Factors and Behaviors Related to Successful Transition of Care After Hospitalization for Ischemic Stroke.

BACKGROUND: Our objective is to describe adoption of the posthospitalization behaviors associated with successful transition of care and related baseline characteristics. METHODS: This study includes 550 participants in the Transition of Care Stroke Disparities Study, a prospective observational cohort derived from the Florida Stroke Registry. Participants had an ischemic stroke (2018-2021), discharged home or to rehabilitation, with modified Rankin Scale score=0-3 (44% women, 24% Black, 48% White, 26% Hispanic, 35% foreign-born). We collected baseline sociodemographic and clinical characteristics. A structured telephone interview at 30-day postdischarge evaluated outcomes including medication adherence, medical appointment attendance, outpatient therapy, exercise, diet modification, toxic habit cessation, and a calculated composite adequate transition of care measure. Multivariable analyses assessed the association of baseline characteristics with 30-day behaviors. RESULTS: At 30 days, medication adherence was achieved by 89%, medical appointments by 82%, outpatient therapy by 76%, exercise by 71%, diet modification by 68%, toxic habit cessation by 35%, and adequate transition of care measure by 67%. Successful adequate transition of care participants were more likely to be used full-time (42% versus 31%, P=0.02), live with a spouse (60% versus 47%, P=0.01), feel close to ≥3 individuals (84% versus 71%, P<0.01), have history of dyslipidemia (45 versus 34%, P=0.02), have thrombectomy (15% versus 8%, P=0.02), but less likely to have a history of smoking (17% versus 32%, P<0.001), coronary artery disease (14% versus 21%, P=0.04), and heart failure (3% versus 11%, P<0.01). Multivariable logistic regression analyses revealed that multiple socio-economic factors and prestroke comorbid diseases predicted fulfillment of transition of care measures. There was no difference in outcomes during the Covid-19 pandemic (2020-2021) compared with prepandemic years (2018-2019). CONCLUSIONS: One in 3 patients did not attain adequate 30-day transition of care behaviors. Their achievement varied substantially among different measures and was influenced by multiple socioeconomic and clinical factors. Interventions aimed at facilitating transition of care from hospital after stroke are needed. REGISTRATION: URL: https://clinicaltrials.gov/; Unique identifier: NCT03452813.

Associations Between Vascular Risk Factors and Perivascular Spaces in Adults with Intact Cognition, Mild Cognitive Impairment, and Dementia.

BACKGROUND: Perivascular spaces (PVS) are fluid-filled compartments surrounding small intracerebral vessels that transport fluid and clear waste. OBJECTIVE: We examined associations between PVS count, vascular and neurodegenerative risk factors, and cognitive status among the predominantly Hispanic participants of the FL-VIP Study of Alzheimer's Disease Risk. METHODS: Using brain MRI (n = 228), we counted PVS in single axial image through the basal ganglia (BG) and centrum semiovale (CSO). PVS per region were scored as 0 (none), 1 (<10), 2 (11-20), 3 (21-40), and 4 (>40). Generalized linear models examined PVS associations with vascular risk factors and a composite vascular comorbidity risk (VASCom) score. RESULTS: Our sample (mean age 72±8 years, 61% women, 60% Hispanic, mean education 15±4 years, 33% APOE4 carriers) was 59% hypertensive, 21% diabetic, 66% hypercholesteremic, and 30% obese. Mean VASCom score was 2.3±1.6. PVS scores ranged from 0-4 in the BG (mean 1.3±0.7) and CSO (mean 1.2±0.9), and 0-7 combined (mean 2.5±1.4). In multivariable regression models, BG PVS was associated with age (ß= 0.03/year, p < 0.0001), Hispanic ethnicity (ß= 0.29, p = 0.01), education (ß= 0.04/year, p = 0.04), and coronary bypass surgery (ß= 0.93, p = 0.02). CSO PVS only associated with age (ß= 0.03/year, p < 0.01). APOE4 and amyloid-ß were not associated with PVS. CONCLUSION: BG PVS may be a marker of subclinical cerebrovascular disease. Further research is needed to validate associations and identify mechanisms linking BG PVS and cerebrovascular disease markers. PVS may be a marker of neurodegeneration despite our negative preliminary findings and more research is warranted. The association between BG PVS and Hispanic ethnicity also requires further investigation.

Rare variants in previously identified linkage regions associated with carotid plaque in Dominican Republic families.

