Projections of Endovascular Therapy-Eligible Patients With Stroke for the US Population.

BACKGROUND: As stroke endovascular thrombectomy (EVT) treatment indications expand, understanding population-based EVT eligibility becomes critical for resource planning. We aimed to project current and future population-based EVT eligibility in the United States. METHODS: We conducted a post hoc analysis of the physician-adjudicated GCNKSS (Greater Cincinnati Northern Kentucky Stroke Study; 2015 epoch), a population-based, cross sectional, observational study of stroke incidence, treatment, and outcomes across a 5-county region. All hospitalized patients ≥18 years of age with acute ischemic stroke were ascertained using the International Classification of Diseases, Ninth Revision codes 430-436 and Tenth Revision codes I60-I67 and G45-G46 and extrapolated to the US adult census 2020. We determined the rate of EVT eligibility within the GCNKSS population using time from last known well to presentation (0-5 versus 5-23 hours), presenting National Institutes of Health Stroke Scale, and prestroke modified Rankin Scale. Both conservative and liberal estimates of prevalence of large vessel occlusion and large core were then applied based on literature review (unavailable within the 2015 GCNKSS). This eligibility was then extrapolated to the 2020 US population. RESULTS: Of the 1 057 183 adults within GCNKSS in 2015, 2741 had an ischemic stroke and 2176 had data available for analysis. We calculated that 8659 to 17 219 patients (conservative to liberal) meet the current guideline-recommended EVT criteria (nonlarge core, no prestroke disability, and National Institutes of Health Stroke Scale score ≥6) in the United States. Estimates (conservative to liberal) for expanded EVT eligibility subpopulations include (1) 5316 to 10 635 by large core; (2) 10 635 to 21 270 by mild presenting deficits with low National Institutes of Health Stroke Scale score; (3) 13 572 to 27 089 by higher prestroke disability; and (4) 7039 to 14 180 by >1 criteria. These expanded eligibility subpopulations amount to 36 562 to 73 174 patients. CONCLUSIONS: An estimated 8659 to 17 219 adult patients in the United States met strict EVT eligibility criteria in 2020. A 4-fold increase in population-based EVT eligibility can be anticipated with incremental adoption of recent or future positive trials. US stroke systems need to be rapidly optimized to handle all EVT-eligible patients with stroke.

Use of deep artificial neural networks to identify stroke during triage via subtle changes in circulating cell counts.

BACKGROUND: The development of tools that could help emergency department clinicians recognize stroke during triage could reduce treatment delays and improve patient outcomes. Growing evidence suggests that stroke is associated with several changes in circulating cell counts. The aim of this study was to determine whether machine-learning can be used to identify stroke in the emergency department using data available from a routine complete blood count with differential. METHODS: Red blood cell, platelet, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts were assessed in admission blood samples collected from 160 stroke patients and 116 stroke mimics recruited from three geographically distinct clinical sites, and an ensemble artificial neural network model was developed and tested for its ability to discriminate between groups. RESULTS: Several modest but statistically significant differences were observed in cell counts between stroke patients and stroke mimics. The counts of no single cell population alone were adequate to discriminate between groups with high levels of accuracy; however, combined classification using the neural network model resulted in a dramatic and statistically significant improvement in diagnostic performance according to receiver-operating characteristic analysis. Furthermore, the neural network model displayed superior performance as a triage decision making tool compared to symptom-based tools such as the Cincinnati Prehospital Stroke Scale (CPSS) and the National Institutes of Health Stroke Scale (NIHSS) when assessed using decision curve analysis. CONCLUSIONS: Our results suggest that algorithmic analysis of commonly collected hematology data using machine-learning could potentially be used to help emergency department clinicians make better-informed triage decisions in situations where advanced imaging techniques or neurological expertise are not immediately available, or even to electronically flag patients in which stroke should be considered as a diagnosis as part of an automated stroke alert system.

Effect of COVID-19 on Emergent Stroke Care: A Regional Experience.

