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1.  Teaching Children to Cross Streets Safely: A Randomized Controlled Trial 
Child pedestrian injury is a global public health challenge. This randomized controlled trial considered comparative efficacy of individualized streetside training, training in a virtual pedestrian environment, training using videos and websites, plus no-training control, to improve children’s street-crossing ability.
Pedestrian safety was evaluated among 231 seven- and eight-year-olds using both streetside (field) and laboratory-based (virtual environment) trials prior to intervention group assignment, immediately post-training, and six months post-training. All training groups received six 30-minute sessions. Four outcomes assessed pedestrian safety: start delay (temporal lag before initiating crossing), hits/close calls (collisions/near-misses with vehicles in simulated crossings), attention to traffic (looks left and right, controlled for time), and missed opportunities (safe crossing opportunities that were missed).
Results showed training in the virtual pedestrian environment and especially individualized streetside training resulted in safer pedestrian behavior post-intervention and at follow-up. As examples, children trained streetside entered safe traffic gaps more quickly post-training than control group children and children trained streetside or in the virtual environment had somewhat fewer hits/close calls in post-intervention VR trials. Children showed minimal change in attention to traffic post-training. Children trained with videos/websites showed minimal learning.
Both individualized streetside training and training within virtual pedestrian environments may improve 7- and 8-year-olds’ street-crossing safety. Individualized training has limitations of adult time and labor. Virtual environment training has limitations of accessibility and cost. Given the public health burden of child pedestrian injuries, future research should explore innovative strategies for effective training that can be broadly disseminated.
PMCID: PMC4101996  PMID: 24447187
pedestrian; street-crossing; injury; safety; randomized controlled trial
2.  Performance of the NINDS-CSN 5-Minute Protocol in a National Population-Based Sample 
In 2006, the National Institute of Neurological Disorders and Stroke-Canadian Stroke Network (NINDS-CSN) Vascular Cognitive Impairment Harmonization Standards recommended a 5-Minute Protocol as a brief screening instrument for vascular cognitive impairment (VCI). We report demographically adjusted norms for the 5-Minute Protocol and its relation to other measures of cognitive function and cerebrovascular risk factors.
Cross-sectional analysis of 7,199 stroke-free adults in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study on the NINDS-CSN 5-Minute Protocol score.
Total scores on the 5-Minute Protocol were inversely correlated with age and positively correlated with years of education, and performance on the Six-Item Screener, Word List Learning, and Animal Fluency (all p-values<0.001). Higher cerebrovascular risk on the Framingham Stroke Risk Profile (FSRP) was associated with lower total 5-Minute Protocol scores (p<0.001). The 5-Minute Protocol also differentiated between participants with and without confirmed stroke and with and without stroke symptom histories (p<0.001).
The NINDS-CSN 5-Minute Protocol is a brief, easily administered screening measure that is sensitive to cerebrovascular risk and offers a valid method of screening for cognitive impairment in populations at risk for VCI.
PMCID: PMC4452126  PMID: 25166350
screening; cerebrovascular disorders; epidemiology; memory; semantic fluency; depression
3.  Assessing the Performance of the Framingham Stroke Risk Score in the REGARDS Cohort 
Background and Purpose
The most well-known stroke risk score is the Framingham Stroke Risk Score (FSRS), which was developed during the higher stroke risk period of the 1990’s, and has not been validated for blacks. We assessed the performance of the FSRS among participants in the Reasons for Geographic And Racial Differences in Stroke (REGARDS) study to determine whether it is useful in both blacks and whites.
Expected annualized stroke rates from the FSRS were compared to observed stroke rates overall and within strata defined by FSRS risk factors (age, sex, systolic blood pressure, use of antihypertensive medications, diabetes, smoking, atrial fibrillation, left ventricular hypertrophy and prevalent coronary heart disease).
Among 27,748 participants stroke-free at baseline, 715 stroke events occurred over 5.6 years of follow-up. FSRS-estimated incidence rates of stroke were 1.6 times higher than observed for black men, 1.9 times higher for white men, 1.7 times higher for black women and 1.7 times higher for white women. This overestimation was consistent among most subgroups of FSRS factors, although the magnitude of overestimation varied by the risk factor assessed.
While higher FSRS was associated with higher stroke risk, the FSRS overestimated observed stroke rates in this study, particularly in certain subgroups. This may be due to temporal declines in stroke rates, secular trends in prevention treatments, or differences in populations studied. More accurate estimates of event rates are critical for planning research, including clinical trials, and targeting health-care efforts.