Carotid plaque is a subclinical measure of atherosclerosis. We have previously shown measures of carotid plaque to be heritable in a sample of 100 Dominican families and found evidence for linkage and association of common variants (CVs) on 7q36, 11p15, 14q32 and 15q23 with plaque presence. Our current study aimed to refine these regions further and identify rare variants (RVs) influencing plaque presence. Therefore, we performed targeted sequencing of the one LOD unit down region on 7q36, 11p15, 14q32 and 15q23 in 12 Dominican families with evidence for linkage to plaque presence. Gene-based RV analyses were performed using the Sequence Association Test for familial data (F-SKAT) under two filtering algorithms; 1. all exonic RVs and 2. non-synonymous RVs. Replication analyses were performed using a sample of 22 Dominican families and 556 unrelated Dominicans with Exome Array data. To identify additional non-synonymous RVs influencing plaque, we looked for co-segregation of RVs with plaque in each of the sequenced families. Our most strongly associated gene with evidence for replication was AMPD3 which showed suggestive association with plaque presence in the sequenced families (exonic RV p = 0.003, nonsynonymous RV p = 0.005) and replication families (exonic RV p = 0.04, nonsynonymous RV p = 0.02). Examination of the sequenced family pedigrees revealed two missense variants on chromosome 11 which co-segregated with plaque presence in one of our families; rs61751342 (located in DENND2B), and rs61760882 (located in RNF141). The rs61751342 missense variant is an eQTL for SCUBE2 in the atrial appendage. Notably, SCUBE2 encodes a protein which interacts with vascular endothelial growth factor (VEGF) receptor 2 to regulate VEGF-induced angiogenesis, thus providing biologic plausibility for this gene in atherosclerosis. In conclusion, using targeted sequencing of previously-identified linkage regions, we have identified suggestive evidence for the role of RVs in carotid plaque pathogenesis.

Extreme Phenotype Approach Suggests Taste Transduction Pathway for Carotid Plaque in a Multi-Ethnic Cohort.

BACKGROUND AND PURPOSE: Carotid plaque is a heritable trait and a strong predictor of vascular events. Several loci have been identified for carotid plaque, however, studies in minority populations are lacking. Within a multi-ethnic cohort, we have identified individuals with extreme total carotid plaque area (TCPA), that is, higher or lower TCPA than expected based on traditional vascular risk factors (age, sex, smoking, diabetes mellitus, hypertension, etc). We hypothesized that these individuals are enriched with genetic variants accounting for the plaque burden that cannot be explained by traditional vascular risk factors. Herein, we sought to identify the genetic basis for TCPA using the multi-ethnic cohort. METHODS: Three hundred forty participants (170 from each extreme group) from 3 race/ethnic groups (53% Hispanic, 29% non-Hispanic Black, and 18% non-Hispanic White) were genotyped using a genome-wide single-nucleotide polymorphism (SNP) array and imputed using 1000Genome data. SNP-based analyses using logistic regression and gene-based analyses using VEGAS2 were performed within each race/ethnic group and then meta-analyzed. Genes with P<0.001 were included in an overrepresentation enrichment pathway analysis using WebGestalt. Promising findings were tested for association with ischemic stroke using the MEGASTROKE Consortium data set. RESULTS: No SNP or gene reached genome-wide significance. In the pathway analysis, GO:0050913 (sensory perception of bitter taste) gene set was significantly enriched (P=4.5×10-6, false discovery rate=0.04), which was confirmed in MEGASTROKE (P=0.01). Within the GO:0050913 gene set, 3 genes were associated with extreme TCPA in our study (P<0.001): TAS2R20, TAS2R50, and ITPR3. In TAS2R50, rs1376251 is the top SNP and has been associated with myocardial infarction by others. In ITPR3, a SNP with high regulatory potential (rs3818527, RegulomeScore=1f), and ITPR3 itself were among the top SNP-based and gene-based results and showed consistent evidence for association in all ethnic groups (P<0.05). CONCLUSIONS: Extreme TCPA analysis identified new candidate genes for carotid plaque in understudied populations.

Global Vascular Risk Score and CAIDE Dementia Risk Score Predict Cognitive Function in the Northern Manhattan Study.

BACKGROUND: Modifiable vascular risk factors (VRF) have been implicated in cognitive impairment. OBJECTIVE: We compared the prediction of cognitive performance between the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) dementia risk score, a validated tool to estimate dementia risk using VRF, and the Northern Manhattan Study (NOMAS) global vascular risk score (GVRS), created to predict vascular events. METHODS: The CAIDE and GVRS scores were calculated based on baseline VRF among 1,290 stroke-free participants in the prospective population-based NOMAS MRI cohort (mean age 64±8 years, 60% women; 66% Hispanic, 17% Black, 15% White; 46% completed high school). Domain-specific Z-scores were derived for episodic and semantic memory, executive function, and processing speed, and averaged to calculate global cognition. RESULTS: The CAIDE score was associated with worse global cognition at initial assessment (Beta per SD = -0.347, p < 0.0001), and with greater decline over time (Beta per SD = -0.033, p = 0.02). These associations were largely due to age and education, and the association with cognitive decline was not significant after adjusting for age, sex, and education. The GVRS was inversely associated with global cognition at initial testing (Beta per SD = -0.247, p < 0.0001) and greater decline over time (Beta per SD = -0.127, p < 0.0001), which persisted after adjusting for sociodemographics. The associations for both scores with initial cognitive performance were driven by executive function and processing speed, and the GVRS was associated with decline in episodic memory and processing speed. CONCLUSIONS: The GVRS was a stronger predictor of cognitive decline than the CAIDE in a multi-ethnic urban cohort. The inclusion of glucose and smoking in the GVRS, which are absent in CAIDE, likely explains the better performance of the GVRS.