BACKGROUND AND PURPOSE: Anecdotal evidence suggests that the coronavirus disease 2019 (COVID-19) pandemic mitigation efforts may inadvertently discourage patients from seeking treatment for stroke with resultant increased morbidity and mortality. Analysis of regional data, while hospital capacities for acute stroke care remained fully available, offers an opportunity to assess this. We report regional Stroke Team acute activations and reperfusion treatments during COVID-19 mitigation activities. METHODS: Using case log data prospectively collected by a Stroke Team exclusively serving ≈2 million inhabitants and 30 healthcare facilities, we retrospectively reviewed volumes of consultations and reperfusion treatments for acute ischemic stroke. We compared volumes before and after announcements of COVID-19 mitigation measures and the prior calendar year. RESULTS: Compared with the 10 weeks prior, stroke consultations declined by 39% (95% CI, 32%-46%) in the 5 weeks after announcement of statewide school and restaurant closures in Ohio, Kentucky, and Indiana. Results compared with the prior year and time trend analyses were consistent. Reperfusion treatments also appeared to decline by 31% (95% CI, 3%-51%), and specifically thrombolysis by 33% (95% CI, 4%-55%), but this finding had less precision. CONCLUSIONS: Upon the announcement of measures to mitigate COVID-19, regional acute stroke consultations declined significantly. Reperfusion treatment rates, particularly thrombolysis, also appeared to decline qualitatively, and this finding requires further study. Urgent public education is necessary to mitigate a possible crisis of avoiding essential emergency care due to COVID-19.

Intensive Blood Pressure Reduction and Perihematomal Edema Expansion in Deep Intracerebral Hemorrhage.

Background and Purpose- It is unknown whether blood pressure (BP) reduction influences secondary brain injury in spontaneous intracerebral hemorrhage (ICH). We tested the hypothesis that intensive BP reduction is associated with decreased perihematomal edema expansion rate (PHER) in deep ICH. Methods- We performed an exploratory analysis of the ATACH-2 randomized trial (Antihypertensive Treatment of Acute Cerebral Hemorrhage-2). Patients with deep, supratentorial ICH were included. PHER was calculated as the difference in perihematomal edema volume between baseline and 24-hour computed tomography scans divided by hours between scans. We used regression analyses to determine whether intensive BP reduction was associated with PHER and if PHER was associated with poor outcome (3-month modified Rankin Scale score 4-6). We then used interaction analyses to test whether specific deep location (basal ganglia versus thalamus) modified these associations. Results- Among 1000 patients enrolled in ATACH-2, 870 (87%) had supratentorial, deep ICH. Of these, 780 (90%) had neuroimaging data (336 thalamic and 444 basal ganglia hemorrhages). Baseline characteristics of the treatment groups remained balanced (P>0.2). Intensive BP reduction was associated with a decrease in PHER in univariable (ß= -0.15; 95% CI, -0.26 to -0.05; P=0.007) and multivariable (ß=-0.12; 95% CI, -0.21 to -0.02; P=0.03) analyses. PHER was not independently associated with outcome in all deep ICH (odds ratio, 1.14; 95% CI, 0.93-1.41; P=0.20), but this association was modified by the specific deep location involved (multivariable interaction P=0.02); in adjusted analyses, PHER was associated with poor outcome in basal ganglia (odds ratio, 1.42; 1.05-1.97; P=0.03) but not thalamic (odds ratio, 1.02; 95% CI, 0.74-1.40; P=0.89) ICH. Conclusions- Intensive BP reduction was associated with decreased 24-hour PHER in deep ICH. PHER was not independently associated with outcome in all deep ICH but was associated with poor outcome in basal ganglia ICH. PHER may be a clinically relevant end point for clinical trials in basal ganglia ICH.

Intracerebral hemorrhage induces monocyte-related gene expression within six hours: Global transcriptional profiling in swine ICH.

Intracerebral hemorrhage (ICH) is a severe neurological disorder with no proven treatment. Our prior research identified a significant association with monocyte level and ICH mortality. To advance our understanding, we sought to identify gene expression after ICH using a swine model to test the hypothesis that ICH would induce peripheral blood mononuclear cell (PBMC) gene expression. In 10 pigs with ICH, two PBMC samples were drawn from each with the first immediately prior to ICH induction and the second six hours later. RNA-seq was performed with subsequent bioinformatics analysis using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Ingenuity® Pathway Analysis (IPA). There were 182 significantly upregulated and 153 significantly down-regulated differentially expressed genes (DEGs) after ICH. Consistent with findings in humans, significant GO and KEGG pathways were primarily related to inflammation and the immune response. Five genes, all upregulated post-ICH and known to be associated with monocyte activation, were repeatedly DEGs in the significant KEGG pathways: CD14, TLR4, CXCL8, IL-18, and CXCL2. In IPA, the majority of upregulated disease/function categories were related to inflammation and immune cell activation. TNF and LPS were the most significantly activated upstream regulators, and ERK was the most highly connected node in the top network. ICH induced changes in PBMC gene expression within 6 h of onset related to inflammation, the immune response, and, more specifically, monocyte activation. Further research is needed to determine if these changes affect outcomes and may represent new therapeutic targets.

