]), three Chinese databases (China National Knowledge Infrastructure, Wanfang, and Chinese Science and Technology Periodical Database), two Korean databases (Oriental Medicine Advanced Searching Integrated System and Korean traditional Knowledge Portal), and one Japanese database (Citation Information by NII). All randomized controlled trials (RCTs) using TST or modified TST (MTST) were included. Three independent reviewers extracted the data, assessed the risk of bias according to the Cochrane criteria, and performed a meta-analysis. Results A total of 85 possibly relevant articles were identified, and five trials met our inclusion criteria. The meta-analysis showed a favorable effect of MTST compared to non-steroidal anti-inflammatory drugs (NSAIDs) (n = 486, risk ratio [RR] = 1.53, 95% confidence interval [95% CI] = 1.37–1.72, I2 = 39%). Among the included trials, one RCT showed superior effects of MTST on primary dysmenorrhea recurrence rate compared to NSAIDs (n = 246, RR = 0.31, 95% CI = 0.15–0.63, P = 0.001). Another RCT revealed a beneficial impact of oral contraceptives (OCs) used in combination with TST compared to OCs alone (n = 60, RR = 1.35, 95% CI = 1.02–1.79, P = 0.04). Conclusion This systematic review and meta-analysis provides moderate quality evidence for the superiority of MTST over NSAIDs as well as that of TST plus OCs over OCs in the treatment of primary dysmenorrhea.

INTRODUCTION: Malignant cerebral edema develops in a small subset of patients with hemispheric strokes, precipitating deterioration and death if decompressive hemicraniectomy (DHC) is not performed in a timely manner. Predicting which stroke patients will develop malignant edema is imprecise based on clinical data alone. Head computed tomography (CT) imaging is often performed at baseline and 24-hours. We determined the incremental value of incorporating imaging-derived features from serial CTs to enhance prediction of malignant edema. METHODS: We identified hemispheric stroke patients at three sites with NIHSS ≥ 7 who had baseline as well as 24-hour clinical and CT-imaging data. We extracted quantitative imaging features from baseline and follow-up CTs, including CSF volume, intracranial reserve (CSF/cranial volume), as well as midline shift (MLS) and infarct-related hypodensity volume. Potentially lethal malignant edema was defined as requiring DHC or dying with MLS over 5-mm. We built machine-learning models using logistic regression first with baseline data and then adding 24-hour data including reduction in CSF volume (ΔCSF). Model performance was evaluated with cross-validation using metrics of recall (sensitivity), precision (predictive value), as well as area under receiver-operating-characteristic and precision-recall curves (AUROC, AUPRC). RESULTS: Twenty of 361 patients (6%) died or underwent DHC. Baseline clinical variables alone had recall of 60% with low precision (7%), AUROC 0.59, AUPRC 0.15. Adding baseline intracranial reserve improved recall to 80% and AUROC to 0.82 but precision remained only 16% (AUPRC 0.28). Incorporating ΔCSF improved AUPRC to 0.53 (AUROC 0.91) while all imaging features further improved prediction (recall 90%, precision 38%, AUROC 0.96, AUPRC 0.66). CONCLUSION: Incorporating quantitative CT-based imaging features from baseline and 24-hour CT enhances identification of patients with malignant edema needing DHC. Further refinements and external validation of such imaging-based machine learning models are required.

Background and Purpose— Cerebral edema (CED) develops in the hours to days after stroke; the resulting increase in brain volume may lead to midline shift (MLS) and neurological deterioration. The time course and implications of edema formation are not well characterized across the spectrum of stroke. We analyzed displacement of cerebrospinal fluid (ΔCSF) as a dynamic quantitative imaging biomarker of edema formation. Methods— We selected subjects enrolled in a stroke cohort study who presented within 6 hours of onset and had baseline and ≥1 follow-up brain computed tomography scans available. We applied a neural network-based algorithm to quantify hemispheric CSF volume at each imaging time point and modeled CSF trajectory over time (using a piecewise linear mixed-effects model). We evaluated ΔCSF within the first 24 hours as an early biomarker of CED (defined as developing MLS on computed tomography beyond 24 hours) and poor outcome (modified Rankin Scale score, 3–6). Results— We had serial imaging in 738 subjects with stroke, of whom 91 (13%) developed CED with MLS. Age did not differ (69 versus 70 years), but baseline National Institutes of Health Stroke Scale was higher (16 versus 7) and baseline CSF volume lower (132 versus 161 mL, both P P Conclusions— CSF volumetrics provides quantitative evaluation of early edema formation. ΔCSF from baseline to 24-hour computed tomography is a promising early biomarker for the development of MLS and worse neurological outcome.

Malignant cerebral edema is a devastating complication of stroke, resulting in deterioration and death if hemicraniectomy is not performed prior to herniation. Current approaches for predicting this relatively rare complication often require advanced imaging and still suffer from suboptimal performance. We performed a pilot study to evaluate whether neural networks incorporating data extracted from routine computed tomography (CT) imaging could enhance prediction of edema in a large diverse stroke cohort. An automated imaging pipeline retrospectively extracted volumetric data, including cerebrospinal fluid (CSF) volumes and the hemispheric CSF volume ratio, from baseline and 24 h CT scans performed in participants of an international stroke cohort study. Fully connected and long short-term memory (LSTM) neural networks were trained using serial clinical and imaging data to predict those who would require hemicraniectomy or die with midline shift. The performance of these models was tested, in comparison with regression models and the Enhanced Detection of Edema in Malignant Anterior Circulation Stroke (EDEMA) score, using cross-validation to construct precision-recall curves. Twenty of 598 patients developed malignant edema (12 required surgery, 8 died). The regression model provided 95% recall but only 32% precision (area under the precision-recall curve [AUPRC] 0.74), similar to the EDEMA score (precision 28%, AUPRC 0.66). The fully connected network did not perform better (precision 33%, AUPRC 0.71), but the LSTM model provided 100% recall and 87% precision (AUPRC 0.97) in the overall cohort and the subgroup with a National Institutes of Health Stroke Scale (NIHSS) score ≥ 8 (p = 0.0001 vs. regression and fully connected models). Features providing the most predictive importance were the hemispheric CSF ratio and NIHSS score measured at 24 h. An LSTM neural network incorporating volumetric data extracted from routine CT scans identified all cases of malignant cerebral edema by 24 h after stroke, with significantly fewer false positives than a fully connected neural network, regression model, and the validated EDEMA score. This preliminary work requires prospective validation but provides proof of principle that a deep learning framework could assist in selecting patients for surgery prior to deterioration.

In women with primary dysmenorrhea (PD), the use of complementary and alternative medicine (CAM) and productivity losses at both workplaces and schools have not been comprehensively assessed. In this study, researchers evaluated the disease burden in women with PD in patients' perspective in two categories: direct cost (the use of CAM and associated costs) and indirect cost (productivity losses). Women with PD aged 16-49 years were asked to fill an online survey in 2017. The survey consisted of 49 questions. CAM included traditional Korean medicines, over-the-counter products, dietary supplements, and traditional remedies. All costs were expressed in US dollars in this study. The survey data from 86 patients with PD were analyzed. The total mean annual cost per patient with PD was $4053, comprising direct costs ($1245) and indirect costs ($2807). PD causes considerable expenditure on CAM and impairs work productivity (especially in presenteeism).

ObjectiveTo determine the contribution of common genetic variants to risk of early onset ischemic stroke (IS).MethodsWe performed a meta-analysis of genome-wide association studies of early onset IS, ages 18-59, using individual level data or summary statistics in 16,927 cases and 576,353 non-stroke controls from 48 different studies across North America, Europe, and Asia. We further compared effect sizes at our most genome-wide significant loci between early and late onset IS and compared polygenic risk scores for venous thromboembolism between early versus later onset IS.ResultsWe observed an association between early onset IS and ABO, a known stroke locus. The effect size of the peak ABO SNP, rs8176685, was significantly larger in early compared to late onset IS (OR 1.17 (95% C.I.: 1.11-1.22) vs 1.05 (0.99-1.12); p for interaction = 0.008). Analysis of genetically determined ABO blood groups revealed that early onset IS cases were more likely to have blood group A and less likely to have blood group O compared to both non-stroke controls and to late onset IS cases. Using polygenic risk scores, we observed that greater genetic risk for venous thromboembolism, another prothrombotic condition, was more strongly associated with early, compared to late, onset IS (p=0.008).ConclusionThe ABO locus, genetically predicted blood group A, and higher genetic propensity for venous thrombosis are more strongly associated with early onset IS, compared with late onset IS, supporting a stronger role of prothrombotic factors in early onset IS.