Ryanodine Receptor to Mitochondrial Reactive Oxygen Species Pathway Plays an Important Role in Chronic Human Immunodeficiency Virus gp120MN-Induced Neuropathic Pain in Rats.

BACKGROUND: Chronic pain is one of the most common complaints in patients with human immunodeficiency virus (HIV)-associated sensory neuropathy. Ryanodine receptor (RyR) and mitochondrial oxidative stress are involved in neuropathic pain induced by nerve injury. Here, we investigated the role of RyR and mitochondrial superoxide in neuropathic pain induced by repeated intrathecal HIV glycoprotein 120 (gp120) injection. METHODS: Recombinant HIV glycoprotein gp120MN was intrathecally administered to induce neuropathic pain. Mechanical threshold was tested using von Frey filaments. Peripheral nerve fiber was assessed by the quantification of the intraepidermal nerve fiber density in the skin of the hindpaw. The expression of spinal RyR was examined using Western blots. Colocalization of RyR with neuronal nuclei (NeuN; neuron marker), glial fibrillary acidic protein (GFAP; astrocyte marker), or ionizing calcium-binding adaptor molecule 1 (Iba1; microglia marker) in the spinal cord was examined using immunohistochemistry. MitoSox-positive profiles (a mitochondrial-targeted fluorescent superoxide indicator) were examined. The antiallodynic effects of intrathecal administration of RyR antagonist, dantrolene (a clinical drug for malignant hyperthermia management), or selective mitochondrial superoxide scavenger, Mito-Tempol, were evaluated in the model. RESULTS: We found that repeated but not single intrathecal injection of recombinant protein gp120 induced persistent mechanical allodynia. Intraepidermal nerve fibers in repeated gp120 group was lower than that in sham at 2 weeks, and the difference in means (95% confidence interval) was 8.495 (4.79-12.20), P = .0014. Repeated gp120 increased expression of RyR, and the difference in means (95% confidence interval) was 1.50 (0.504-2.495), P = .007. Repeated gp120 also increased mitochondrial superoxide cell number in the spinal cord, and the difference in means (95% confidence interval) was 6.99 (5.99-8.00), P < .0001. Inhibition of spinal RyR or selective mitochondrial superoxide scavenger dose dependently reduced mechanical allodynia induced by repeated gp120 injection. RyR and mitochondrial superoxide were colocalized in the neuron, but not glia. Intrathecal injection of RyR inhibitor lowered mitochondrial superoxide in the spinal cord dorsal horn in the gp120 neuropathic pain model. CONCLUSIONS: These data suggest that repeated intrathecal HIV gp120 injection induced an acute to chronic pain translation in rats, and that neuronal RyR and mitochondrial superoxide in the spinal cord dorsal horn played an important role in the HIV neuropathic pain model. The current results provide evidence for a novel approach to understanding the molecular mechanisms of HIV chronic pain and treating chronic pain in patients with HIV.

Ideal Cardiovascular Health and Biomarkers of Subclinical Brain Aging: The Northern Manhattan Study.

Background The American Heart Association Life's Simple 7 metric defines ideal cardiovascular health (CVH) on 7 factors: smoking, diet, physical activity, body mass index, blood sugar, blood pressure, and cholesterol. This metric has been used to define optimal brain health, but data relative to subclinical imaging biomarkers of brain aging are lacking. This study examines the association between Life's Simple 7 with white matter hyperintensity volume, silent brain infarcts, and cerebral volume. Methods and Results A subsample of stroke-free participants from the population-based Northern Manhattan Study underwent brain magnetic resonance imaging an average of 7 years after baseline. Linear and logistic regression models were constructed to estimate associations between the number of ideal CVH metrics achieved with imaging biomarkers of brain aging, adjusting for sociodemographics. Among 1031 participants (mean age at magnetic resonance imaging=72±8, 40% men, 19% black, 16% white, and 65% Hispanic), no one had ideal status in all 7 factors, 1% had ideal status in 6 factors, 18% in 4 to 5 factors, 30% in 3 factors, 33% in 2 factors, and 18% in 0 to 1 factors. The number of ideal CVH factors achieved was inversely associated with white matter hyperintensity volume (beta per factor=-0.047; P=0.04) and silent brain infarct (odds ratio per factor=0.84; 95% confidence interval=0.72-0.97) and positively associated with cerebral volume (beta per factor=0.300; P=0.002). Conclusions An increasing ideal CVH score was associated with less white matter hyperintensity volume and silent brain infarcts and greater cerebral volumes, supporting the Life's Simple 7 metric as a useful measure to quantify optimal brain health. Monitoring and promoting achievement of Life's Simple 7 ideal CVH factors may improve subclinical and clinical brain health outcomes.