Modulating acute neuroinflammation in intracerebral hemorrhage: the potential promise of currently approved medications for multiple sclerosis.

The secondary inflammatory injury following intracerebral hemorrhage (ICH) results in increased morbidity and mortality. White blood cells have been implicated as critical mediators of this inflammatory injury. Currently, no medications have been clinically proven to ameliorate or beneficially modulate inflammation, or to improve outcomes by any mechanism, following ICH. However, other neuroinflammatory conditions, such as multiple sclerosis, have approved pharmacologic therapies that modulate the inflammatory response and minimize the damage caused by inflammatory cells. Thus, there is substantial interest in existing therapies for neuroinflammation and their potential applicability to other acute neurological diseases such as ICH. In this review, we examined the mechanism of action of twelve currently approved medications for multiple sclerosis: alemtuzumab, daclizumab, dimethyl fumarate, fingolimod, glatiramer acetate, interferon beta-1a, interferon beta-1b, mitoxantrone, natalizumab, ocrelizumab, rituximab, teriflunomide. We analyzed the existing literature pertaining to the effects of these medications on various leukocytes and also with emphasis on mechanisms of action during the acute period following initiation of therapy. As a result, we provide a valuable summary of the current body of knowledge regarding these therapies and evidence that supports or refutes their likely promise for treating neuroinflammation following ICH.

High-throughput profiling of the circulating proteome suggests sexually dimorphic corticosteroid signaling following ischemic stroke.

Increasing evidence suggests that there are innate differences between sexes with respect to stroke pathophysiology; however, the molecular mechanisms underlying these differences remain unclear. In this investigation, we employed a shotgun approach to broadly profile sex-associated differences in the plasma proteomes of a small group of male ( n = 6) and female ( n = 4) ischemic stroke patients. Peripheral blood was sampled during the acute phase of care, and liquid chromatography electrospray ionization mass spectrometry was used to quantify plasma proteins. We observed widespread differences in plasma composition, as 77 out of 294 detected proteins were significantly differentially expressed between sexes. Corticosteroid-binding globulin (CBG), a negative acute-phase reactant that inversely regulates levels of bioactive free cortisol, was the most dramatically differentially regulated, exhibiting 16-fold higher abundance in plasma from women relative to men. Furthermore, functional annotation analysis revealed that the remaining differentially expressed proteins were significantly enriched for those involved in response to corticosteroid signaling. Plasma CBG levels were further examined in an additional group of male ( n = 19) and female ( n = 28) ischemic stroke patients, as well as a group of male ( n = 13) and female ( n = 18) neurologically normal controls. CBG levels were significantly reduced in male stroke patients relative to male controls; however, no differences were observed between female stroke patients and female controls, suggesting that women may exhibit an attenuated cortisol response to stroke. Collectively, our findings reinforce the idea that there are sex-associated differences in stroke pathophysiology and suggest that cortisol signaling should be investigated further as a potential molecular mediator.

Untreated Hypertension: A Powerful Risk Factor for Lobar and Nonlobar Intracerebral Hemorrhage in Whites, Blacks, and Hispanics.