Producción Científica, Stroke is one of the most common causes of death and disability. Reperfusion therapies are the only treatment available during the acute phase of stroke. Due to recent clinical trials, these therapies may increase their frequency of use by extending the time-window administration, which may lead to an increase in complications such as hemorrhagic transformation, with parenchymal hematoma (PH) being the more severe subtype, associated with higher mortality and disability rates. Our aim was to find genetic risk factors associated with PH, as that could provide molecular targets/pathways for their prevention/treatment and study its genetic correlations to find traits sharing genetic background. We performed a GWAS and meta-analysis, following standard quality controls and association analysis (fastGWAS), adjusting age, NIHSS, and principal components. FUMA was used to annotate, prioritize, visualize, and interpret the meta-analysis results. The total number of patients in the meta-analysis was 2034 (216 cases and 1818 controls). We found rs79770152 having a genome-wide significant association (beta 0.09, p-value 3.90 × 10−8) located in the RP11-362K2.2:RP11-767I20.1 gene and a suggestive variant (rs13297983: beta 0.07, p-value 6.10 × 10−8) located in PCSK5 associated with PH occurrence. The genetic correlation showed a shared genetic background of PH with Alzheimer’s disease and white matter hyperintensities. In addition, genes containing the ten most significant associations have been related to aggregated amyloid-β, tau protein, white matter microstructure, inflammation, and matrix metalloproteinases., Instituto de Salud Carlos III y Fondo Europeo de Desarrollo Regional (FEDER) - ( Projects PI 11/0176 and PI18/01338), Instituto de Salud Carlos III - (Project CM18/00198), Agencia de Gestión de Ayudas Universitarias y de Investigación (AGAUR) y Fondo Social Europeo - (Grant 2020FI_B1 00157), Instituto de Salud Carlos III y Fondo Europeo de Desarrollo Regional (FEDER) - (Project CD20/00043), Instituto de Salud Carlos III - (Projects FI19/00309, CP12/03298, CPII17/00027, CPII19/00020)

Chronic transfusion therapy (CTT) prevents stroke in selected patients with sickle cell anemia (SCA). We have shown that CTT mitigates signatures of cerebral metabolic stress, reflected by elevated oxygen extraction fraction (OEF), which likely drives stroke risk reduction. The region of highest OEF falls within the border zone, where cerebral blood flow (CBF) nadirs; OEF in this region was reduced after CTT. The neuroprotective efficacy of hydroxyurea (HU) remains unclear. To test our hypothesis that patients receiving HU therapy have lower cerebral metabolic stress compared with patients not receiving disease-modifying therapy, we prospectively obtained brain magnetic resonance imaging scans with voxel-wise measurements of CBF and OEF in 84 participants with SCA who were grouped by therapy: no disease-modifying therapy, HU, or CTT. There was no difference in whole-brain CBF among the 3 cohorts (P = .148). However, whole-brain OEF was significantly different (P < .001): participants without disease-modifying therapy had the highest OEF (median 42.9% [interquartile range (IQR) 39.1%-49.1%]), followed by HU treatment (median 40.7% [IQR 34.9%-43.6%]), whereas CTT treatment had the lowest values (median 35.3% [IQR 32.2%-38.9%]). Moreover, the percentage of white matter at highest risk for ischemia, defined by OEF greater than 40% and 42.5%, was lower in the HU cohort compared with the untreated cohort (P = .025 and P = .034 respectively), but higher compared with the CTT cohort (P = .018 and P = .029 respectively). We conclude that HU may offer neuroprotection by mitigating cerebral metabolic stress in patients with SCA, but not to the same degree as CTT.

Background: Cold hypersensitivity in the hands and feet (CHHF) is frequent in Asian countries including Korea. The quality of life can be degraded by the symptoms of CHHF. In particular, gynecological disorders such as menstrual pain, infertility, leucorrhea, and irregular bleeding may be related to CHHF. Sipjeondaebo-tang(SDT) is widely used in the treatment of various diseases including CHHF by balancing Yin and Yang, restoring the deterioration of physiological function, and improving immunity. However, the efficacy of SDT in the treatment of CHHF has not been assessed in clinical trials. Therefore, we aimed to investigate the feasibility of a full randomized clinical trial of SDT for the treatment of CHHF in Korean women through this trial. Methods: This study will be a pilot, randomized, double-blind, two-arm, placebo-controlled, parallel-group, multicenter clinical trial. Women aged 19-59 years who present with CHHF will be recruited from five university hospitals. A total of 60 subjects will be randomly assigned to a treatment group (SDT) or a placebo group at a 1:1 ratio. The subjects will receive 3 g of either SDT or placebo three times daily for 8 weeks. The primary outcome measures will be the Visual Analogue Scale scores of CHHF. The secondary outcome measures will be changes in body temperature in both the hands and the feet as measured by using a thermometer and the Korean version of the World Health Organization Quality of Life Scale Abbreviated Version. Discussion: This will be the first trial to investigate the efficacy and safety of SDT in the treatment of CHHF. This study will provide basic clinical information regarding Korean herbal medicine treatment of CHHF and a clinical basis for designing a full randomized clinical trial. Trial registration: This study is registered at ClinicalTrials.gov, ID: NCT03374345. Registered on (15 February 2018). Keywords: Herbal medicine, Cold Hypersensitivity, Sipjeondaebo-tang, Cold intolerance.

BACKGROUND: Remote limb ischemic conditioning (RLIC) is a technique in which tissues distant from the target organ are exposed to brief, sub-lethal bouts of ischemia. The effects of remotely applied ischemic conditioning are systemically transferred to the target organ, and typically manifested as protection from subsequent ischemic injury. Previous studies in our lab have found and confirmed that RLIC enhances learning and retention during motor training on a balance task. The current study tested the effect of RLIC dose (number of cycles) on learning enhancement in young, healthy adults. METHODS: Forty healthy participants age 18–40 years were randomized to receive 5 cycles of sham conditioning (n = 9), 3 cycles of RLIC (n = 11), 4 cycles of RLIC (n = 10), or 5 cycles of RLIC (n = 10) using a blood pressure cuff around the upper arm once a day for 7 consecutive weekdays (Days 1 – 7). Participants concurrently trained on a balance task, bi-manual cup stacking task, and a discrete sequence production task on Days 3 – 7. Change in performance on each of the three tasks was compared across groups. RESULTS: Participants in all four groups improved their performance on each of the three tasks over time. However, RLIC at any dose did not enhance learning on any of the three tasks. CONCLUSIONS: While RLIC is safe, inexpensive, and clinically-feasible, reproducibility may be challenged by unidentified factors, raising critical challenges to the straightforward translation of RLIC for improving rehabilitation outcomes in individuals recovering from neurological injury.

Background and Purpose— We sought to explore the effect of genetic imbalance on functional outcome after ischemic stroke (IS). Methods— Copy number variation was identified in high-density single-nucleotide polymorphism microarray data of IS patients from the CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) and SiGN (Stroke Genetics Network)/GISCOME (Genetics of Ischaemic Stroke Functional Outcome) networks. Genetic imbalance, defined as total number of protein-coding genes affected by copy number variations in an individual, was compared between patients with favorable (modified Rankin Scale score of 0–2) and unfavorable (modified Rankin Scale score of ≥3) outcome after 3 months. Subgroup analyses were confined to patients with imbalance affecting ohnologs—a class of dose-sensitive genes, or to those with imbalance not affecting ohnologs. The association of imbalance with outcome was analyzed by logistic regression analysis, adjusted for age, sex, stroke subtype, stroke severity, and ancestry. Results— The study sample comprised 816 CADISP patients (age 44.2±10.3 years) and 2498 SiGN/GISCOME patients (age 67.7±14.2 years). Outcome was unfavorable in 122 CADISP and 889 SiGN/GISCOME patients. Multivariate logistic regression analysis revealed that increased genetic imbalance was associated with less favorable outcome in both samples (CADISP: P =0.0007; odds ratio=0.89; 95% CI, 0.82–0.95 and SiGN/GISCOME: P =0.0036; odds ratio=0.94; 95% CI, 0.91–0.98). The association was independent of age, sex, stroke severity on admission, stroke subtype, and ancestry. On subgroup analysis, imbalance affecting ohnologs was associated with outcome (CADISP: odds ratio=0.88; 95% CI, 0.80–0.95 and SiGN/GISCOME: odds ratio=0.93; 95% CI, 0.89–0.98) whereas imbalance without ohnologs lacked such an association. Conclusions— Increased genetic imbalance was associated with poorer functional outcome after IS in both study populations. Subgroup analysis revealed that this association was driven by presence of ohnologs in the respective copy number variations, suggesting a causal role of the deleterious effects of genetic imbalance.

