Clonal hematopoiesis driven by mutated DNMT3A promotes inflammatory bone loss.

Clonal hematopoiesis of indeterminate potential (CHIP) arises from aging-associated acquired mutations in hematopoietic progenitors, which display clonal expansion and produce phenotypically altered leukocytes. We associated CHIP-DNMT3A mutations with a higher prevalence of periodontitis and gingival inflammation among 4,946 community-dwelling adults. To model DNMT3A-driven CHIP, we used mice with the heterozygous loss-of-function mutation R878H, equivalent to the human hotspot mutation R882H. Partial transplantation with Dnmt3aR878H/+ bone marrow (BM) cells resulted in clonal expansion of mutant cells into both myeloid and lymphoid lineages and an elevated abundance of osteoclast precursors in the BM and osteoclastogenic macrophages in the periphery. DNMT3A-driven clonal hematopoiesis in recipient mice promoted naturally occurring periodontitis and aggravated experimentally induced periodontitis and arthritis, associated with enhanced osteoclastogenesis, IL-17-dependent inflammation and neutrophil responses, and impaired regulatory T cell immunosuppressive activity. DNMT3A-driven clonal hematopoiesis and, subsequently, periodontitis were suppressed by rapamycin treatment. DNMT3A-driven CHIP represents a treatable state of maladaptive hematopoiesis promoting inflammatory bone loss.

Dental Caries, Race and Incident Ischemic Stroke, Coronary Heart Disease, and Death.

BACKGROUND: Dental caries is a highly prevalent disease worldwide. In the United States, untreated dental caries is present in >1 in 5 adults. The objective of this study was to determine the relationship between dental caries and incident ischemic stroke, coronary heart disease (CHD) events, and death. METHODS: The dental cohort (n=6351) of the ARIC study (Atherosclerosis Risk in Communities) was followed for incident ischemic stroke, CHD event, and all-cause mortality. Of all the participants at visit 4 (n=11 656), those who were unable to go through dental examination, or with prevalent ischemic stroke and CHD events, were excluded. The full-mouth dental examination was conducted at visit 4 (1996-1998), assessing dental caries. The dose response of decayed, missing, and filled surfaces due to caries was assessed and related to the outcome. Outcomes were assessed through the end of 2019. Additionally, the effect of regular dental care utilization on dental caries was evaluated. RESULTS: Participants with ≥1 dental caries had an increased risk of stroke (adjusted hazard ratio [HR], 1.40 [95% CI, 1.10-1.79]) and death (adjusted HR, 1.13 [95% CI, 1.01-1.26]) but not for CHD events (adjusted HR, 1.13 [95% CI, 0.93-1.37]). The association of dental caries and ischemic incident stroke was significantly higher in the African American population compared with the White subgroup (interaction term P=0.0001). Increasing decayed, missing, and filled surfaces were significantly associated with stroke (adjusted HR, 1.006 [95% CI, 1.001-1.011]) and death (adjusted HR, 1.003 [95% CI, 1.001-1.005]) but not CHD (adjusted HR, 1.002 [95% CI, 1.000-1.005]). Regular dental care utilization lowered (adjusted odds ratio, 0.19 [95% CI, 0.16-0.22]; P<0.001) the chance of caries. CONCLUSIONS: Among the cohort, dental caries was independently associated with the risk of ischemic stroke and death, with the effect higher in African American participants. Regular dental care utilization was associated with a lower chance of caries, emphasizing its relevance in the prevention of these events.

Improved naming in patients with Broca's aphasia with tDCS.

BACKGROUND: Language impairment (aphasia) is a common neurological deficit after strokes. For individuals with chronic aphasia (beyond 6 months after the stroke), language improvements with speech therapy (ST) are often limited. Transcranial direct current stimulation (tDCS) is a promising approach to complement language recovery but interindividual variability in treatment response is common after tDCS, suggesting a possible relationship between tDCS and type of linguistic impairment (aphasia type). METHODS: This current study is a subgroup analysis of a randomised controlled phase II futility design clinical trial on tDCS in chronic post-stroke aphasia. All participants received ST coupled with tDCS (n=31) vs sham tDCS (n=39). Confrontation naming was tested at baseline, and 1, 4, and 24 weeks post-treatment. RESULTS: Broca's aphasia was associated with maximal adjunctive benefit of tDCS, with an average improvement of 10 additional named items with tDCS+ST compared with ST alone at 4 weeks post-treatment. In comparison, tDCS was not associated with significant benefits for other aphasia types F(1)=4.23, p=0.04. Among participants with Broca's aphasia, preservation of the perilesional posterior inferior temporal cortex was associated with higher treatment benefit (R=0.35, p=0.03). CONCLUSIONS: These results indicate that adjuvant tDCS can enhance ST to treat naming in Broca's aphasia, and this may guide intervention approaches in future studies.