BACKGROUND: Hypertension is a significant risk factor for intracerebral hemorrhage (ICH). Although ethnic/racial disparities related to hypertension and ICH have been reported, these previous studies were limited by a lack of Hispanics and inadequate power to analyze by ICH location. In the current study, while overcoming these prior limitations, we investigated whether there was variation by ethnicity/race of treated and untreated hypertension as risk factors for ICH. METHODS: The ERICH study (Ethnic/Racial Variations of Intracerebral Hemorrhage) is a prospective, multicenter, case-control study of ICH among whites, blacks, and Hispanics. Cases were enrolled from 42 recruitment sites. Controls matched to cases 1:1 by age (±5 years), sex, ethnicity/race, and metropolitan area were identified by random-digit dialing. Subjects were interviewed to determine history of hypertension and use of antihypertensive medications. Cases and controls within ethnic groups were compared by using conditional logistic regression. Multivariable conditional logistic regression models were computed for ICH as an overall group and separately for the location subcategories deep, lobar, and infratentorial (brainstem/cerebellar). RESULTS: Nine hundred fifty-eight white, 880 black, and 766 Hispanic ICH patients were enrolled. For ICH cases, untreated hypertension was higher in blacks (43.6%, P<0.0001) and Hispanics (46.9%, P<0.0001) versus whites (32.7%). In multivariable analyses adjusted for alcohol use, anticoagulation, hypercholesterolemia, education, and medical insurance status, treated hypertension was a significant risk factor across all locations of ICH in whites (odds ratio [OR], 1.57; 95% confidence interval [CI], 1.24-1.98; P<0.0001), blacks (OR, 3.02; 95% CI, 2.16-4.22; P<0.0001), and Hispanics (OR, 2.50; 95% CI, 1.73-3.62; P<0.0001). Untreated hypertension was a substantially greater risk factor for all 3 racial/ethnic groups across all locations of ICH: whites (OR, 8.79; 95% CI, 5.66-13.66; P<0.0001), blacks (OR, 12.46; 95% CI, 8.08-19.20; P<0.0001), and Hispanics (OR, 10.95; 95% CI, 6.58-18.23; P<0.0001). There was an interaction between race/ethnicity and ICH risk (P<0.0001). CONCLUSIONS: Untreated hypertension confers a greater ICH risk in blacks and Hispanics relative to whites across all anatomic locations of ICH. Accelerated research efforts are needed to improve overall hypertension treatment rates and to monitor the impact of such efforts on racial/ethnic disparities in stroke. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01202864.

M2 Monocyte Microparticles Are Increased in Intracerebral Hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) is a severe neurologic condition with no proven treatment. Recent evidence suggests that monocytes, a heterogenous group of cells with M1 and M2 phenotypes, contribute to secondary damage following ICH. Microparticles are vesicles .1-1 µm in size that are released from cells. We hypothesized that M1 and M2 monocyte microparticles (mMP) would be differentially expressed in ICH cases and controls. METHODS: In a single-center, prospective, observational study, consecutive ICH cases were enrolled within 12 hours of symptom onset. Age (±5 years)-, race-, and sex-matched controls were recruited. M1 and M2 mMP numbers were determined in plasma samples using flow cytometry and protein biomarkers using standardized assays. The Mann-Whitney U test compared M1 and M2 mMP counts between cases and controls. Standardized regression coefficients compared M1 and M2 mMP with C-reactive protein (CRP) and serum amyloid A (SAA). RESULTS: Nineteen ICH case-control pairs were enrolled. The median number of M1 mMP was not significantly different between ICH cases (8.63 × 107/milliliter (mL)) compared with controls (8.64 × 107/mL), (P = .525). The median number of M2 mMP was significantly higher in ICH cases (1.61 × 106/mL) compared with controls (4.46 × 105/mL) (P = .027). There were no significant associations for M1 or M2 mMP with CRP or SAA. CONCLUSION: Higher numbers of M2 mMP in ICH cases compared with controls is hypothesis generating. It may represent differences in the chronic inflammatory status in patients susceptible to ICH, such as cellular activation or apoptosis. Further research is needed, including serial plasma samples, to elucidate the pathophysiology of monocytes and mMP following ICH.

Apolipoprotein A-I and Paraoxonase-1 Are Potential Blood Biomarkers for Ischemic Stroke Diagnosis.