Rationale: Ischemic stroke is among the leading causes of adult disability. Part of the variability in functional outcome after stroke has been attributed to genetic factors but no locus has been consistently associated with stroke outcome. Objective: Our aim was to identify genetic loci influencing the recovery process using accurate phenotyping to produce the largest GWAS (genome-wide association study) in ischemic stroke recovery to date. Methods and Results: A 12-cohort, 2-phase (discovery-replication and joint) meta-analysis of GWAS included anterior-territory and previously independent ischemic stroke cases. Functional outcome was recorded using 3-month modified Rankin Scale. Analyses were adjusted for confounders such as discharge National Institutes of Health Stroke Scale. A gene-based burden test was performed. The discovery phase (n=1225) was followed by open (n=2482) and stringent joint-analyses (n=1791). Those cohorts with modified Rankin Scale recorded at time points other than 3-month or incomplete data on previous functional status were excluded in the stringent analyses. Novel variants in PATJ (Pals1-associated tight junction) gene were associated with worse functional outcome at 3-month after stroke. The top variant was rs76221407 (G allele, β=0.40, P =1.70×10 −9 ). Conclusions: Our results identify a set of common variants in PATJ gene associated with 3-month functional outcome at genome-wide significance level. Future studies should examine the role of PATJ in stroke recovery and consider stringent phenotyping to enrich the information captured to unveil additional stroke outcome loci.

Stroke is one of the leading causes of death and disability worldwide. Reducing this disease burden through drug discovery and evaluation of stroke patient outcomes requires broader characterization of stroke pathophysiology, yet the underlying biologic and genetic factors contributing to outcomes are largely unknown. Remedying this critical knowledge gap requires deeper phenotyping, including large-scale integration of demographic, clinical, genomic, and imaging features. Such big data approaches will be facilitated by developing and running processing pipelines to extract stroke-related phenotypes at large scale. Millions of stroke patients undergo routine brain imaging each year, capturing a rich set of data on stroke-related injury and outcomes. The Stroke Neuroimaging Phenotype Repository (SNIPR) was developed as a multi-center centralized imaging repository of clinical computed tomography (CT) and magnetic resonance imaging (MRI) scans from stroke patients worldwide, based on the open source XNAT imaging informatics platform. The aims of this repository are to: (i) store, manage, process, and facilitate sharing of high-value stroke imaging data sets, (ii) implement containerized automated computational methods to extract image characteristics and disease-specific features from contributed images, (iii) facilitate integration of imaging, genomic, and clinical data to perform large-scale analysis of complications after stroke; and (iv) develop SNIPR as a collaborative platform aimed at both data scientists and clinical investigators. Currently, SNIPR hosts research projects encompassing ischemic and hemorrhagic stroke, with data from 2,246 subjects, and 6,149 imaging sessions from Washington University’s clinical image archive as well as contributions from collaborators in different countries, including Finland, Poland, and Spain. Moreover, we have extended the XNAT data model to include relevant clinical features, including subject demographics, stroke severity (NIH Stroke Scale), stroke subtype (using TOAST classification), and outcome [modified Rankin Scale (mRS)]. Image processing pipelines are deployed on SNIPR using containerized modules, which facilitate replicability at a large scale. The first such pipeline identifies axial brain CT scans from DICOM header data and image data using a meta deep learning scan classifier, registers serial scans to an atlas, segments tissue compartments, and calculates CSF volume. The resulting volume can be used to quantify the progression of cerebral edema after ischemic stroke. SNIPR thus enables the development and validation of pipelines to automatically extract imaging phenotypes and couple them with clinical data with the overarching aim of enabling a broad understanding of stroke progression and outcomes.

Background and Purpose: Mechanical thrombectomy has dramatically increased patient volumes transferred to comprehensive stroke centers (CSCs), resulting in transfer denials for patients who need higher level of care only available at a CSC. We hypothesized that a distributive stroke network (DSN), triaging low severity acute stroke patients to a primary stroke center (PSC) upon initial telestroke consultation, would safely reduce transfer denials, thereby providing additional volume to treat severe strokes at a CSC. Methods: In 2017, a DSN was implemented, in which mild stroke patients were centrally triaged, via telestroke consultation, to a PSC based upon a simple clinical severity algorithm, while higher acuity/severity strokes were triaged to the CSC. In an observational cohort study, data on acute ischemic stroke patients presenting to regional community hospitals were collected pre- versus post-DSN implementation. Safety outcomes and rate of CSC transfer denials were compared pre-DSN versus post-DSN. Results: The pre-DSN cohort (n=150), triaged to the CSC, had a similar rate of symptomatic intracerebral hemorrhage and discharge location compared with the post-DSN cohort (n=150), triaged to the PSC. Time to stroke unit admission was faster post-DSN (2 hours 40 minutes) versus pre-DSN (3 hours 29 minutes; P P =0.02), despite an increase in telestroke consultation volume over the same period (median, 3 calls per day pre-DSN versus 5 calls per day post-DSN; P =0.001). No patients who were triaged to the PSC required subsequent transfer to the CSC. Conclusions: A DSN, triaging mild ischemic stroke patients from community hospitals to a PSC, safely reduced transfer denials to the CSC, allowing greater capacity at the CSC to treat higher acuity stroke patients.

Pathological aggregation of Aβ peptides results in the deposition of amyloid in the brain parenchyma (senile plaques in Alzheimer’s disease [AD]) and around cerebral microvessels (cerebral amyloid angiopathy [CAA]). Our current understanding of the amyloid-induced microvascular changes has been limited to the structure and hemodynamics—leaving the oxygen-metabolic aspect unattended. In this Letter, we report a dual-contrast photoacoustic microscopy (PAM) technique, which integrates the molecular contrast of dichroism PAM and the physiological contrast of multi-parametric PAM for simultaneous, intravital imaging of amyloid deposition and cerebrovascular function in a mouse model that develops AD and CAA. This technique opens up new opportunities to study the spatiotemporal interplay between amyloid deposition and vascular-metabolic dysfunction in AD and CAA.

As swelling occurs, CSF is preferentially displaced from the ischemic hemisphere. The ratio of CSF volume in the stroke-affected hemisphere to that in the contralateral hemisphere may quantify the progression of cerebral edema. We automatically segmented CSF from 1,875 routine CTs performed within 96 hours of stroke onset in 924 participants of a stroke cohort study. In 737 subjects with follow-up imaging beyond 24-hours, edema severity was classified as affecting less than one-third of the hemisphere (CED-1), large hemispheric infarction (LHI, over one-third the hemisphere), without midline shift (CED-2) or with midline shift (CED-3). Malignant edema was LHI resulting in deterioration, requiring osmotic therapy, surgery, or resulting in death. Hemispheric CSF ratio was lower on baseline CT in those with LHI (0.91 vs. 0.97, p

Background and Purpose: MMP (matrix metalloproteinase) levels have been widely associated with ischemic stroke risk and poststroke outcome. However, their role as a risk factor or as a subeffect because of ischemia is uncertain. Methods: We performed a literature search of genome-wide studies that evaluate serum/plasma levels of MMPs. We used a 2-sample Mendelian randomization approach to evaluate the causality of MMP levels on ischemic stroke risk or poststroke outcome, using 2 cohorts: MEGASTROKE (n=440 328) and GODs (n=1791). Results: Genome-wide association studies of MMP-1, MMP-8, and MMP-12 plasma/serum levels were evaluated. A significant association, which was also robust in the sensitivity analysis, was found with all ischemic strokes: MMP-12 (odds ratio=0.90 [95% CI, 0.86–0.94]; q value=7.43×10 − 5 ), and with subtypes of stroke, large-artery atherosclerosis: MMP-1 (odds ratio=0.95 [95% CI, 0.92–0.98]; q value=0.01) and MMP-12 (odds ratio=0.71 [95% CI, 0.65–0.77]; q value=5.11×10 − 14 ); small-vessel occlusion: MMP-8 (odds ratio=1.24 [95% CI, 1.06–1.45]; q value=0.03). No associations were found in relation to stroke outcome. Conclusions: Our study suggests a causal link between lower serum levels of MMP-12 and the risk of ischemic stroke, lower serum levels of MMP-1 and MMP-12 and the risk of large-artery stroke and higher serum levels of MMP-8 and the risk of lacunar stroke.