Racial-Ethnic Disparities in Acute Stroke Care in the Florida-Puerto Rico Collaboration to Reduce Stroke Disparities Study.

BACKGROUND: Racial-ethnic disparities in acute stroke care can contribute to inequality in stroke outcomes. We examined race-ethnic disparities in acute stroke performance metrics in a voluntary stroke registry among Florida and Puerto Rico Get With the Guidelines-Stroke hospitals. METHODS AND RESULTS: Seventy-five sites in the Florida Puerto Rico Stroke Registry (66 Florida and 9 Puerto Rico) recorded 58 864 ischemic stroke cases (2010-2014). Logistic regression models examined racial-ethnic differences in acute stroke performance measures and defect-free care (intravenous tissue plasminogen activator treatment, in-hospital antithrombotic therapy, deep vein thrombosis prophylaxis, discharge antithrombotic therapy, appropriate anticoagulation therapy, statin use, smoking cessation counseling) and temporal trends. Among ischemic stroke cases, 63% were non-Hispanic white (NHW), 18% were non-Hispanic black (NHB), 14% were Hispanic living in Florida, and 6% were Hispanic living in Puerto Rico. NHW patients were the oldest, followed by Hispanics, and NHBs. Defect-free care was greatest among NHBs (81%), followed by NHWs (79%) and Florida Hispanics (79%), then Puerto Rico Hispanics (57%) (P<0.0001). Puerto Rico Hispanics were less likely than Florida whites to meet any stroke care performance metric other than anticoagulation. Defect-free care improved for all groups during 2010-2014, but the disparity in Puerto Rico persisted (2010: NHWs=63%, NHBs=65%, Florida Hispanics=59%, Puerto Rico Hispanics=31%; 2014: NHWs=93%, NHBs=94%, Florida Hispanics=94%, Puerto Rico Hispanics=63%). CONCLUSIONS: Racial-ethnic/geographic disparities were observed for acute stroke care performance metrics. Adoption of a quality improvement program improved stroke care from 2010 to 2014 in Puerto Rico and all Florida racial-ethnic groups. However, stroke care quality delivered in Puerto Rico is lower than in Florida. Sustained support of evidence-based acute stroke quality improvement programs is required to improve stroke care and minimize racial-ethnic disparities, particularly in resource-strained Puerto Rico.

Fibroblast Growth Factor 23 and Cause-Specific Mortality in the General Population: The Northern Manhattan Study.

CONTEXT: An elevated fibroblast growth factor (FGF) 23 is an independent risk factor for cardiovascular disease and mortality in patients with kidney disease. The relationship between FGF23 and cause-specific mortality in the general population is unknown. OBJECTIVE: To investigate the association of elevated FGF23 with the risk of cause-specific mortality in a racially and ethnically diverse urban general population. DESIGN, SETTING, PARTICIPANTS: The Northern Manhattan Study is a population-based prospective cohort study. Residents who were > 39 years old and had no history of stroke were enrolled between 1993 and 2001. Participants with available blood samples for baseline FGF23 testing were included in the current study (n = 2525). MAIN OUTCOME MEASURES: Cause-specific death events. RESULTS: A total of 1198 deaths (474 vascular, 612 nonvascular, 112 unknown cause) occurred during a median follow-up of 14 years. Compared to participants in the lowest FGF23 quintile, those in the highest quintile had a 2.07-fold higher risk (95% confidence interval [CI], 1.45, 2.94) of vascular death and a 1.64-fold higher risk (95% CI, 1.22, 2.20) of nonvascular death in fully adjusted models. Higher FGF23 was independently associated with increased risk of mortality due to cancer, but only in Hispanic participants (hazard ratio per 1 unit increase in ln FGF23 of 1.87; 95% CI, 1.40, 2.50; P for interaction = .01). CONCLUSIONS: Elevated FGF23 was independently associated with increased risk of vascular and nonvascular mortality in a diverse general population and with increased risk of cancer death specifically in Hispanic individuals.

Ideal Cardiovascular Health and Cognitive Aging in the Northern Manhattan Study.