BACKGROUND: Blood biomarkers for ischemic and hemorrhagic stroke diagnosis remain elusive. Recent investigations suggested that apolipoprotein (Apo), matrix metalloproteinase (MMP), and paraoxonase-1 may be associated with stroke. We hypothesized that Apo A-I, Apo C-I, Apo C-III, MMP-3, MMP-9, and paraoxonase-1 are differentially expressed in ischemic stroke, hemorrhagic stroke, and controls. METHODS: In a single-center prospective observational study, consecutive stroke cases were enrolled if blood samples were obtainable within 12 hours of symptom onset. Age- (±5 years), race-, and sex-matched controls were recruited. Multiplex assays were used to measure protein levels. The Wilcoxon signed-rank test and the Mann-Whitney U-test were used to compare biomarker values between ischemic stroke patients and controls, hemorrhagic stroke patients and controls, and ischemic and hemorrhagic stroke patients. The 95% confidence intervals (CIs) for the difference of 2 medians were calculated. RESULTS: Fourteen ischemic stroke case-control pairs and 23 intracerebral hemorrhage (ICH) case-control pairs were enrolled. Median Apo A-I levels were lower in ischemic stroke cases versus controls (140 mg/dL versus 175 mg/dL, difference of 35 mg/dL, 95% CI -54 to -16) and in ischemic stroke versus ICH cases (140 mg/dL versus 180 mg/dL, difference of 40 mg/dL, 95% CI -57 to -23). Median paraoxonase-1 was lower in ischemic stroke cases than in both ICH cases and matched controls. Median Apo C-I was slightly lower in ischemic stroke cases than in ICH cases. There were no differences between groups for MMP-3, MMP-9, and Apo C-III. CONCLUSION: Apo A-I and paraoxonase-1 levels may be clinically useful for ischemic stroke diagnosis and for differentiating between ischemic and hemorrhagic strokes.

Monocyte Count and 30-Day Case Fatality in Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: Monocytes may contribute to secondary injury after intracerebral hemorrhage (ICH). We tested the association of absolute monocyte count with 30-day ICH case fatality in a multiethnic cohort. METHODS: Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study is a prospective, multicenter, case-control study of ICH among white, black, and Hispanic patients. In 240 adults with nontraumatic ICH within 24 hours of symptom onset, we evaluated the influence of ICH score and complete blood count components on 30-day case fatality using generalized linear models. RESULTS: Mean age was 62.8 years (SD, 14 years); 61.7% were men, 33.3% black, and 29.6% Hispanic. Median ICH volume was 9.9 mL (interquartile range, 4.4-26.7). After adjusting for patient age and initial hemoglobin, higher total white blood cell count (P=0.0011), driven by higher absolute neutrophil count (P=0.002), was associated with larger ICH volume, whereas absolute monocyte count was not (P=0.15). After adjusting for age, Glasgow Coma Scale, ICH volume, location, and the presence or absence of intraventricular hemorrhage, baseline absolute monocyte count was independently associated with higher 30-day case-fatality (odds ratio, 5.39; 95% confidence interval, 1.87-15.49; P=0.0018), whereas absolute neutrophil count (odds ratio, 1.04; 0.46-2.32; P=0.93) and white blood cell count (odds ratio, 1.62; 0.58-4.54; P=0.36) were not. CONCLUSIONS: These data support an independent association between higher admission absolute monocyte count and 30-day case-fatality in ICH. Inquiry into monocyte-mediated pathways of inflammation and apoptosis may elucidate the basis for the observed association and may be targets for ICH neuroprotection.

Impact of Poverty on Stroke Recurrence: A Population-Based Study.

BACKGROUND AND OBJECTIVES: Poverty is associated with greater stroke incidence. The relationship between poverty and stroke recurrence is less clear. METHODS: In this population-based study, incident strokes within the Greater Cincinnati/Northern Kentucky region were ascertained during the 2015 study period and followed up for recurrence until December 31, 2018. The primary exposure was neighborhood socioeconomic status (nSES), defined by the percentage of households below the federal poverty line in each census tract in 4 categories (≤5%, >5%-10%, >10%-25%, >25%). Poisson regression models provided recurrence rate estimates per 100,000 residents using population data from the 2015 5-year American Community Survey, adjusting for age, sex, and race. In a secondary analysis, Cox models allowed for the inclusion of vascular risk factors in the assessment of recurrence risk by nSES among those with incident stroke. RESULTS: Of 2,125 patients with incident stroke, 245 had a recurrent stroke during the study period. Poorer nSES was associated with increased stroke recurrence, with rates of 12.5, 17.5, 25.4, and 29.9 per 100,000 in census tracts with ≤5%, >5%-10%, >10%-25%, and >25% below the poverty line, respectively (p < 0.01). The relative risk (95% CI) for recurrent stroke among Black vs White individuals was 2.54 (1.91-3.37) before adjusting for nSES, and 2.00 (1.47-2.74) after adjusting for nSES, a 35.1% decrease. In the secondary analysis, poorer nSES (HR 1.74, 95% CI 1.10-2.76 for lowest vs highest category) and Black race (HR 1.31, 95% CI 1.01-1.70) were both independently associated with recurrence risk, though neither retained significance after full adjustment. Age, diabetes, and left ventricular hypertrophy were associated with increased recurrence risk in fully adjusted models. DISCUSSION: Residents of poorer neighborhoods had a dose-dependent increase in stroke recurrence risk, and neighborhood poverty accounted for approximately one-third of the excess risk among Black individuals. These results highlight the importance of poverty, race, and the intersection of the 2 as potent drivers of stroke recurrence.