Introduction: Perihematomal Edema (PHE) is a neuroimaging biomarker of secondary brain injury in patients with spontaneous, non-traumatic intracerebral hemorrhage (ICH). There are limited data on racial/ethnic differences in the development of PHE. This dearth of data is partially driven by the time-consuming process of manually segmenting PHE. Leveraging a validated automated pipeline for PHE segmentation, we evaluated whether race and ethnicity influence baseline PHE volume in patients with ICH. Methods: The Ethnic/Racial Variations in Intracerebral Hemorrhage (ERICH) study is a prospective, multicenter study of ICH that recruited 1,000 adult participants from each of three racial/ethnic groups (non-Hispanic White, non-Hispanic Black, and Hispanic). We applied a previously validated deep learning algorithm to automatically determine PHE volumes on baseline CTs in these study participants. Quality control procedures were used to include only sufficiently accurate PHE measurements. Linear regression was used to identify factors associated with log-transformed PHE volume and to identify differences across Ethnic/Racial groups. Results: Our imaging pipeline provided good quality baseline PHE measurements on 2,008 out of 3,000 ERICH study participants. After excluding infratentorial hemorrhages (273) and those with missing or null baseline ICH volume (49), 1,686 remained for analysis (median age 59 [IQR 51-71], 687 [41%] female sex). Median PHE volume was 12.0 (IQR 4.8-27.1) for whites, 11.9 (IQR 4.5-26.1) for Hispanics and 8.3 (IQR 3.0-19.2) for blacks. Compared to Blacks, Hispanics (beta 0.22; 95%CI 0.11-0.32; p Conclusion: Race and ethnicity influence the volume of baseline PHE. Further studies are needed to validate our results and investigate the biological underpinnings of this difference.

Domain-specific endpoints are assessments that correspond to the output of individual neural systems and are useful for capturing treatment effects on specific behaviors. By contrast, global endpoints combine several attributes into a single score and are useful for capturing broad treatment effects in a summary way. While global endpoints have become the de facto mechanism required to define benefit in stroke trials, they also have important limitations, some of which might be addressed by simultaneously measuring domain-specific endpoints. Substantial opportunity remains to identify quantifiable patient benefit that would otherwise not be captured by global endpoints. Potential advantages of incorporating domain-specific endpoints in acute stroke trials are discussed, such as increased granularity of measurement, improved understanding of how therapies affect the brain between acute treatment and day 90, and optimized therapeutic translation. Potential disadvantages are also considered, including time and cost of administering domain-specific endpoints, as well as statistical implications. Domain-specific endpoints and global endpoints are not mutually exclusive, and both capture clinical benefits to patients. Incorporating a broader set of outcome assessments in stroke trials, including both global and domain-specific endpoints, is warranted.

Background and Purpose: Large-scale observational studies of acute ischemic stroke (AIS) promise to reveal mechanisms underlying cerebral ischemia. However, meaningful quantitative phenotypes attainable in large patient populations are needed. We characterize a dynamic metric of AIS instability, defined by change in National Institutes of Health Stroke Scale score (NIHSS) from baseline to 24 hours baseline to 24 hours (NIHSS baseline – NIHSS 24hours = ΔNIHSS 6-24h ), to examine its relevance to AIS mechanisms and long-term outcomes. Methods: Patients with NIHSS prospectively recorded within 6 hours after onset and then 24 hours later were enrolled in the GENISIS study (Genetics of Early Neurological Instability After Ischemic Stroke). Stepwise linear regression determined variables that independently influenced ΔNIHSS 6 –24h . In a subcohort of tPA (alteplase)-treated patients with large vessel occlusion, the influence of early sustained recanalization and hemorrhagic transformation on ΔNIHSS 6–24h was examined. Finally, the association of ΔNIHSS 6 –24h with 90-day favorable outcomes (modified Rankin Scale score 0–2) was assessed. Independent analysis was performed using data from the 2 NINDS-tPA stroke trials (National Institute of Neurological Disorders and Stroke rt-PA). Results: For 2555 patients with AIS, median baseline NIHSS was 9 (interquartile range, 4–16), and median ΔNIHSS 6 –24h was 2 (interquartile range, 0–5). In a multivariable model, baseline NIHSS, tPA-treatment, age, glucose, site, and systolic blood pressure independently predicted ΔNIHSS 6 –24h (R 2 =0.15). In the large vessel occlusion subcohort, early sustained recanalization and hemorrhagic transformation increased the explained variance (R 2 =0.27), but much of the variance remained unexplained. ΔNIHSS 6 –24h had a significant and independent association with 90-day favorable outcome. For the subjects in the 2 NINDS-tPA trials, ΔNIHSS 3 –24h was similarly associated with 90-day outcomes. Conclusions: The dynamic phenotype, ΔNIHSS 6–24h , captures both explained and unexplained mechanisms involved in AIS and is significantly and independently associated with long-term outcomes. Thus, ΔNIHSS 6 –24h promises to be an easily obtainable and meaningful quantitative phenotype for large-scale genomic studies of AIS.

Neurological instability during the first days following ischemic stroke reflects the potential to salvage brain tissue at risk for infarct growth, hemorrhagic transformation, or malignant edema. However, current clinical care provides intermittent assessments on the order of at least an hour apart potentially missing the early detection of neurological deterioration. Optical imaging offers a continuous, portable alternative to the current combination of physical exams and radiological imaging. However, optical imaging technology has heretofore lacked the crucial combination of portability, resolution, and coverage required for assessing distributed brain function. Here, we present a portable high-density diffuse optical tomography (HD-DOT) system that overcomes these limitations to assess neurological disruption at the bedside. We imaged patients within 72 hours after ischemic stroke onset and demonstrate that HD-DOT is sensitive to both the presence of stoke (Cohen’s d = 1.5, p = 1.2 × 10− 3) as well as the degree of neurological disruption measured by NIH Stroke Scale (R2 = 0.69, p = 4.7 × 10− 4).

ObjectiveTo determine whether treatment with escitalopram compared with placebo would lower CSF β-amyloid 42 (Aβ42) levels.RationaleSerotonin signaling suppresses Aβ42 in animal models of Alzheimer disease (AD) and young healthy humans. In a prospective study in older adults, we examined dose and treatment duration effects of escitalopram.MethodsUsing lumbar punctures to sample CSF levels before and after a course of escitalopram treatment, cognitively normal older adults (n = 114) were assigned to placebo, 20 mg escitalopram × 2 weeks, 20 mg escitalopram × 8 weeks, or 30 mg escitalopram × 8 weeks; CSF sampled pretreatment and posttreatment and within-subject percent change in Aβ42 was used as the primary outcome in subsequent analyses.ResultsAn overall 9.4% greater reduction in CSF Aβ42 was found in escitalopram-treated compared with placebo-treated groups (p < 0.001, 95% confidence interval [CI] 4.9%–14.2%, d = 0.81). Positive baseline Aβ status (CSF Aβ42 levels 42 reduction (p = 0.006, 95% CI −16.7% to 0.5%, d = −0.52) compared with negative baseline amyloid status (CSF Aβ42 levels >250 pg/mL).ConclusionsShort-term longitudinal doses of escitalopram decreased CSF Aβ42 in cognitively normal older adults, the target group for AD prevention.Clinicaltrials.gov identifierNCT02161458.Classification of evidenceThis study provides Class II evidence that for cognitively normal older adults, escitalopram decreases CSF Aβ42.