Dental Caries a Risk Factor for Intracerebral Hemorrhage.

INTRODUCTION: Streptococcus mutans is a known cause of dental caries that contains a collagen-binding protein, Cnm, and exhibits inhibition of platelet aggregation and matrix metalloproteinase-9 activation. This strain has been linked to aggravation of experimental intracerebral hemorrhage (ICH) and may be a risk factor for ICH. The purpose of this study was to test the association between dental caries and incident ICH. METHODS: The presence of dental caries and periodontal disease was assessed in subjects from the Dental Atherosclerosis Risk in Communities (DARIC) study without prior stroke or ICH. This cohort was followed for incident ICH over a period of 10 years. Cox regression was used to compute crude and adjusted hazards ratio from the dental assessment. RESULTS: Among 6,315 subjects, dental surface caries and/or root caries were recorded in 1,338 (27%) subjects. Of those, 7 (0.5%) had incident ICH over a period of 10 years following the visit 4 assessment. Of the remaining 4,977 subjects, 10 (0.2%) had incident ICH. Those with dental caries versus those without dental caries were slightly younger (mean age 62.0 ± 5.7 vs. 62.4 ± 5.6, p = 0.012), had a greater proportion of males (51 vs. 44%, p < 0.001), African Americans (44 vs. 10%, p < 0.001), and were hypertensive (42 vs. 31%, p < 0.001). The association between caries and ICH was significant (crude HR 2.69, 95% CI 1.02-7.06) and strengthened after adjustment for age, gender, race, education level, hypertension, and periodontal disease (adjusted HR 3.88, 95% CI 1.34-11.24). CONCLUSION: Dental caries is a potential risk for incident ICH after caries detection. Future studies are needed to determine if treatment of dental caries can reduce the risk of ICH.

Association of Dental Infections with Intracranial Atherosclerotic Stenosis.

INTRODUCTION: Periodontal disease (PD) and dental caries are oral infections leading to tooth loss that are associated with atherosclerosis and cerebrovascular disease. We assessed the hypothesis that PD and caries are associated with asymptomatic intracranial atherosclerosis (ICAS) in the Atherosclerosis Risk in Communities (ARIC) study. METHODS: Full-mouth clinical periodontal measurements (7 indices) collected at 6 sites per tooth from 6,155 subjects from the Dental Atherosclerosis Risk in Communities Study (DARIC) without prior stroke were used to differentiate seven PD stages (Periodontal Profile Class [PPC]-I to -VII) and dental caries on coronal dental surface (DS) and dental root surface (DRS). A stratified subset underwent 3D time-of-flight MR angiogram and 3D high isotropic-resolution black blood MRI. ICAS was graded according to the criteria established by the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial. We evaluated the relationship between PD stage and dental caries with asymptomatic ICAS, graded as no ICAS, <50% ICAS, and ≥50% ICAS. RESULTS: Among dentate subjects who underwent vascular imaging, 801 (70%) had no ICAS, 232 (20%) had <50% ICAS, and 112 (10%) had ≥50% ICAS. Compared to participants without gum disease (PPC-I), participants with mild-moderate tooth loss (PPC-VI), severe tooth loss (PPC-VII), and severe PD (PPC-IV) had higher odds of having <50% ICAS. Participants with extensive gingivitis (PPC-V) had significantly higher odds of having ≥50% ICAS. This association remained significant after adjusting for confounding variables: age, gender, race, hypertension, diabetes, dyslipidemia, 3-level education, and smoking status. There was no association between dental caries (DS and DRS) and ICAS <50% and ≥50%. CONCLUSION: We report significant associations between mild-moderate tooth loss, severe tooth loss, and severe PD with <50% ICAS as well as an association between extensive gingivitis and ≥50% ICAS. We did not find an association between dental caries and ICAS.

Can machine learning predict late seizures after intracerebral hemorrhages? Evidence from real-world data.