Temporal Trends and Racial Disparities in Long-Term Survival After Stroke.

BACKGROUND AND OBJECTIVES: Few studies have examined trends and disparities in long-term outcome after stroke in a representative US population. We used a population-based stroke study in the Greater Cincinnati Northern Kentucky region to examine trends and racial disparities in poststroke 5-year mortality. METHODS: All patients with acute ischemic strokes (AISs) and intracerebral hemorrhages (ICHs) among residents ≥20 years old were ascertained using ICD codes and physician-adjudicated using a consistent case definition during 5 periods: July 1993-June 1994 and calendar years 1999, 2005, 2010, and 2015. Race was obtained from the medical record; only those identified as White or Black were included. Premorbid functional status was assessed using the modified Rankin Scale, with a score of 0-1 being considered "good." Mortality was assessed with the National Death Index. Trends and racial disparities for each subtype were analyzed with logistic regression. RESULTS: We identified 8,428 AIS cases (19.3% Black, 56.3% female, median age 72) and 1,501 ICH cases (23.5% Black, 54.8% female, median age 72). Among patients with AIS, 5-year mortality improved after adjustment for age, race, and sex (53% in 1993/94 to 48.3% in 2015, overall effect of study year p = 0.009). The absolute decline in 5-year mortality in patients with AIS was larger than what would be expected in the general population (5.1% vs 2.8%). Black individuals were at a higher risk of death after AIS (odds ratio [OR] 1.23, 95% CI 1.08-1.39) even after adjustment for age and sex, and this effect was consistent across study years. When premorbid functional status and comorbidities were included in the model, the primary effect of Black race was attenuated but race interacted with sex and premorbid functional status. Among male patients with a good baseline functional status, Black race remained associated with 5-year mortality (OR 1.4, 95% CI 1.1-1.7, p = 0.002). There were no changes in 5-year mortality after ICH over time (64.4% in 1993/94 to 69.2% in 2015, overall effect of study year p = 0.32). DISCUSSION: Long-term survival improved after AIS but not after ICH. Black individuals, particularly Black male patients with good premorbid function, have a higher mortality after AIS, and this disparity did not change over time.

Trends Over Time in Stroke Incidence by Race in the Greater Cincinnati Northern Kentucky Stroke Study.

BACKGROUND AND OBJECTIVES: Understanding the current status of and temporal trends of stroke epidemiology by age, race, and stroke subtype is critical to evaluate past prevention efforts and to plan future interventions to eliminate existing inequities. We investigated trends in stroke incidence and case fatality over a 22-year time period. METHODS: In this population-based stroke surveillance study, all cases of stroke in acute care hospitals within a 5-county population of southern Ohio/northern Kentucky in adults aged ≥20 years were ascertained during a full year every 5 years from 1993 to 2015. Temporal trends in stroke epidemiology were evaluated by age, race (Black or White), and subtype (ischemic stroke [IS], intracranial hemorrhage [ICH], or subarachnoid hemorrhage [SAH]). Stroke incidence rates per 100,000 individuals from 1993 to 2015 were calculated using US Census data and age-standardized, race-standardized, and sex-standardized as appropriate. Thirty-day case fatality rates were also reported. RESULTS: Incidence rates for stroke of any type and IS decreased in the combined population and among White individuals (any type, per 100,000, 215 [95% CI 204-226] in 1993/4 to 170 [95% CI 161-179] in 2015, p = 0.015). Among Black individuals, incidence rates for stroke of any type decreased over the study period (per 100,000, 349 [95% CI 311-386] in 1993/4 to 311 [95% CI 282-340] in 2015, p = 0.015). Incidence of ICH was stable over time in the combined population and in race-specific subgroups, and SAH decreased in the combined groups and in White adults. Incidence rates among Black adults were higher than those of White adults in all time periods, and Black:White risk ratios were highest in adults in young and middle age groups. Case fatality rates were similar by race and by time period with the exception of SAH in which 30-day case fatality rates decreased in the combined population and White adults over time. DISCUSSION: Stroke incidence is decreasing over time in both Black and White adults, an encouraging trend in the burden of cerebrovascular disease in the US population. Unfortunately, however, Black:White disparities have not decreased over a 22-year period, especially among younger and middle-aged adults, suggesting the need for more effective interventions to eliminate inequities by race.