BACKGROUND: The American Heart Association defined target levels for 7 cardiovascular health (CVH) factors: smoking, body mass index, physical activity, diet, blood pressure, cholesterol, and glucose. We hypothesized that a greater number of American Heart Association ideal CVH metrics would be associated with less decline in cognitive performance in our multiethnic population. METHODS AND RESULTS: A subsample from the population-based Northern Manhattan Study underwent repeated neuropsychological testing (mean interval 6±2 years). Domain-specific Z scores were derived by using factor analysis for the domains of Episodic Memory, Semantic Memory, Executive Function, and Processing Speed, based on initial performance and decline over time. Linear regression models were constructed to examine the relationship between the number of ideal CVH metrics at enrollment with later cognitive performance and decline, adjusting for sociodemographics and magnetic resonance imaging brain markers. Among 1033 participants (mean age at initial cognitive assessment 72±8 years, 39% male, 19% black, 16% white, 65% Hispanic; n=722 with repeat testing), 3% had 0 ideal factors, 15% had 1 factor, 33% had 2 factors, 30% had 3 factors, 14% had 4 factors, 4% had 5 factors, 1% had 6 factors, and 0% had 7 factors. An increasing number of ideal CVH factors was associated with better processing speed at initial assessment and less decline. The association was driven by nonsmoking and glucose. Among those with better cognitive performance at initial assessment, positive associations were observed between the number of ideal CVH factors and less decline in the domains of Executive Function and Episodic Memory. CONCLUSIONS: The number of ideal CVH metrics was associated with less decline in the domains of Processing Speed and, to a lesser extent, of Executive Function and Episodic Memory. Ideal CVH promotion benefits brain health and cognitive aging.

Integration of 2-hydroxyglutarate-proton magnetic resonance spectroscopy into clinical practice for disease monitoring in isocitrate dehydrogenase-mutant glioma.

BACKGROUND: The majority of WHO grades II and III gliomas harbor a missense mutation in the metabolic gene isocitrate dehydrogenase (IDH) and accumulate the metabolite R-2-hydroxyglutarate (R-2HG). Prior studies showed that this metabolite can be detected in vivo using proton magnetic-resonance spectroscopy (MRS), but the sensitivity of this methodology and its clinical implications are unknown. METHODS: We developed an MR imaging protocol to integrate 2HG-MRS into routine clinical glioma imaging and examined its performance in 89 consecutive glioma patients. RESULTS: Detection of 2-hydroxyglutarate (2HG) in IDH-mutant gliomas was closely linked to tumor volume, with sensitivity ranging from 8% for small tumors (<3.4 mL) to 91% for larger tumors (>8 mL). In patients undergoing 2HG-MRS prior to surgery, tumor levels of 2HG corresponded with tumor cellularity but not with tumor grade or mitotic index. Cytoreductive therapy resulted in a gradual decrease in 2HG levels with kinetics that closely mirrored changes in tumor volume. CONCLUSIONS: Our study demonstrates that 2HG-MRS can be linked with routine MR imaging to provide quantitative measurements of 2HG in glioma and may be useful as an imaging biomarker to monitor the abundance of IDH-mutant tumor cells noninvasively during glioma therapy and disease monitoring.

Cigarette Smoking and Carotid Plaque Echodensity in the Northern Manhattan Study.

BACKGROUND: We sought to determine the association between cigarette smoking and carotid plaque ultrasound morphology in a multiethnic cohort. METHODS: We analyzed 1,743 stroke-free participants (mean age 65.5 ± 8.9 years; 60% women; 18% white, 63% Hispanic, 19% black; 14% current and 38% former smokers, 48% never smoked) from the Northern Manhattan Study using an ultrasound index of plaque echodensity, the Gray-Scale Median (GSM). Echolucent plaque (low GSM) represents soft plaque and echodense (high GSM) more calcified plaque. The mean GSM weighted by plaque area for each plaque was calculated for those with multiple plaques. Quintiles of GSM were compared to no plaque. Multinomial logistic regression models were used to assess associations of cigarette smoking with GSM, adjusting for demographics and vascular risk factors. RESULTS: Among subjects with carotid plaque (58%), the mean GSM scores for quintiles 1-5 were 48, 72, 90, 105, and 128, respectively. Current smokers had over a two fold increased risk of having GSM in quintile 1 (odds ratio (OR) = 2.17; 95% confidence interval (CI), 1.34-3.52), quintile 2 (OR = 2.33; 95% CI, 1.42-3.83), quintile 4 (OR = 2.05; 95% CI, 1.19-3.51), and quintile 5 (OR = 2.13; 95% CI, 1.27-3.56) but not in quintile 3 (OR = 1.18; 95% CI, 0.67-2.10) as compared to never smokers in fully adjusted models. Former smokers had increased risk in quintile 2 (OR = 1.46; 95% CI, 1.00-2.12), quintile 3 (OR = 1.56; 95% CI, 1.09-2.24), quintile 4 (OR = 1.66; 95% CI, 1.13-2.42), and quintile 5 (OR = 1.73; 95% CI, 1.19-2.51), but not in quintile 1 (OR = 1.05; 95% CI, 0.72-1.55). CONCLUSIONS: A nonlinear, V-shaped-like relationship between current cigarette smoking and plaque echodensity was observed. Former smokers were at the highest risk for plaques in high GSM quintiles. Thus, current smokers were more likely to have either soft or calcified plaques and former smokers were at greater risk of having only echodense plaques when compared to those who have never smoked. Further research is needed to determine if plaque morphology mediates an association between smoking and clinical vascular events.