Objective Children with sickle cell disease experience cognitive deficits even when unaffected by stroke. Using functional connectivity MRI as a potential biomarker of cognitive function, we tested our hypothesis that children with sickle cell disease would have decreased functional connectivity, and that children experiencing the greatest metabolic stress, indicated by elevated oxygen extraction fraction, would have the lowest connectivity. Methods We prospectively obtained brain MRIs and cognitive testing in healthy controls and children with sickle cell disease. Results We analyzed data from 60 participants (20 controls, 40 sickle cell disease). There was no difference in global cognition or cognitive subdomains between cohorts. However, we found decreased functional connectivity within the sensory-motor, lateral sensory-motor, auditory, salience and subcortical networks in participants with sickle cell disease compared to controls. Further, as white matter oxygen extraction fraction increased, connectivity within the visual (p = 0.008, parameter estimate [95% CI] = -0.760 [-1.297, -0.224]), default mode (p = 0.012, parameter estimate [95% CI] = -0.417 [-0.731, -0.104]), and cingulo-opercular (p = 0.009, parameter estimate [95% CI] = -0.883 [-1.517, -0.250]) networks decreased. Interpretation We conclude that there is diminished functional connectivity within these anatomically-contiguous networks in children with sickle cell disease compared to controls, even when differences are not seen with cognitive testing. Increased white matter oxygen extraction fraction was associated with decreased connectivity in select networks. These data suggest that elevated oxygen extraction fraction and disrupted functional connectivity are potentially pre-symptomatic neuroimaging biomarkers for cognitive decline in sickle cell disease. This article is protected by copyright. All rights reserved.

OBJECTIVE: To compare the effectiveness of non-pharmacological interventions on depressive symptoms in people after stroke. DATA SOURCES: A literature search was performed through the following databases from January 2000 to August 2018: MEDLINE; CINAHL Plus; Scopus; Academic Search Complete; Cochrane Central Register of Controlled Trials; Scopus; and Library, Information Science and Technology Abstracts. Search terms included depression, stroke, non-pharmacologic, and intervention. STUDY SELECTION: We included randomized controlled trials comparing non-pharmacological interventions to control conditions for depressive symptoms in people following stroke. Of 1703 identified articles, 22 trials were included in narrative synthesis, of which 13 were eligible for meta-analysis. All trials were included once their outcome assessments were blinded. DATA EXTRACTION: Two reviewers were involved in the data extraction process. Characteristics of participants, interventions, and methods and results (means and standard deviations) were extracted from all included trials. DATA SYNTHESIS: Thirteen non-pharmacological interventions were categorized into four types: complementary and alternative therapy (five trials, 228 participants), exercise (four trials, 263 participants), psychosocial therapy (two trials, 216 participants), and multifactorial therapy (two trials, 358 participants). Overall beneficial effects of non-pharmacological interventions on depressive symptoms were found both post-intervention (effect size [ES] = −0.24, 95% confidence Interval [CI]: −0.37 to −0.11, p < 0.05) and at follow-up (ES = −0.22, CI: −0.36 to −0.07, p < 0.05). We found individual beneficial effects for complementary and alternative therapy (ES = −0.29, CI: −0.55 to −0.02, p < 0.05) and psychosocial therapy (ES = − 0.33, CI: −0.60 to −0.06, p < 0.05) post-intervention. CONCLUSIONS: Non-pharmacological interventions can be effective in addressing depressive symptoms in people after stroke. Complementary and alternative therapy and psychosocial therapy appear to be promising strategies for improving post-stroke depressive symptoms. Future studies are required to identify a personalized approach for people with specific conditions such as cognitive impairment.

Background and Purpose: Stroke is a complex disease with multiple genetic and environmental risk factors. Blacks endure a nearly 2-fold greater risk of stroke and are 2× to 3× more likely to die from stroke than European Americans. Methods: The COMPASS (Consortium of Minority Population Genome-Wide Association Studies of Stroke) has conducted a genome-wide association meta-analysis of stroke in >22 000 individuals of African ancestry (3734 cases, 18 317 controls) from 13 cohorts. Results: In meta-analyses, we identified one single nucleotide polymorphism (rs55931441) near the HNF1A gene that reached genome-wide significance ( P =4.62×10 −8 ) and an additional 29 variants with suggestive evidence of association ( P −6 ), representing 24 unique loci. For validation, a look-up analysis for a 100 kb region flanking the COMPASS single nucleotide polymorphism was performed in SiGN (Stroke Genetics Network) Europeans, SiGN Hispanics, and METASTROKE (Europeans). Using a stringent Bonferroni correction P value of 2.08×10 −3 (0.05/24 unique loci), we were able to validate associations at the HNF1A locus in both SiGN ( P =8.18×10 −4 ) and METASTROKE ( P =1.72×10 −3 ) European populations. Overall, 16 of 24 loci showed evidence for validation across multiple populations. Previous studies have reported associations between variants in the HNF1A gene and lipids, C-reactive protein, and risk of coronary artery disease and stroke. Suggestive associations with variants in the SFXN4 and TMEM108 genes represent potential novel ischemic stroke loci. Conclusions: These findings represent the most thorough investigation of genetic determinants of stroke in individuals of African descent, to date.

This study aimed to evaluate the effect of acupuncture intervention and manipulation types on poststroke dysarthria. Electronic database, including PubMed, CENTRAL, Scopus, RISS, and CNKI, were searched for randomized controlled trials (RCT), treating dysarthria using acupuncture, speech-language therapy (SLT), and general management (GM), published before April 2019. The number, distribution, intensity, depth, and repetition of acupuncture and bleeding therapy on the sublingual veins were considered as manipulation types. Risk of bias of the included trials was evaluated, and their efficacy was assessed using risk ratio (RR) and the standard mean differences in the Frenchay Dysarthria Assessment and Speech Function Grading, with 95% confidence intervals (CIs).Fifteen RCT trials involving 1453 patients were isolated. Electroacupuncture plus SLT and manual acupuncture plus SLT were more effective than SLT only, respectively (RR = 1.520, 95% CI [1.183–1.952], RR = 1.380, 95% CI [1.281–1.488]). The clinical efficacy of acupuncture plus GM was higher than that of GM alone (RR = 1.165, 95% CI [1.050–1.293]). Meta-ANOVA showed that none of the manipulation types increased the clinical efficacy of acupuncture on dysarthria. The methodological quality was low. In conclusion, our study suggests that the effect of acupuncture on poststroke dysarthria may be maximized when manual acupuncture or electroacupuncture is combined with SLT, irrespective of manipulation types.

Introduction: White matter hyperintensity volume (WMHv), a quantitative neuroimaging biomarker of cerebral small vessel disease (CSVD), is associated worse outcomes after ischemic stroke. In this study, we hypothesized that worse outcomes in CSVD patients were due to poor collateral flow during acute ischemia. Methods: 47 patients with acute ischemic stroke (AIS) were prospectively enrolled in this study. Serial MRIs were performed at 3 hours and 30 days after stroke onset. 3-hour FLAIR images were used to determine WMHv, after manually delineating lesions with MIPAV. An index of collateral flow (delayed perfusion to the penumbra) was determined by subtracting core volume (volume of tissue with ADC2. Patient’s NIHSS was scored at 3 hours and 30 days after stroke onset and the difference was calculated (ΔNIHSS). Log-transformed WMHv was correlated to ΔNIHSS and the collateral flow index, using Pearson correlation. Results: Mean age = 63.9 years (SD 13.5); 37% female; median 3-hour NIHSS = 13 (IQR 6.5-20); median change in NIHSS between 3h and 30d = 4 (IQR: 0-7); median core volume = 13cm3 (IQR 4.3-35.6); median WMHv = 1.257cm3 (IQR 641-3595). WMHv was associated with reduced improvement in ΔNIHSS (R=-0.42, ρ=0.005). Furthermore, WMHv demonstrated a trend for association with poor collateral flow (R=-0.28, ρ=0.062). In this dataset, we will explore the relationship between WMHv and other tissue-based metrics of collateral flow, including the hypoperfusion intensity ratio (HIR) and the cerebral blood volume ratio (rCBV). Conclusions: Our study confirms that patients with CSVD have worse outcomes after AIS. The data also raise the possibility that these worse outcomes in CSVD patients may be mediated by compromised collateral flow in the setting of acute ischemia.