INTRODUCTION: Intracerebral hemorrhage represents 15 % of all strokes and it is associated with a high risk of post-stroke epilepsy. However, there are no reliable methods to accurately predict those at higher risk for developing seizures despite their importance in planning treatments, allocating resources, and advancing post-stroke seizure research. Existing risk models have limitations and have not taken advantage of readily available real-world data and artificial intelligence. This study aims to evaluate the performance of Machine-learning-based models to predict post-stroke seizures at 1 year and 5 years after an intracerebral hemorrhage in unselected patients across multiple healthcare organizations. DESIGN/METHODS: We identified patients with intracerebral hemorrhage (ICH) without a prior diagnosis of seizures from 2015 until inception (11/01/22) in the TriNetX Diamond Network, using the International Classification of Diseases, Tenth Revision (ICD-10) I61 (I61.0, I61.1, I61.2, I61.3, I61.4, I61.5, I61.6, I61.8, and I61.9). The outcome of interest was any ICD-10 diagnosis of seizures (G40/G41) at 1 year and 5 years following the first occurrence of the diagnosis of intracerebral hemorrhage. We applied a conventional logistic regression and a Light Gradient Boosted Machine (LGBM) algorithm, and the performance of the model was assessed using the area under the receiver operating characteristics (AUROC), the area under the precision-recall curve (AUPRC), the F1 statistic, model accuracy, balanced-accuracy, precision, and recall, with and without seizure medication use in the models. RESULTS: A total of 85,679 patients had an ICD-10 code of intracerebral hemorrhage and no prior diagnosis of seizures, constituting our study cohort. Seizures were present in 4.57 % and 6.27 % of patients within 1 and 5 years after ICH, respectively. At 1-year, the AUROC, AUPRC, F1 statistic, accuracy, balanced-accuracy, precision, and recall were respectively 0.7051 (standard error: 0.0132), 0.1143 (0.0068), 0.1479 (0.0055), 0.6708 (0.0076), 0.6491 (0.0114), 0.0839 (0.0032), and 0.6253 (0.0216). Corresponding metrics at 5 years were 0.694 (0.009), 0.1431 (0.0039), 0.1859 (0.0064), 0.6603 (0.0059), 0.6408 (0.0119), 0.1094 (0.0037) and 0.6186 (0.0264). These numerical values indicate that the statistical models fit the data very well. CONCLUSION: Machine learning models applied to electronic health records can improve the prediction of post-hemorrhagic stroke epilepsy, presenting a real opportunity to incorporate risk assessments into clinical decision-making in post-stroke care clinical care and improve patients' selection for post-stroke epilepsy research.

Periodontal Disease Treatment After Stroke or Transient Ischemic Attack: The PREMIERS Study, a Randomized Clinical Trial.

BACKGROUND: Patients with stroke/transient ischemic attack and periodontal disease (PD) are at increased risk for cardiovascular events. PD treatments that can improve stroke risk factors were tested if they might assist patients with cerebrovascular disease. METHODS: In this multicenter phase II trial, patients with stroke/transient ischemic attack and moderately severe PD were randomly assigned to intensive or standard PD treatment arms. The primary outcome measure was a composite of death, myocardial infarction, and recurrent stroke, as well as adverse events. Secondary outcome included changes in stroke risk factors. RESULTS: A total of 1209 patients with stroke/transient ischemic attack were screened, of whom 481 met the PD eligibility criteria; 280 patients were randomized to intensive arm (n=140) and standard arm (n=140). In 12-month period, primary outcome occurred in 11 (8%) in the intensive arm and 17 (12%) in the standard arm. The intensive arm was nonsuperior to the standard arm (hazard ratio, 0.65 [95% CI, 0.30-1.38]) with similar rates of adverse events (sepsis 2.1% versus 0.7%; dental bleeding 1.4% versus 0%; and infective endocarditis 0.7% versus 0%). Secondary-outcome improvements were noted in both arms with diastolic blood pressure and high-density lipoprotein cholesterol (P<0.05). CONCLUSIONS: In patients with recent stroke/transient ischemic attack and PD, intensive PD treatment was not superior to standard PD treatment in prevention of stroke/myocardial infarction/death. Fewer events were noted in the intensive arm and the 2 arms were comparable in the safety outcomes. Secondary-outcome measures showed a trend toward improvement, with significant changes noted in diastolic blood pressure and high-density lipoprotein in both the treatment arms.

Racial Disparities in Utilization of Emergency Medical Services and Related Impact on Poststroke Disability.