Genetic variants in LEKR1 and GALNT10 modulate sex-difference in carotid intima-media thickness: a genome-wide interaction study.

BACKGROUND: There is an established sex-difference in carotid artery intima-media thickness (cIMT), a recognized marker of subclinical atherosclerosis. However, the genetic underpinnings of sex-differences in gene-IMT associations are largely unknown. METHODS: With a multistage design using 731,037 single nucleotide polymorphisms (SNP), a genome wide interaction study was performed in a discovery sample of 931 unrelated Hispanics, followed by replication in 153 non-Hispanic whites and 257 non-Hispanic blacks. Assuming an additive genetic model, we tested for sex-SNP interactions on cIMT using regression analysis. RESULTS: We did not identify any genome-wide significant SNPs but identified 14 loci with suggestive significance. Specifically, SNP-by-sex interaction was found for rs7616559 within LEKR1 gene (P = 3.5E-06 in Hispanic discovery sample, P = 0.018 in White, and P = 1.3E-06 in combined analysis) and for rs2081015 located within GALNT10 gene (P = 4.5E-06 in Hispanic discovery sample, P = 0.042 in Blacks, and P = 5.3E-07 in combined analysis). For rs7616559 within LEKR1, men had greater cIMT than women in G allele carriers (beta ± SE: 0.044 ± 0.007, P = 4.2E-09 in AG carriers; beta ± SE: 0.064 ± 0.007, P = 6.2E-05 in GG carriers). For rs2081015 within GALNT10, men had greater cIMT than women in C allele carriers (beta ± SE: 0.022 ± 0.007, P = 0.002 in CT carriers; beta ± SE: 0.051 ± 0.008, P = 3.1E-10 in CC carriers). CONCLUSIONS: Our genome-wide interaction analysis reveals multiple loci that may modulate sex difference in cIMT. Of them, genetic variants on LEKR1 and GALNT10 genes have been associated with control of adiposity and weight. Given the consistent findings across different-ethnic groups, further studies are warranted to perform investigations of functional genetic variants in these regions.

Prevalence of alcohol-interactive prescription medication use among current drinkers: United States, 1999 to 2010.

BACKGROUND: The majority of Americans consume alcoholic beverages. Alcohol interacts negatively with numerous commonly prescribed medications. Yet, on a population level, little is known about use of alcohol-interactive (AI) prescription medications among drinkers. The purpose of our study was to determine the prevalence of AI prescription medication use among current drinkers in the U.S. population. METHODS: Data were from the National Health and Nutrition Examination Survey (NHANES 1999 to 2010); 26,657 adults aged ≥20 years had data on past year alcohol consumption and past month prescription medication use. Analyses were adjusted for covariates: age, race/ethnicity, education, marital status, and smoking. Statistical procedures accounted for survey stratification, clustering, and nonresponse. Analyses were weighted to be nationally representative. RESULTS: The unadjusted total prevalence of AI medication use was 42.8% (95% confidence interval [CI] 41.5 to 44.0). Among current drinkers, adjusted prevalence was 41.5% (CI 40.3 to 42.7). Among participants aged ≥65 total prevalence of AI medication use was 78.6% (CI 77.3 to 79.9) and adjusted prevalence among current drinkers was 77.8% (CI 75.7 to 79.7). The AI medications most commonly used by current drinkers were cardiovascular agents, central nervous system agents, and metabolic agents. CONCLUSIONS: Our results suggest that there could be substantial simultaneous exposure to alcohol and AI prescription medications in the U.S. population. Given the adverse health risks of combining alcohol with AI prescription medications, future efforts are needed to collect data to determine actual simultaneous prevalence.

Modeling metabolic syndrome and its association with cognition: the Northern Manhattan study.

Metabolic syndrome (MetS) is a clustering of vascular risk factors and is associated with increased risk of cardiovascular disease. Less is known about the relationship between MetS and cognition. We examined component vascular risk factors of MetS as correlates of different cognitive domains. The Northern Manhattan Study (NOMAS) includes 1290 stroke-free participants from a largely Hispanic multi-ethnic urban community. We used structural equation modeling (SEM) to model latent variables of MetS, assessed at baseline and an average of 10 years later, at which time participants also underwent a full cognitive battery. The two four-factor models, of the metabolic syndrome (blood pressure, lipid levels, obesity, and fasting glucose) and of cognition (language, executive function, psychomotor, and memory), were each well supported (CFI=0.97 and CFI=0.95, respectively). When the two models were combined, the correlation between metabolic syndrome and cognition was -.31. Among the metabolic syndrome components, only blood pressure uniquely predicted all four cognitive domains. After adjusting for age, gender, race/ethnicity, education, smoking, alcohol, and risk factor treatment variables, blood pressure remained a significant correlate of all domains except memory. In this stroke-free race/ethnically diverse community-based cohort, MetS was associated with cognitive function suggesting that MetS and its components may be important predictors of cognitive outcomes. After adjusting for sociodemographic and vascular risk factors, blood pressure was the strongest correlate of cognitive performance. Findings suggest MetS, and in particular blood pressure, may represent markers of vascular or neurodegenerative damage in aging populations.