Introduction: Hemorrhagic transformation (HT) after acute ischemic stroke (AIS) may contribute to neurologic deterioration. The current radiologic classification of HT is qualitative and distinguishes petechial hemorrhagic infarction from parenchymal hematoma (PH-1 and PH-2). However, this grading scheme is subjective and may not accurately reflect the impact of HT on neurological status and outcome. We sought to evaluate whether the volume of hemorrhage was a better marker of deterioration. Methods: We evaluated AIS patients with follow-up CT imaging from a prospective stroke genetics study. HT seen within 36 hours of AI was classified using ECASS criteria. In addition, we outlined all confluent areas of hemorrhage to derive hemorrhage volume (HV). We calculated ΔNIHSS as the difference between baseline and 24-hour NIHSS. Early neurological deterioration (END) was defined as ΔNIHSS of -4 points or more. Association of radiologic HT grade and HV with ΔNIHSS and END were analyzed using linear regression and receiver-operating-curve testing. Results: We analyzed 948 stroke patients with median NIHSS 7 (IQR 4-14), 64% receiving tPA and ΔNIHSS +2 (IQR 0-5). 294 (31%) had HT (146 HI1, 63 HI2, 42 PH1 and 43 PH2). HT was associated with higher baseline NIHSS but not with tPA treatment or ΔNIHSS. END occurred in 113 (12%) including 46 with HT (16%) vs. 67 (10%) without HT (p=0.02). Amongst those with HT, the radiologic grade was not associated with ΔNIHSS or END (20% of PH2, 20% of PH1 vs. 15% of HI1/HI2, p=0.40). However, greater HV was associated with ΔNIHSS (adjusting for baseline NIHSS and tPA, estimate -1.5 point per 10-ml, p=0.0001) and with END (those with END had median HV 7 vs. 3-ml, p=0.001). A cut-off of 12-ml had 45% sensitivity and 90% specificity for END (AUC of 0.72). Conclusion: We demonstrated that while HT was associated with a higher risk of END, the ECASS classification alone did not distinguish those who worsened. It appears that hemorrhage volume may better predict worsening NIHSS and END with moderate sensitivity.

Remote limb ischemic conditioning (RLIC) is a clinically feasible method in which brief, sub-lethal bouts of ischemia protects remote organs or tissues from subsequent ischemic injury. A single session of RLIC can improve exercise performance and increase muscle activation. The purpose of this study, therefore, was to assess the effects of a brief, two-week protocol of repeated RLIC combined with strength training on strength gain and neural adaptation in healthy young adults. Participants age 18-40 years were randomized to receive either RLIC plus strength training (n = 15) or sham conditioning plus strength training (n = 15). Participants received RLIC or sham conditioning over 8 visits using a blood pressure cuff on the dominant arm with 5 cycles of 5 minutes each alternating inflation and deflation. Visits 3-8 paired conditioning with wrist extensors strength training on the non-dominant (non-conditioned) arm using standard guidelines. Changes in one repetition maximum (1 RM) and electromyography (EMG) amplitude were compared between groups. Both groups were trained at a similar workload. While both groups gained strength over time (P = 0.001), the RLIC group had greater strength gains (9.38 ± 1.01 lbs) than the sham group (6.3 ± 1.08 lbs, P = 0.035). There was not a significant group x time interaction in EMG amplitude (P = 0.231). The RLIC group had larger percent changes in 1 RM (43.8% vs. 26.1%, P = 0.003) and EMG amplitudes (31.0% vs. 8.6%, P = 0.023) compared to sham conditioning. RLIC holds promise for enhancing muscle strength in healthy young and older adults, as well as clinical populations that could benefit from strength training.

Background: Children with sickle cell anemia (SCA) invoke compensatory mechanisms to meet cerebral oxygen demand in the setting of low oxygen carrying capacity. Whereas cerebral blood flow (CBF) is largely regulated by cerebral arterioles as one compensatory mechanism, we sought to determine if the cross-sectional area of the large in-flow arteries was also increased. Methods: Children and young adults with SCA underwent 3 Tesla magnetic resonance angiography (MRA) and imaging (MRI) with pseudocontinuous arterial spin labeling (pCASL) and asymmetric spin echo sequence to measure CBF and oxygen extraction fraction (OEF) respectively. Using the double oblique method, we measured artery diameters and calculated the area (A) of the vessel as A=πr 2 . The total inflow area (A T-inflow ) was the summation of the areas of distal portions of both internal carotid arteries and basilar artery. CBF, OEF, arterial oxygen content [(CaO 2 ) = 1.36*Hemoglobin*%saturation on pulse oximetry] and A T-inflow were compared between groups with nonparametric statistics. Spearman’s correlation determined relationship of A T-inflow with other variables. Results: Data was available for 29 subjects with SCA (median age 15 years (range 9-26), 45% male) and 17 age-matched controls (15y (range 9-18), 47% male) underwent scanning. Children with SCA had larger A T-inflow (36 [29, 40] mm 2 ) compared to age-matched controls (29 [26, 31] mm 2 , p=0.01). CBF and OEF were higher (p=0.001, p=0.002), and CaO 2 was lower (pT-inflow positively correlated with CBF (p=0.002) and OEF (p2 (p=0.02; Figure ). Conclusion: Increased cross sectional area of large cerebral arteries may provide an additional compensatory mechanism in SCA to augment CBF and aid in meeting cerebral oxygen demand. Further work is needed to determine if MRA measurements provide a non-invasive precursor to increased cerebral metabolic stress and stroke risk.

Dramatic cardiomegaly arising from gain-of-function (GoF) mutations in the ATP-sensitive potassium (KATP) channels genes, ABCC9 and KCNJ8, is a characteristic feature of Cantú syndrome (CS). How potassium channel over-activity results in cardiac hypertrophy, as well as the long-term consequences of cardiovascular remodeling in CS, is unknown. Using genome-edited mouse models of CS, we therefore sought to dissect the pathophysiological mechanisms linking KATP channel GoF to cardiac remodeling. We demonstrate that chronic reduction of systemic vascular resistance in CS is accompanied by elevated renin–angiotensin signaling, which drives cardiac enlargement and blood volume expansion. Cardiac enlargement in CS results in elevation of basal cardiac output, which is preserved in aging. However, the cardiac remodeling includes altered gene expression patterns that are associated with pathological hypertrophy and are accompanied by decreased exercise tolerance, suggestive of reduced cardiac reserve. Our results identify a high-output cardiac hypertrophy phenotype in CS which is etiologically and mechanistically distinct from other myocardial hypertrophies, and which exhibits key features of high-output heart failure (HOHF). We propose that CS is a genetically-defined HOHF disorder and that decreased vascular smooth muscle excitability is a novel mechanism for HOHF pathogenesis.

Silent cerebral infarcts (SCIs) are associated with cognitive impairment in sickle cell anemia (SCA). SCI risk factors include low hemoglobin and elevated systolic blood pressure; however, mechanisms underlying their development are unclear. Using the largest prospective study evaluating SCIs in pediatric SCA, we identified brain regions with increased SCI density. We tested the hypothesis that infarct density is greatest within regions in which cerebral blood flow is lowest, further restricting cerebral oxygen delivery in the setting of chronic anemia. Neuroradiology and neurology committees reached a consensus of SCIs in 286 children in the Silent Infarct Transfusion (SIT) Trial. Each infarct was outlined and coregistered to a brain atlas to create an infarct density map. To evaluate cerebral blood flow as a function of infarct density, pseudocontinuous arterial spin labeling was performed in an independent pediatric SCA cohort. Blood flow maps were aligned to the SIT Trial infarct density map. Mean blood flow within low, moderate, and high infarct density regions from the SIT Trial were compared. Logistic regression evaluated clinical and imaging predictors of overt stroke at 3-year follow-up. The SIT Trial infarct density map revealed increased SCI density in the deep white matter of the frontal and parietal lobes. A relatively small region, measuring 5.6% of brain volume, encompassed SCIs from 90% of children. Cerebral blood flow was lowest in the region of highest infarct density (P < .001). Baseline infarct volume and reticulocyte count predicted overt stroke. In pediatric SCA, SCIs are symmetrically located in the deep white matter where minimum cerebral blood flow occurs.

Background : This study was conducted to demonstrate the effectiveness and safety of herbal medicine and acupuncture treatment in unexplained infertile females. Methods : One hundred patients were recruited from 3 Korean Medicine hospitals in Korea and they voluntarily signed informed consent agreements. Participants took the Onkyeong-tang (120cc) twice daily between menstrual cycle day (MCD) 3 and 12, and herbal medicine for ovulation and implantation (120cc) twice daily between MCD 13 and 28. They also received acupuncture and moxibustion treatment during 4 menstrual cycles. After the 4 menstrual cycle treatment period, there were 3 menstrual cycle observation periods. The primary outcome is signified by clinical pregnancy rates (CPR) and the secondary outcomes were implantation rates (IR), ongoing pregnancy rates (OPR), and live birth rates. Results : 90 patients completed the study. 13 of the 90 subjects became pregnant. The CPR and IR was 14.44%. 7 of 13 pregnant subjects had continuing pregnancy for over 12 weeks, so that the OPR was 53.85%. The birth rate was 7.78%. All 7 pregnant patients gave birth to their babies and all the babies were live singletons and healthy. There were no serious adverse events. Conclusions : The findings of this study may provide the possibility of effectiveness and safety of Korea medicine treatment for unexplained infertile women. However, further study is required because of several limitations including lack of control and small sample size.