BACKGROUND: Prompt seeking of emergency medical services (EMS) assistance at stroke onset is critical to minimize poststroke disability. OBJECTIVE: The aim was to study how racial differences in EMS decision-relevant factors and EMS use impact stroke care and disability outcomes. DESIGN: A prospective observational study. PARTICIPANTS: A total of 1168 acute ischemic stroke patients discharged from April 2016 to October 2017 at a safety net hospital were included; 108 patients were surveyed before discharge. MEASURES: (1) Prehospital delay: EMS use, timely hospital arrival; (2) Stroke care: alteplase receipt and inpatient rehab; (3) Outcomes: Functional improvement at discharge (admission minus discharge scores on National Institutes of Health Stroke Scale), 90-day modified Rankin Scale; (4) EMS decision-relevant factors: Stroke symptom knowledge, source of knowledge, unfavorable past EMS/care experiences, and financial barriers to EMS use. RESULTS: Despite more Black patients using EMS than Whites/Asians (56% vs. 48%, P =0.003), their timely hospital arrival was 30% less likely. Adjusted for stroke severity, receipt of alteplase, and inpatient rehab were similar, but Black patients fared worse on functional improvement at discharge (among severe strokes, 2.4 National Institutes of Health Stroke Scale points less improvement, P <0.01), and on functional normalcy at 90 days (modified Rankin Scale score 0-1 being 60% less likely across severity categories) ( P <0.01). Fewer Black patients knew any stroke symptoms before the stroke (72% vs. 87%, P =0.03), and fewer learned about stroke from providers ( P =0.01). Financial barriers and provider mistrust were similar. CONCLUSIONS: Black patients had less knowledge of stroke symptoms, more care-seeking delay, and poorer outcomes. Including stroke education as a standard of chronic disease care may mitigate stroke outcome disparities.

Preclusion of methemoglobinemia caused by nitrate drugs in diabetics and nondiabetics: Possible role of Vitamin C.

The drugs containing nitrates like isosorbide dinitrate, isosorbide mononitrate and glyceryl trinitrate, etc., trigger the oxidation of hemoglobin which is manifested in the pathological disorder named methemoglobinemia. It was considered interesting to investigate the preventive roles of vitamin C towards the toxic effects of nitrate containing drugs used for the treatment of angina. The aim is to find whether these drugs need to be administered with special care to diabetic patients who are more prone to develop methemoglobinemia. Vitamin C (500 mg/day) was administered orally to reduce the methemoglobin (metHb) level in both the diabetic and nondiabetic patients consuming nitrate containing drugs regularly, keeping diabetic and nondiabetic patients not on nitrate drugs as control. Concentration of metHb and hemoglobin A (HbA) was estimated spectrophotometrically assuming the molar extinction coefficient values of metHb as 3.78 mM--1 cm--1 at 630 nm and HbA as 125,000 M --1 cm --1 at 415 nm. MetHb level was found to be lower after the treatment with vitamin C for 30 consecutive days than that before the trial with statistically significant two tailed p value. Additionally, fasting insulin level was also found to decrease after 4 weeks of consumption of vitamin C with moderate lowering of fasting serum glucose level as well, indicating a higher insulin sensitivity for the treated patients.

Stenting as a treatment for cranio-cervical artery dissection: Improved major adverse cardiovascular event-free survival.

INTRODUCTION: Cranio-cervical artery dissection (CeAD) is a common cause of cerebrovascular events in young subjects with no clear treatment strategy established. We evaluated the incidence of major adverse cardiovascular events (MACE) in CeAD patients treated with and without stent placement. METHODS: COMParative effectiveness of treatment options in cervical Artery diSSection (COMPASS) is a single high-volume center observational, retrospective longitudinal registry that enrolled consecutive CeAD patients over a 2-year period. Patients were ≥ 18 years of age with confirmed extra- or intracranial CeAD on imaging. Enrolled participants were followed for 1 year evaluating MACE as the primary endpoint. RESULTS: One-hundred ten patients were enrolled (age 53 ± 15.9, 56% Caucasian, and 50% male, BMI 28.9 ± 9.2). Grade I, II, III, and IV blunt vascular injury was noted in 16%, 33%, 19%, and 32%, respectively. Predisposing factors were noted in the majority (78%), including sneezing, carrying heavy load, chiropractic manipulation. Stent was placed in 10 (10%) subjects (extracranial carotid n = 9; intracranial carotid n = 1; extracranial vertebral n = 1) at the physician's discretion along with medical management. Reasons for stent placement were early development of high-grade stenosis or expanding pseudoaneurysm. Stented patients experienced no procedural or in-hospital complications and no MACE between discharge and 1 year follow up. CeAD patients treated with medical management only had 14% MACE at 1 year. CONCLUSION: In this single high-volume center cohort of CeAD patients, stenting was found to be beneficial, particularly with development of high-grade stenosis or expanding pseudoaneurysm. These results warrant confirmation by a randomized clinical trial.

Reduction in cerebral oxygen metabolism in subcortical regions may be a biomarker of cognitive decline in people living with human immunodeficiency virus.