Initial antihypertensive agent effects on acute blood pressure after intracerebral haemorrhage.

INTRODUCTION: Current guidelines recommend blood pressure (BP) lowering in patients after acute intracerebral haemorrhage (ICH) without guidance on initial choice of antihypertensive class. This study sought to determine if initial antihypertensive class differentially effects acute BP lowering in a large multiethnic ICH cohort. METHODS: Subjects enrolled in the Ethnic/Racial Variations in ICH study between August 2010 and August 2017 with elevated admission BP and who received labetalol, nicardipine or hydralazine monotherapy as initial antihypertensive were analysed. Primary outcomes were systolic and diastolic BP changes from baseline to first BP measurement after initial antihypertensive treatment. Secondary outcomes included haematoma expansion (HE), hospital length of stay (LOS) and modified Rankin Score (mRS) up to 12 months after ICH. Exploratory outcomes assessed effects of race/ethnicity. Linear and logistic regression analyses, adjusted for relevant covariates, were performed to determine associations of antihypertensive class with outcomes. RESULTS: In total, 1156 cases were used in analyses. Antihypertensive class was associated with diastolic BP change (p=0.003), but not systolic BP change (p=0.419). Initial dosing with nicardipine lowered acute diastolic BP than labetalol (least square mean difference (labetalol-nicardipine)=5.47 (2.37, 8.57), p<0.001). Initial antihypertensive class was also found to be associated with LOS (p=0.028), but not with HE (p=0.406), mortality (p=0.118), discharge disposition (p=0.083) or mRS score at discharge, 3, 6 and 12 months follow-up (p=0.262, 0.276, 0.152 and 0.36, respectively). Race/ethnicity variably affected multivariable models. CONCLUSION: In this large acute ICH cohort, initial antihypertensive class was associated with acute diastolic, but not systolic, BP-lowering suggesting differential effects of antihypertensive agents. TRIAL REGISTRATION NUMBER: NCT01202864.

MicroRNA expression within neuronal-derived small extracellular vesicles in frontotemporal degeneration.

MicroRNAs (miRNAs) are small non-coding RNA that are powerful regulators of gene expression and can affect the expression of hundreds of genes. miRNAs can be packed in small extracellular vesicles (SEV) and released into the extracellular space by neurons and microglia to act locally as well as pass through the blood-brain barrier and act systemically. We sought to understand the differences in neuronal SEV miRNA expression between frontotemporal dementia (FTD), Alzheimer's disease (AD), and healthy aging. Plasma was obtained from FTD, AD, and healthy aging participants that were matched based on age, sex, and race/ethnicity. Additionally, a subset of participants also provided paired cerebrospinal fluid samples to compare neuronal SEV miRNAs in plasma and cerebrospinal fluid. Neuronal SEV were isolated using differential ultracentrifugation and antibody conjugated Dynabeads® for the neuronal surface marker, L1CAM. RNA sequencing was performed. 12 FTD, 11 with AD, and 10 healthy aging participants were enrolled in the study. In FTD, SEV miRNA-181c was downregulated compared to healthy controls. In AD, miRNA-122 and miRNA-3591 were downregulated compared to those in healthy controls and FTD. Using an FDR <0.2, only miRNA-21-5p was found to have increased expression in the cerebrospinal fluid compared to plasma in a group of AD and FTD participants. SEV miRNA-181c is significantly downregulated in FTD compared to healthy controls and may mediate its effects through microglial-directed neuroinflammation and interaction with TAR DNA-binding protein 43 (TDP-43) based on pathway analysis. Additionally, the FOXO and Hippo pathways may be important mediators of FTD, based on pathway analysis. Lastly, because only one SEV miRNA was differentially expressed between the plasma and cerebrospinal fluid in paired samples, plasma represents an appropriate biofluid for studying neuronal SEV miRNA.