Background This study aimed to obtain the symptom, prescription and therapeutic patterns for the treatment of patients with menopausal syndrome in major Korean medicine (KM) hospitals. Methods We used a retrospective chart review of climacteric disorder and postmenopausal syndrome patients by examining medical records (ICD-10, menopausal and female climacteric states: N95.1, Menopausal and perimenopausal disorder, unspecified: N95.9) from eight university KM hospitals in South Korea. Results The main symptoms of 1,682 patients with menopausal disorders visiting 8 college-affiliated oriental medicine hospitals were hot flush, hyperhidrosis, fatigue, insomnia, and chest tightness. Guipi-tang (decoction), Siwu Guipi-tang (decoction), Qingxin Lianzi-yin (decoction), Jiawei Xiaoyao-san (powder) and Guipi Wendan-tang (decoction) were the most commonly prescribed herbal medicines for menopausal disorders. Patients were most often treated with a combination of herbal medicine and acupuncture. Conclusion Our study shows that the current prescribed herbal medicines were used for treating menopausal disorders in Korean medicine hospitals. However, the objectivity of the efficacy assessment should be studied further.

Introduction Obesity is characterized by hyperleptinemia and leptin resistance. Numerous animal and clinical studies on obesity previously demonstrated a reduction in leptin levels using acupuncture. In this study, we aimed to evaluate the available evidence regarding the efficacy and safety of acupuncture on serum leptin levels in obese patients. Methods We searched 10 data bases (EMBASE, MEDLINE, CENTRAL, KoreaMed, China National Knowledge Infrastructure (CNKI), Chinese Science and Technology Periodical Database (VIP), Wanfang, Allied and complementary medicine database (AMED), Cumulative index to nursing and allied health literature (CINAHL), and Japan medical abstracts society (JAMAS)). Our study included randomized controlled trials(RCTs) that measured serum leptin level to evaluate the efficacy of acupuncture in obese patients. Risk of bias in each article was assessed according to Cochrane risk of bias tool for RCTs. A meta-analysis was performed using the Review Manager software (RevMan v5.3). Results Eight RCTs (n = 468) were finally included in this meta-analysis, and most showed low or unclear risk of bias. Compared to the control arm receiving no treatment (95% confidence interval (CI) [7.79, 12.31]; P Conclusions Our review suggests that acupuncture for obesity has beneficial effect on serum leptin levels compared to no treatment or oral anorexiant. Additional acupuncture treatment on diet therapy or exercise demonstrated greater reduction in serum leptin levels, whereas no significant difference was shown between the acupuncture and sham acupuncture groups. Although the results are of limited value due to the moderate quality and clinical heterogeneity, acupuncture can be used as an effective and safe treatment in obese patients.

Large-vessel vasculopathy (LVV) increases stroke risk in pediatric sickle cell disease beyond the baseline elevated stroke risk in this vulnerable population. The mechanisms underlying this added risk and its unique impact on the developing brain are not established.We analyzed magnetic resonance imaging and angiography scans of 66 children with sickle cell disease and infarcts by infarct density heatmaps and Jacobian determinants, a metric utilized to delineate focal volume change, to investigate if infarct location, volume, frequency, and cerebral atrophy differed among hemispheres with and without LVV.Infarct density heatmaps demonstrated infarct "hot spots" within the deep white matter internal border zone region in both LVV and non-LVV hemispheres, but with greater infarct density and larger infarct volumes in LVV hemispheres (2.2 mL versus 0.25 mL, P 0.001). Additional scattered cortical infarcts in the internal carotid artery territory occurred in LVV hemispheres, but were rare in non-LVV hemispheres. Jacobian determinants revealed greater atrophy in gray and white matter of the parietal lobes of LVV compared with non-LVV hemispheres.Large-vessel vasculopathy in sickle cell disease appears to increase ischemic vulnerability in the borderzone region, as demonstrated by the increased frequency and extent of infarction within deep white matter, and increased risk of focal atrophy. Scattered infarctions across the LVV-affected hemispheres suggest additional stroke etiologies of vasculopathy (i.e., thromboembolism) in addition to chronic hypoxia-ischemia.

Background and Purpose— Clinical trials have demonstrated improved 90-day outcomes for patients with acute ischemic stroke treated with stent retriever thrombectomy plus tissue-type plasminogen activator (SST+tPA) compared with tPA. Previous studies suggested that this strategy may be cost-effective, but models were derived from pooled data and older assumptions. Methods— In this prospective economic substudy conducted alongside the SWIFT-PRIME trial (Solitaire With the Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke), in-trial costs were measured for patients using detailed medical resource utilization and hospital billing data. Utility weights were assessed at 30 and 90 days using the EuroQol-5 dimension questionnaire. Post-trial costs and life-expectancy were estimated for each surviving patient using a model based on trial data and inputs derived from a contemporary cohort of ischemic stroke survivors. Results— Index hospitalization costs were $17 183 per patient higher for SST+tPA than for tPA ($45 761 versus $28 578; P P =0.014); total 90-day costs remained higher with SST+tPA ($57 031 versus $44 752; P P =0.005). In lifetime projections, SST+tPA was associated with substantial gains in quality-adjusted life years (6.79 versus 5.05), cost savings of $23 203 per patient and was economically dominant when compared with tPA in 90% of bootstrap replicates. Conclusions— Among patients with acute ischemic stroke enrolled in the SWIFT-PRIME trial, SST increased initial treatment costs, but was projected to improve quality-adjusted life-expectancy and reduce healthcare costs over a lifetime horizon compared with tPA. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01657461.

Children with sickle cell anemia (SCA) experience a host of neurologic complications, including cognitive dysfunction, silent and overt stroke. Oxygen extraction fraction (OEF), the percent of oxygen removed from the blood into the brain tissue, can increase to compensate for decreased oxygen delivery and maintain the cerebral metabolic rate of oxygen utilization (CMRO2), as stroke occurs with a decrease in CMRO2. Elevated OEF is an independent predictor for ischemic injury in adults without SCA. We have previously shown that OEF is increased in children with SCA compared to healthy controls. Furthermore, the region of the brain with greatest elevation in OEF in SCA co-localizes with the regions at greatest risk for stroke, and OEF indirectly correlates with hemoglobin. However, it remains unclear if OEF is only elevated due to decreased arterial oxygen content with severe anemia in SCA, or if other factors contribute to this ongoing cerebral metabolic stress. We prospectively obtained brain MRIs in children with SCA, children with non-sickle cell anemia (ACTL) and healthy controls (CTL) to test our hypothesis that all children with anemia would have elevated OEF compared to controls, but those with SCA would have more elevated OEF than children with non-sickle cell anemia. Brain MRI measured voxel-wise OEF with an asymmetric spin echo sequence. OEF processing is described in Fields et al. Blood. 2019; 133(22):2436-2444. Group comparisons were made with a Mann-WhitneyUor chi-square tests. General linear models were used to understand the difference in whole brain (WB), gray matter (GM) and white matter (WM) OEF between cohorts while controlling for hemoglobin. Table 1 describes the 78 participants (20 CTL, 17 ACTL, 41 SCA). The CTL cohort includes 11 HbAA and 9 HbAS participants; the ACTL cohort includes 4 hereditary spherocytosis, 1 congenital dyserythropoietic anemia, 1 beta thalassemia intermedia, 6 iron deficiency, 4 aplastic anemia and 1 loxoscelism participant; the SCA cohort includes 36 HbSS and 5 HbS beta thalassemia null participants. Hemoglobin was lower in the ACTL (p < 0.001) and SCA (p < 0.001) cohorts compared to CTL, but was not different between the ACTL and SCA cohorts (p = 0.682). Ninety percent of the SCA cohort was receiving hydroxyurea at a median dose of 29.1 [21.5-33.1] mg/kg/day, and none were receiving chronic transfusions. Thirty-four percent of the SCA cohort had a history of silent cerebral infarct, while none had a history of overt stroke or vasculopathy identified on screening MRA. OEF was significantly elevated in the ACTL cohort compared to the CTL cohort, but significantly lower than the SCA cohort in the WB, GM and WM (Table 1, Figure 1). Final general linear models predicting WB, GM and WM OEF used a quadratic fit for hemoglobin, and included hemoglobin, hemoglobin2, and cohort as covariates. After accounting for hemoglobin and hemoglobin2(indicating that the relationship between hemoglobin and OEF is not linear), OEF is significantly higher in the SCA cohort compared to the ACTL cohort in WB, GM and WM, while there was not a significant difference in OEF between the ACTL and CTL cohorts (Table 2, Figure 2). The volume of WM with elevated OEF was significantly higher in the ACTL cohort compared to the CTL cohort (OEF 35%: p < 0.001, OEF 37%: p < 0.001, OEF 39%: p < 0.001), but lower in ACTL cohort compared to the SCA cohort (OEF 35%: p = 0.032, OEF 37%: p = 0.028, OEF 39%: p = 0.029). We conclude that OEF is significantly higher in children with SCA compared to age- and sex-matched children that are equally anemic for reasons other than SCA. While severity of anemia was a significant predictor of OEF, cohort (SCA vs. ACTL) remained an independent predictor of OEF across the WB, GM and WM while accounting for hemoglobin. These data suggest that further investigation is required to understand additional covariates contributing to increased cerebral metabolic stress, as measured by OEF, in children with SCA, as these may be clinical targets to reduce OEF and provide further neuroprotection in this vulnerable population. Disclosures Ford: Bluebird Bio: Honoraria. Lee:Biogen: Research Funding. Fields:Global Blood Therapeutics: Other: Speaking engagement without financial compensation; Proclara Biosciences: Current equity holder in private company; Bluebird Bio: Honoraria.