BACKGROUND AND PURPOSE: Regional cerebral blood flow (rCBF) and oxygen metabolism (rCMRO2 ) in whole brain, white matter, gray matter and lenticular nuclei were studied in people living with human immunodeficiency virus (PLHIV) as well as HIV-associated neurocognitive disorder (HAND). METHODS: Treatment-naïve PLHIV underwent neurocognitive assessment and magnetic resonance (MR) measurement of rCBF and rCMRO2 with repeat after 12 months of antiretroviral therapy (ART). Age- and sex-matched controls underwent single MR measurements. Regional CBF and rCMRO2 were compared amongst symptomatic, asymptomatic, normal HAND and controls using analysis of variance. Longitudinal analysis of HAND worsening (≥1 category) was assessed after 12 months of ART and correlated with rCBF and rCMRO2 measured by MR imaging using the paired-sample t test. RESULTS: Thirty PLHIV completed baseline and 12-month assessments (29 with rCMRO2 measurement). At baseline HAND assessment, 13% had no cognitive impairment, 27% had asymptomatic neurocognitive impairment, 60% had mild neurocognitive disorder and none had HIV-associated dementia. At 12 months, 13% had no cognitive impairment, 20% had asymptomatic neurocognitive impairment, 50% had mild neurocognitive disorder and 17% had HIV-associated dementia. In those without HAND worsening (N = 21) rCMRO2 remained stable and in those with HAND worsening (N = 8) rCMRO2 measurement declined from baseline to 12 months in white matter (2.05 ± 0.40 to 1.73 ± 0.51, p = 0.03) and lenticular nuclei (4.32 ± 0.39 to 4.00 ± 0.51, p = 0.05). CONCLUSIONS: In recently diagnosed PLHIV, no association was found between rCBF or rCMRO2 and cognitive impairment at baseline. There was a reduction in rCMRO2 in those with worsening of cognitive function at 12 months on ART. Reduction in rCMRO2 may be a biomarker of cognitive decline in PLHIV.

The prospective association between periodontal disease and brain imaging outcomes: The Atherosclerosis Risk in Communities study.

AIM: We investigate if periodontal disease is prospectively associated with cerebrovascular and neurodegenerative markers of dementia and Alzheimer's pathology. MATERIALS AND METHODS: N = 1306 participants (Visit 5 mean age = 76.5 [standard deviation = 5.4] years) in the Atherosclerosis Risk in Communities study with completed dental exams at Visit 4 underwent brain magnetic resonance imaging scans at Visit 5 while N = 248 underwent positron emission tomography scans. Participants were classified as edentulous or, among the dentate, by the modified Periodontal Profile Class. Brain volumes were regressed on periodontal status in linear regressions. Cerebrovascular measures and ß-amyloid positivity were regressed on periodontal status in logistic regressions. RESULTS: Periodontal disease was not associated with brain volumes, microhaemorrhages, or elevated ß-amyloid. Compared with periodontally healthy individuals, odds ratios [95% confidence interval] for all-type infarcts were 0.37 [0.20, 0.65] for severe tooth loss and 0.56 [0.31, 0.99] for edentulous participants. CONCLUSIONS: Within the limitations of this study, periodontal disease was not associated with altered brain volumes, microhaemorrhages, or ß-amyloid positivity. Tooth loss was associated with lower odds of cerebral infarcts.

Free serum sorbitol and its interaction with caffeine: A suggestive approach for plausible remediation of diabetic neuropathy.

The measure of sorbitol in serum can act as a good indicator in the monitoring of the diabetic complications. To analyze the sorbitol level in serum medium, fluorometric enzymatic assay was performed. To remove the excess sorbitol from the body, proposed binding of sorbitol with caffeine was investigated. Their interaction in serum medium was studied and established by UV-Vis, fluorescence spectrophotometry, and time-correlated single photon counting (TCSPC). The linear calibration of sorbitol (in the range 10-50 mM) was done using UV-Vis spectrophotometry. Time scan experiments furnished the reaction rate of sorbitol assayed solution as well as sorbitol-caffeine complex as 0.021 min-1 and 0.018 min-1 , respectively. A sudden drop was observed in the fluorescence lifetime of reduced nicotinamide adenine dinucleotide (NADH) present in sorbitol assayed solution upon complexation with caffeine, that is, from 1.774 × 10-09 to 1.23 × 10-10 Sec, which indicates the hindrance in the formation of NADH and the probable formation of some other species. Isothermal titration calorimetric experiments clearly indicate the number of binding sites (i.e., 3.89, 1.40, and 2.07) that exist between sorbitol and caffeine at the complexation ratio of 1:1.2, 1:1.5, and 1:3. The present method can be helpful in pharmacological and therapeutic studies of sorbitol using caffeine for treating diabetic neuropathy.

Periodontal Disease, Atrial Fibrillation and Stroke.