Serum levels of soluble receptor for advanced glycation end-products and metabolic syndrome: the Northern Manhattan Study.

OBJECTIVE: Recent studies have shown a strong link between serum soluble receptor for advanced glycation end-products (sRAGE) levels and cardiovascular risk factors and disease. What is less clear is the relationship between metabolic risk factors and sRAGE levels. Here, we tested the hypothesis that lower sRAGE levels may be associated with the metabolic syndrome (MetS) in an urban multi ethnic population. MATERIALS/METHODS: From the Northern Manhattan Study (NOMAS), we included 1101 stroke-free participants (mean age: 71 ± 9 years, 60% women, 64% Hispanic, 18% black, 16% white). Serum sRAGE was measured by ELISA. Quantile regression analysis was performed to evaluate the association between sRAGE and MetS components and MetS, after adjusting for sociodemographics, smoking status and kidney function. RESULTS: The median (interquartile) sRAGE was 899 pg/ml (647-1248 pg/ml), 42% had metabolic syndrome. The prevalence of unfavorable metabolic factors was 50% for waist circumference (WC), 81% for blood pressure, 39% for fasting glucose, 35% for reduced high density lipoproteins (HDL), and 23% for triglycerides. After adjustment, the median sRAGE levels were at least 120 pg/ml lower in those who had elevated WC (p<0.0001), blood pressure (p=0.0014), and fasting glucose (p<0.0001), and those who had 2 or more unfavorable metabolic factors. No relationship was seen between sRAGE levels and elevated triglycerides or reduced HDL levels. Interaction and stratified analyses revealed that the association of sRAGE with MetS was more prominent in Hispanics compared to whites, and displaying no association with components of MetS in blacks. CONCLUSIONS: sRAGE levels were mainly associated with MetS factors related to obesity, diabetes and hypertension, and displayed variation with ethnicity in a multi-ethnic population. Further studies of sRAGE, MetS and their relationship to cardiovascular disease are warranted.

Novel genetic variants modify the effect of smoking on carotid plaque burden in Hispanics.

BACKGROUND AND PURPOSE: Smoking greatly increases the risk of atherosclerotic plaque and the effect may vary from individual to individual. A genome-wide scan was performed for smoking×single nucleotide polymorphism (SNP) interactions on carotid plaque burden (CPB) to identify the potential genetic moderators in Hispanics. METHODS: Carotid B-mode ultrasonography and genotyping by the Affymetrix 6.0 chip were performed in a discovery sample of 665 Caribbean Hispanics, followed by replication analyses in 264 Caribbean Hispanics. CPB was expressed as the sum of plaque areas over the segments in common and internal carotid arteries and bifurcation. Smoking was classified as 0, <20, and ≥20 cigarette pack-years. Assuming an additive genetic model, regression analysis was conducted to test for smoking×SNP interaction on the cube root transformed CPB while controlling for age, sex, and the top 3 principal components of ancestry. RESULTS: Two SNPs showed a significant interaction with smoking on CPB with the similar effects in both discovery (P<1.0E-5) and replication (P<0.05) populations. Specifically, for SNP rs10205487 within MXD1, more smoking was significantly associated with greater CPB in A allele carriers (beta±SE: 0.24±0.08, P=0.005 in AG carriers; beta±SE: 0.48±0.12, P=0.0002 in AA carriers) but not in GG (P=0.06). For SNP rs7001413 within LY96 and JPH1, more smoking was significantly associated with greater CPB in GG carriers (beta±SE: 0.24±0.06, P=6.8E-5) but not in T carriers (P=0.06). CONCLUSIONS: Our study suggests that genetic variants may modulate the effect of smoking on CPB and highlights several genes for further investigation of their role in atherosclerosis, especially in smoking population.

Efficacy and dose-dependent safety of intra-arterial delivery of mesenchymal stem cells in a rodent stroke model.