Cirrhosis of the liver has been linked to several changes in risk of cerebrovascular disease and may increase the risk of hemorrhage while reducing the risk of ischemic stroke.1,2 The pathophysiology underlying these changes remains unclear, though intracranial hemorrhage and vascular malformations related to liver disease have been described.1,3 Cirrhosis may be complicated by hepatopulmonary syndrome (HPS), in which distal pulmonary arteries dilate, become tortuous, produce shunt physiology, and often produce arteriovenous (AV) malformations.4

[Background and Purpose] Immune cells play a key role in the first 24h poststroke (acute phase), being associated with stroke outcome. We aimed to find genetic risk factors associated with leukocyte counts during the acute phase of stroke., [Methods] Ischemic stroke patients with leukocyte counts data during the first 24h were included. Genome-wide association study and gene expression studies were performed., [Results] Our genome-wide association study, which included 2064 (Discovery) and 407 (Replication) patients, revealed a new locus (14q24.3) associated with leukocyte counts. After Joint analysis (n=2471) 5 more polymorphisms reached genome-wide significance (P, [Conclusions] We have found the first locus associated with leukocyte counts in ischemic stroke, also associated with acute outcome. Genetic analysis of acute endophenotypes could be useful to find the genetic factors associated with stroke outcome. Our findings suggested a different modulation of immune cells in stroke compared with healthy conditions.

Individuals with sickle cell disease (SCD) experience cognitive deficits; however, it remains unclear whether medical treatments for SCD improve cognition. Given that executive abilities are typically impaired in individuals with SCD, they were the focus of the current study. Our primary hypothesis was that executive abilities would be higher acutely soon after a blood transfusion in children and young adults with SCD. We used tests from the NIH Toolbox to assess executive abilities in 27 participants with SCD receiving chronic transfusion in comparison to 34 participants with SCD receiving hydroxyurea (HU) and 41 non-SCD demographically matched controls, all of whom were tested at two time points. Participants in the transfusion group completed cognitive testing within 3 days after a transfusion (soon after transfusion) and then within 3 days before their next transfusion (long after transfusion) over an interval of 3-7 weeks. We found that executive abilities were significantly poorer for the transfusion and HU groups than for the control group. In support of our primary hypothesis, executive abilities for the transfusion group were significantly better soon after a transfusion compared to long after a transfusion, χ2 (1) = 17.8, P < .0001. Our results demonstrate that executive abilities were higher acutely following a blood transfusion. These findings have implications for daily functioning, medical decision making, and academic achievement in children and young adults with SCD.

Cantú syndrome (CS), first described in 1982, is caused by pathogenic variants in ABCC9 and KCNJ8, which encode the regulatory and pore forming subunits of ATP-sensitive potassium (K(ATP)) channels, respectively. Multiple case reports of affected individuals have described the various clinical features of CS, but systematic studies are lacking. To define the effects of genetic variants on CS phenotypes and clinical outcomes, we have developed a standardized REDCap-based registry for CS. We report phenotypic features and associated genotypes on 74 CS subjects, with confirmed ABCC9 variants in 72 of the individuals. Hypertrichosis and a characteristic facial appearance are present in all individuals. Polyhydramnios during fetal life, hyperflexibility, edema, patent ductus arteriosus (PDA), cardiomegaly, dilated aortic root, vascular tortuosity of cerebral arteries, and migraine headaches are common features, although even with this large group of subjects, there is incomplete penetrance of CS-associated features, without clear correlation to genotype.

Background Inverse association between hospital case-volume and case-fatality has been observed for various nonsurgical interventions and surgical procedures. Aims To study the impact of hospital case-volume on outcome after aneurysmal subarachnoid hemorrhage (aSAH). Methods We included aSAH patients who underwent aneurysm coiling or clipping from tertiary care medical centers across three continents using the Dr Foster Stroke GOAL database 2007–2014. Hospitals were categorized by annual case-volume (low volume: 70/year). Primary outcome was 14-day in-hospital case-fatality. We calculated proportions, and used multiple logistic regression to adjust for age, sex, differences in comorbidity or disease severity, aneurysm treatment modality, and hospital. Results We included 8525 patients (2363 treated in low volume hospitals, 3563 treated in intermediate volume hospitals, and 2599 in high-volume hospitals). Crude 14-day case-fatality for hospitals with low case-volume was 10.4% (95% confidence interval (CI) 9.2–11.7%), for intermediate volume 7.0% (95% CI 6.2–7.9%; adjusted odds ratio (OR) 0.63 (95%CI 0.47–0.85)) and for high volume 5.4% (95% CI 4.6–6.3%; adjusted OR 0.50 (95% CI 0.33–0.74)). In patients with clipped aneurysms, adjusted OR for 14-day case-fatality was 0.46 (95% CI 0.30–0.71) for hospitals with intermediate case-volume and 0.42 (95% CI 0.25–0.72) with high case-volume. In patients with coiled aneurysms, adjusted OR was 0.77 (95% CI 0.55–1.07) for hospitals with intermediate case-volume and 0.56 (95% CI 0.36–0.87) with high case-volume. Conclusions Even within a subset of large, tertiary care centers, intermediate and high hospital case-volume is associated with lower case-fatality after aSAH regardless of treatment modality, supporting centralization to higher volume centers.

Introduction: The introduction of thrombectomy into evidence-based stroke care has dramatically increased the volume of stroke patients transferred to comprehensive stroke centers (CSC), often overwhelming their capacity. This has led to increased transfer denials of severe stroke patients who needed thrombectomy. Hypothesis: A “distributive stroke network” (DSN) to triage low severity acute stroke patients to a primary stroke center (PSC) upon initial neurology consultation will be safe, thereby providing additional volume to treat severe strokes at a CSC. Methods: A clinical severity algorithm for external consultations based on NIHSS and time since last known well was created to triage mild acute ischemic stroke patients (both tPA-treated and untreated) to the PSC, while triaging more severe strokes to the CSC. We evaluated clinical outcomes, safety endpoints, stroke consultation volumes, and transfer denials by comparing a stroke cohort after DSN implementation, to a cohort (matched for NIHSS and acuity) admitted to the CSC prior to DSN implementation. Results: The pre-DSN CSC cohort had similar demographics to the post-DSN PSC cohort. Safety outcomes (symptomatic hemorrhage or the need for PSC to CSC transfer) and favorable discharge outcome (home/inpatient rehabilitation vs. nursing home/death) did not differ between pre- and post-DSN cohorts. The post-DSN PSC cohort had a faster time from consult to admission (3 vs. 5 hours) and shorter hospital length of stay (LOS) (2 vs. 3.5 days) compared to the pre-DSN CSC cohort. After DSN implementation, there were fewer CSC stroke transfer denials. Total consultation rates increased over the same period. Conclusion: Triaging external patients to a PSC or CSC during initial consultation (distributive stroke network) based on stroke severity and acuity significantly reduced transfer denials to the CSC. In addition, this DSN algorithm was safe, led to faster admission, and a shorter LOS.