BACKGROUND: We recently described the association between periodontal disease (PD) and stroke risk. PURPOSE: The purpose of this study was to test the association between PD, dental care utilization and incident atrial fibrillation (AF), as well as AF as a mediator to PD- stroke association. METHODS: In dental cohort of the Atherosclerosis Risk in Communities Study (ARIC), participants without prior AF underwent full-mouth periodontal measurements. PD was defined on an ordinal scale as healthy (referent), mild, moderate and severe. In ARIC main cohort, participants were classified as regular or episodic dental care users. These patients were followed for AF, over 17 years. Cox proportional hazards models adjusted for AF risk factors were used to study relationships between PD severity, dental care utilization and AF. Mediation analysis was used to test if AF mediated the PD- stroke association. RESULTS: In dental ARIC cohort, 5,958 were assessed without prior AF, 754 were found to have AF. Severe PD was associated with AF on both univariable (crude HR, 1.54; 95% CI, 1.26-1.87) and multivariable (adjusted HR, 1.31, 95% CI, 1.06-1.62) analyses. Mediation analysis suggested AF mediates the association between PD and stroke. In the main ARIC cohort, 9,666 participants without prior AF were assessed for dental care use, 1558 were found to have AF. Compared with episodic users, regular users had a lower risk for AF on univariable (crude HR, 0.82, 95% CI, 0.74-0.90) and multivariable (adjusted HR, 0.88, 95% CI, 0.78-0.99) analyses. CONCLUSIONS: PD is associated with AF. The association may explain the PD-stroke risk. Regular users had a lower risk of incident AF compared with episodic users.

Development and initial validation of a patient-centered stroke outcome measure in young stroke survivors.

BACKGROUND AND PURPOSE: This study was undertaken to develop a patient-centered stroke outcome measure and initial validation of the proposed Young Stroke Questionnaire (YSQ). METHODS: This study assessed the reliability and discriminant validity of the YSQ. The initial questionnaire evolved from a focus group comprised of six young stroke survivors and six stroke neurologists centralized around four patient-centered domains. To determine the reliability and discriminant validity of the YSQ, 100 young stroke survivors were recruited and provided consent. Standardized clinical assessments completed included the modified Rankin Scale (mRS), National Institutes of Health Stroke Scale, and Stroke Impact Scale. Additionally, all patients were asked to complete the patient-centered YSQ. RESULTS: Of the 100 enrolled patients in the study (mean age ± standard deviation = 49 ± 11.3, 58% females, 53% African American, 44% White), Cronbach alpha for all domains was >0.7. Moreover, Cronbach alpha for entire questionnaire was >0.9, indicating that the scale, with four subdomains, is internally consistent and reproducible. Discriminant validity of the scale was assessed by comparing the means of each subdomain of the YSQ among healthy subjects to the groups of stroke patients as defined by the mRS. The YSQ was able to differentiate subjects with good outcome (mRS = 0-1) from subjects with varying degree of disability as defined by the mRS (p = 0.026). CONCLUSIONS: Standardized clinical assessments are not sensitive to disabilities in young stroke survivors. When compared to standardized clinical assessments, the YSQ is significantly capable of differentiating the young survivor perspective of the impact of stroke in all four subdomains.

Program to Avoid Cerebrovascular Events through Systematic Electronic Tracking and Tailoring of an Eminent Risk factor: Protocol of a RCT.

BACKGROUND: Geographical and racial disparities in stroke outcomes are especially prominent in the Southeastern United States, which represents a region more heavily burdened with stroke compared to the rest of the country. While stroke is eminently preventable, particularly via blood pressure control, fewer than one third of patients with a stroke have their blood pressure controlled ≥ 75% of the time, and low consistency of blood pressure control is linked to higher stroke risk. OBJECTIVE: To demonstrate that a mHealth technology-centered, integrated approach can effectively improve sustained blood pressure control among stroke patients (half of whom will be Black). DESIGN: The Program to Avoid Cerebrovascular Events through Systematic Electronic Tracking and Tailoring of an Eminent Risk-factor is a prospective randomized controlled trial, which will include a cohort of 200 patients with a stroke, encountered at two major safety net health care systems in South Carolina. The intervention comprises utilization of a Vaica electronic pill tray & blue-toothed UA-767Plus BT blood pressure device and a dedicated app installed on patients' smart phones for automatic relay of data to a central server. Providers will follow care protocols based on expert consensus practice guidelines to address optimal blood pressure management. STUDY OUTCOMES: Primary outcome is systolic blood pressure at 12-months, which is the major modifiable step to stroke event rate reduction. Secondary endpoints include control of other stroke risk factors, medication adherence, functional status, and quality of life. DISCUSSION: We anticipate that a successful intervention will serve as a scalable model of effective chronic blood pressure management after stroke, to bridge racial and geographic disparities in stroke outcomes in the United States. TRIAL REGISTRATION: ClinicalTrials.gov - NCT03401489.