What is the median volume of intracerebral hemorrhage and is it changing?

OBJECTIVES: Population-level estimates of the median intracerebral hemorrhage (ICH) volume would allow for the evaluation of clinical trial external validity and determination of temporal trends. We previously reported the median ICH volume in 1988. However, differences in risk factor management, neuroimaging, and demographics may have affected ICH volumes. The goal of this study is to determine the median volume of ICH within a population-based cross-sectional study, including whether it has changed over time. METHODS: The Genetic and Environmental Risk Factors for Hemorrhagic Stroke study was a population-based study of ICH among residents of the Greater Cincinnati/Northern Kentucky region from 2008 through 2012. This study utilizes those data and compares with ICH cases from the same region in 1988. Initial computed tomography images of the head were reviewed, and ICH volumes were calculated using consistent methodology. RESULTS: From 2008 through 2012, we identified 1117 cases of ICH. The median volume of ICH was 14.0 mL and was lower in black (11.6) than in white (15.5) patients. Median volumes of lobar and deep ICH were 28.8 mL and 9.8 mL, respectively. Median ICH volume changed significantly from 1988 to 2008-2012, with age-and-race-adjusted volume decreasing from 18.3 mL to 13.76 mL (p = 0.025). CONCLUSIONS: Median volume of ICH was 13.76 mL, and this should be considered in clinical trial design. Median ICH volume has apparently decreased from 1988 to 2008-2012.

miR-181a Mediates Inflammatory Gene Expression After Intracerebral Hemorrhage: An Integrated Analysis of miRNA-seq and mRNA-seq in a Swine ICH Model.

Intracerebral hemorrhage (ICH) is a severe neurological disorder with no proven treatment. Inflammation after ICH contributes to clinical outcomes, but the relevant molecular mechanisms remain poorly understood. In studies of peripheral leukocyte counts and mRNA-sequencing (mRNA-seq), our group previously reported that monocytes and Interleukin-8 (IL-8) were important contributors to post-ICH inflammation. microRNA (miRNA) are powerful regulators of gene expression and promising therapeutic targets. We now report findings from an integrated analysis of miRNA-seq and mRNA-seq in peripheral blood mononuclear cells (PBMCs) from a swine ICH model. In 10 pigs, one PBMC sample was collected immediately prior to ICH induction and a second 6 h later; miRNA-seq and mRNA-seq were completed for each sample. An aggregate score calculation determined which miRNA regulated the differentially expressed mRNA. Networks of molecular interactions were generated for the combined miRNA/target mRNA. A total of 227 miRNA were identified, and 46 were differentially expressed after ICH (FDR < 0.05). The anti-inflammatory miR-181a was decreased post-ICH, and it was the most highly connected miRNA in the miRNA/mRNA bioinformatic network analysis. miR-181a has interconnected pathophysiology with IL-8 and monocytes; in prior studies, we found that IL-8 and monocytes contributed to post-ICH inflammation and ICH clinical outcome, respectively. miR-181a was a significant mediator of post-ICH inflammation and is promising for further study, including as a potential therapeutic target. This investigation also demonstrated feasible methodology for miRNA-seq/mRNA-seq analysis in swine that is innovative, and with unique challenges, compared with transcriptomics research in more established species.

Inflammatory mediators of liver ischemia-reperfusion injury.

Liver ischemia and reperfusion--which cause liver damage that is significant in a variety of diseases, injuries, and procedures (including but not limited to trauma and transplant)--have been the focus of many investigations in recent years. Although the mechanisms of ischemia-reperfusion injury are numerous and complex, many advances in treatment have been made. The following review considers recent advances in the understanding of hepatic ischemia-reperfusion injury and focuses on inflammatory mediators of significance. To provide a unique analysis and evaluation, we emphasized the most recent pertinent investigations of the last decade. Specific topics addressed include reactive oxygen species, nitric oxide, toll-like receptors, ischemic preconditioning, T cells, heme oxygenase-1, heat shock proteins, erythropoietin, selectins, protein kinases, matrix metalloproteinases, and cytokines.