Intra-arterial (IA) delivery of mesenchymal stem cells (MSCs) for acute ischemic stroke is attractive for clinical translation. However, studies using rat model of stroke have demonstrated that IA MSCs delivery can decrease middle cerebral artery (MCA) flow, which may limit its clinical translation. The goal of this study is to identify a dose of IA MSCs (maximum tolerated dose; MTD) that does not compromise MCA flow and evaluate its efficacy and optimal timing in a rat model of reversible middle cerebral artery occlusion (rMCAo). We sought to determine if there is a difference in efficacy of acute (1 h) versus sub-acute (24 h) IA MSCs treatment after rMCAo. Adult female Sprague-Dawley rats underwent rMCAo (90 min) and an hour later a single dose of MSCs (at de-escalating doses 1 × 10(6), 5 × 10(5), 2 × 10(5), 1 × 10(5) and 5 × 10(4)) was given using IA route. MSCs were suspended in phosphate buffered saline (PBS) and PBS alone was used for control experiments. We measured the percent change in mean laser Doppler flow signal over the ipsilateral MCA in de-escalating doses groups to determine MTD. The results demonstrated that the lowering of IA MSC dose to 1 × 10(5) and below did not compromise MCA flow and hence an IA MSC dose of 1 × 10(5) considered as MTD. Subsequently, 1 h and 24 h after rMCAo, rats were treated with IA MSCs or PBS. The 24 h delivery of IA MSCs significantly improved neurodeficit score and reduced the mean infarct volume at one month as compared to control, but not the 1 h delivery. Overall, this study suggests that the IA delivery of MSCs can be performed safely and efficaciously at the MTD of 1 × 10(5) delivered at 24 hours in rodent model of stroke.

Genome-wide interaction study identifies RCBTB1 as a modifier for smoking effect on carotid intima-media thickness.

OBJECTIVE: Carotid intima-media thickness (cIMT), a marker for atherosclerosis, is affected by smoking and has substantial interindividual variation. We sought to identify the genetic moderators influencing the effect of smoking on cIMT. APPROACH AND RESULTS: With a multistage design using 722 379 single nucleotide polymorphisms (SNP), a genome-wide interaction study was performed in a discovery sample of 669 Hispanics, followed by replication in 589 subjects (264 Hispanics, 172 non-Hispanic blacks, 153 non-Hispanic whites). Assuming an additive genetic model, regression analysis was performed to test for smoking-SNP interaction on cIMT while controlling for age, sex, and the top 3 principal components of ancestry. The strongest interaction in Hispanics was found with a synonymous splicing SNP (rs3751383) in exon 9 of RCBTB1 (P=2.5e(-6) in discovery sample; P=0.01 in the Hispanic replication sample; P<8.8e(-9) in the combined Hispanic sample). Stratification analysis in the combined Hispanic sample showed that smoking had no effect on cIMT among rs3751383 G homozygote (P=0.15), a moderate effect among rs3751383 heterozygote (P=0.01), and a strong effect among rs3751383 A homozygote (P=2.1e(-7)). A consistent trend was observed in the non-Hispanic white and black data sets, leading to an interaction effect of P<2.9e(-9) in the meta-analysis of all 1258 subjects. CONCLUSIONS: Our study represents the first genome-wide smoking-SNP interaction study of cIMT and identifies RCBTB1 as a modifier of the smoking effect on cIMT. Testing for gene-environment interactions can help uncover genetic factors that contribute to the interindividual variation in response to the same environmental exposure.

Traditional risk factors are not major contributors to the variance in carotid intima-media thickness.

BACKGROUND AND PURPOSE: Carotid intima-media thickness (cIMT) was a widely accepted ultrasound marker of subclinical atherosclerosis in the past. Although traditional risk factors may explain ≈50% of the variance in plaque burden, they may not explain such a high proportion of the variance in IMT, especially when measured in plaque-freel ocations. We aimed this study to identify individuals with cIMT unexplained by traditional risk factors for future environmental and genetic research. METHODS: As part of the Northern Manhattan Study, 1790 stroke-free individuals (mean age, 69±9 years; 60% women; 61% Hispanic; 19% black; 18% white) were assessed for cIMT using B-mode carotid ultrasound. Multiple linear regression models were evaluated: (1) incorporating prespecified traditional risk factors; and (2) including less traditional factors, such as inflammation biomarkers, adiponectin, homocysteine, and kidney function. Standardized cIMT residual scores were constructed to select individuals with unexplained cIMT. RESULTS: Mean total cIMT was 0.92±0.09 mm. The traditional model explained 11% of the variance in cIMT. Age (7%), male sex (3%), glucose (<1%), pack-years of smoking (<1%), and low-density lipoprotein cholesterol (<1%) were significant contributing factors. The model, including inflammatory biomarkers, explained 16% of the variance in cIMT. Adiponectin was the only additional significant contributor to the variance in cIMT. We identified 358 individuals (20%) with cIMT unexplained by the investigated risk factors. CONCLUSIONS: Vascular risk factors explain only a small proportion of variance in cIMT. Identification of novel genetic and environmental factors underlying unexplained subclinical atherosclerosis is of utmost importance for future effective prevention of vascular disease.