Does Emergency Medical Services Transportation Mitigate Post-stroke Discharge Disability? A Prospective Observational Study.

BACKGROUND: Whether emergency medical services (EMS) transport improves disability outcomes compared with other transport among acute ischemic stroke (AIS) patients is unknown. OBJECTIVE: To study severity-adjusted associations of hospital arrival mode (EMS vs. other transport) with in-hospital and discharge disability outcomes. DESIGN: Prospective observational study. PARTICIPANTS: AIS patients discharged April 2016 to October 2017 from a safety-net hospital in South Carolina. MAIN MEASURES: National Institutes of Health Stroke Scale (NIHSS) change at discharge (admission NIHSS score minus discharge NIHSS, continuous variable), 24-h NIHSS change (attaining high improvement, admission NIHSS minus 24-h NIHSS being 75th percentile or higher), door to neuroimaging (DTI) time, and IV alteplase receipt. NIHSS change was assessed within stroke severity groups, mild, moderate, and severe (admission NIHSS 0-5, 6-14, and ≥ 15, respectively). KEY RESULTS: Of 1168 patients, 838 were study-eligible (52% male, 52.4% Black, 72.2% EMS arrivals, 56.6% mild strokes). Severe and moderate stroke patients were more likely than mild stroke patients to use EMS (adjusted odds ratios, AOR [95% CI] 11.7 [5.0, 27.4] and 4.0 [2.6, 6.3], respectively). EMS arrival was associated with shorter DTI time (adjusted difference - 88.4 min) and higher likelihood of alteplase administration (AOR 5.3 [2.5, 11.4]), both key mediating variables in disability outcomes. High 24-h NIHSS improvement was more likely for EMS arrivals vs. other arrivals among moderate strokes (AOR 3.4 [1.1, 10.9]) and severe strokes (AOR > 999). EMS arrivals had substantially higher NIHSS improvement at discharge within the severe stroke group (adjusted NIHSS change at discharge, 5.9 points higher, p = 0.01). Alteplase recipients showed higher discharge NIHSS improvement than non-recipients (by 2.8 and 1.9 points among severe and moderate strokes, respectively; p = 0.01, 0.02). CONCLUSIONS: The findings offer evidence for including stroke education as a standard of care in the primary care management of patients with stroke-risk comorbidities/lifestyle in order to minimize post-stroke disability.

Early Anticoagulation or Antiplatelet Therapy Is Critical in Craniocervical Artery Dissection: Results from the COMPASS Registry.

INTRODUCTION: Craniocervical artery dissection (CeAD) is a leading cause of stroke in the young patient population. Recent studies reported a low rate of major adverse cardiac events (MACEs) in patients with CeAD, with no significant difference between patients randomized to anticoagulation or antiplatelet therapy. OBJECTIVE: To compare the effectiveness of anticoagulation and antiplatelet therapy in patients with CeAD. METHODS: All CeAD patients from 2015 to 2017 were consecutively identified by an electronic medical record-based application and enrolled in this prospective longitudinal registry. CeAD was confirmed by imaging and graded using the Denver scale for blunt cerebrovascular injury. Patients were followed for 12 months for MACE defined as stroke, transient ischemic attack (TIA), or death. RESULTS: The cohort included 111 CeAD patients (age 53 ± 15.9 years, 56% Caucasian, 50% female). CeAD was detected by magnetic resonance (5%), computed tomography (88%), or catheter angiography (7%). CeAD was noted in the carotid (59%), vertebral (39%), and basilar (2%) arteries, 82% of which were extracranial dissections. CeAD was classified as grade I, II, III, and IV in 16, 33, 19, and 32%, respectively. A total of 40% of dissections were due to known trauma. A predisposing factor was noted in the majority (78%) of patients, including violent sneezing (21%), carrying a heavy load (19%), sports/recreational activity (11%), chiropractic manipulation (9%), abrupt/prolonged rotation of head (9%), and prolonged phone use (9%). At presentation, 41% had a stroke, 5% had TIA, 39% had headache, and 36% were asymptomatic. Favorable outcome defined as a modified Rankin Scale score of 0-2 was noted in 68% at 3 months and 71% at 12 months. The rate of MACEs at 3 and 12 months was 11 and 14%, respectively, with more events observed in patients who were not receiving anticoagulation/antiplatelet therapy due to contraindications (p = 0.008). CONCLUSIONS: We report diagnostic characteristics, as well as short- and long-term outcomes of CeAD. A high MACE rate was observed within the first 2 weeks of CeAD diagnosis, notably in patients not initiated on anticoagulation or antiplatelet therapy.

Aortic Arch Atherosclerosis in Patients With Embolic Stroke of Undetermined Source: An Exploratory Analysis of the NAVIGATE ESUS Trial.

Background and Purpose- Aortic arch atherosclerosis (AAA) is a possible source of embolism in patients with embolic stroke of undetermined source. Previous studies reported high rates of embolic events in patients with AAA, especially those with high-risk AAA. This exploratory analysis of NAVIGATE ESUS (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source) focused on patients with AAA and assessed their characteristics, stroke recurrence rates, and response to treatment. Methods- The detection of AAA and the assessment of its features were based on transesophageal echocardiography that was done in 19% of participants. AAA plaques were considered to have complex features when reported as complex or ulcerated or were ≥4 mm in thickness or had a mobile thrombus present. Results- Among 1382 participants who had transesophageal echocardiography, 397 (29%) had AAA and 112 (8%) had complex AAA. Mean (SD) age (63 [10] versus 67 [9] versus 69 [9]; P<0.001), prevalence of diabetes mellitus (19% versus 26%, versus 32%; P=0.002), and aortic valvulopathy (10 versus 20 versus 20; P<0.001) increased across no versus noncomplex versus complex AAA, respectively. In multivariable analyses, increasing age, diabetes mellitus, aortic valvulopathy, statin use before randomization, chronic infarcts on imaging, and region were independently associated with any AAA versus no AAA and also with complex AAA versus no AAA. Multiterritorial qualifying infarcts rather than single-territory infarcts were observed in 21% with complex AAA versus 17% noncomplex versus 13% no AAA (P=0.07). Annualized rates of ischemic stroke recurrence were 7.2% versus 4.2% versus 5.6% for complex versus noncomplex versus no AAA, respectively. While prevalence of complex AAA increased with increasing risk score, after adjusting for risk score, we did not observe increased risk of recurrent stroke for patients with complex AAA (hazard ratio, 1.1; 95% CI, 0.53-2.4), although the number of outcomes was limited. In patients with complex AAA, 4 strokes occurred among rivaroxaban-assigned patients and 4 strokes among aspirin-assigned patients. Conclusions- Complex AAA is prevalent in embolic stroke of undetermined source patients and is associated with atherosclerotic burden. Whether complex AAA independently increases recurrent stroke risk and whether a non-vitamin-K oral anticoagulant as compared with aspirin may be effective for reducing recurrent stroke requires additional study. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT02313909.

Pioglitazone after Ischemic Stroke or Transient Ischemic Attack.

BACKGROUND: Patients with ischemic stroke or transient ischemic attack (TIA) are at increased risk for future cardiovascular events despite current preventive therapies. The identification of insulin resistance as a risk factor for stroke and myocardial infarction raised the possibility that pioglitazone, which improves insulin sensitivity, might benefit patients with cerebrovascular disease. METHODS: In this multicenter, double-blind trial, we randomly assigned 3876 patients who had had a recent ischemic stroke or TIA to receive either pioglitazone (target dose, 45 mg daily) or placebo. Eligible patients did not have diabetes but were found to have insulin resistance on the basis of a score of more than 3.0 on the homeostasis model assessment of insulin resistance (HOMA-IR) index. The primary outcome was fatal or nonfatal stroke or myocardial infarction. RESULTS: By 4.8 years, a primary outcome had occurred in 175 of 1939 patients (9.0%) in the pioglitazone group and in 228 of 1937 (11.8%) in the placebo group (hazard ratio in the pioglitazone group, 0.76; 95% confidence interval [CI], 0.62 to 0.93; P=0.007). Diabetes developed in 73 patients (3.8%) and 149 patients (7.7%), respectively (hazard ratio, 0.48; 95% CI, 0.33 to 0.69; P<0.001). There was no significant between-group difference in all-cause mortality (hazard ratio, 0.93; 95% CI, 0.73 to 1.17; P=0.52). Pioglitazone was associated with a greater frequency of weight gain exceeding 4.5 kg than was placebo (52.2% vs. 33.7%, P<0.001), edema (35.6% vs. 24.9%, P<0.001), and bone fracture requiring surgery or hospitalization (5.1% vs. 3.2%, P=0.003). CONCLUSIONS: In this trial involving patients without diabetes who had insulin resistance along with a recent history of ischemic stroke or TIA, the risk of stroke or myocardial infarction was lower among patients who received pioglitazone than among those who received placebo. Pioglitazone was also associated with a lower risk of diabetes but with higher risks of weight gain, edema, and fracture. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT00091949.).