PMCID: PMC4102650  PMID: 24736237
Framingham Stroke Risk Score; REGARDS
4.  Training Children in Pedestrian Safety: Distinguishing Gains in Knowledge from Gains in Safe Behavior 
The journal of primary prevention  2014;35(3):151-162.
Pedestrian injuries contribute greatly to child morbidity and mortality. Recent evidence suggests that training within virtual pedestrian environments may improve children’s street crossing skills, but may not convey knowledge about safety in street environments. We hypothesized that (a) children will gain pedestrian safety knowledge via videos/software/internet websites, but not when trained by virtual pedestrian environment or other strategies; (b) pedestrian safety knowledge will be associated with safe pedestrian behavior both before and after training; and (c) increases in knowledge will be associated with increases in safe behavior among children trained individually at streetside locations, but not those trained by means of other strategies. We analyzed data from a randomized controlled trial evaluating pedestrian safety training. We randomly assigned 240 children ages 7–8 to one of four training conditions: videos/software/internet, virtual reality (VR), individualized streetside instruction, or a no-contact control. Both virtual and field simulations of street crossing at 2-lane bi-directional mid-block locations assessed pedestrian behavior at baseline, post-training, and 6-month follow-up. Pedestrian knowledge was assessed orally on all three occasions. Children trained by videos/software/internet, and those trained individually, showed increased knowledge following training relative to children in the other groups (ps < 0.01). Correlations between pedestrian safety knowledge and pedestrian behavior were mostly non-significant. Correlations between change in knowledge and change in behavior from pre- to post-intervention also were non-significant, both for the full sample and within conditions. Children trained using videos/software/internet gained knowledge but did not change their behavior. Children trained individually gained in both knowledge and safer behavior. Children trained virtually gained in safer behavior but not knowledge. If VR is used for training, tools like videos/internet might effectively supplement training. We discovered few associations between knowledge and behavior, and none between changes in knowledge and behavior. Pedestrian safety knowledge and safe pedestrian behavior may be orthogonal constructs that should be considered independently for research and training purposes.
PMCID: PMC4005841  PMID: 24573688
Injury; Walking; Children; Virtual reality
5.  Quality of life after lacunar stroke: the Secondary Prevention of Small Subcortical Strokes Study 
We sought to describe the course and predictors of QOL after lacunar stroke. We hypothesized that there is a decline in QOL after recovery from lacunar stroke.
SPS3 is a clinical trial in lacunar stroke patients with annual assessments of QOL with the Stroke Specific QOL score (SSQOL). The overall score was used and analyzed as a continuous variable (range 0–5). We fit linear mixed models to assess the trend in QOL over time, assuming linearity of time, and adjusted for demographics, medical risk factors, cognitive factors, and functional status in univariable and multivariable models.
Among 2870 participants, mean age was 63.4 years (SD 10.7), 63% were male, 51% White, 32% Hispanic, 36% had college education, 36% had diabetes, 89% had hypertension, and 10% had prior stroke. Mean post-stroke Barthel index score (BI) was 95.4 (assessed on average 6 months after stroke). In the final multivariable model, there was an average increase in QOL of 0.6% per year, and factors associated with decline in QOL over time included age (−0.0003 per year, p<0.0001), any college education (−0.0013 per year, 0.01), prior stroke (−0.004 per year, p<0.0001), and BI (−0.0002 per year, p<0.0001).
In this clinical trial of lacunar stroke patients, there was a slight annual increase in QOL overall, and age, level of education, and prior stroke were associated with changes in QOL over time. Multiple strokes may cause decline in QOL over time in the absence of recurrent events.
PMCID: PMC4002657  PMID: 24177006
Lacunar stroke; quality of life; recovery
7.  The Relationship Between Long-Term Sunlight Radiation and Cognitive Decline in the REGARDS Cohort Study 
Sunlight may be related to cognitive function through vitamin D metabolism or circadian rhythm regulation.
Fifteen-year residential history merged with satellite and ground monitor data were used to determine sunlight (solar radiation) and air temperature exposure for a cohort of 19,896 cognitively intact black and white participants aged 45+ from the 48 contiguous United States. 15, 10, 5, 2, and 1-year exposures were used to predict cognitive status at the most recent assessment in logistic regression models.
1-year insolation and maximum temperatures were chosen as exposure measures. Solar radiation interacted with temperature, age, and gender in its relationships with incident cognitive impairment. After adjustment for covariates, the odds ratios of cognitive decline for solar radiation exposure below the median vs. above the median in the 3rd tertile of maximum temperatures was 1.88 (95% CI: 1.24, 2.85), the 2nd tertile was 1.33 (95% CI: 1.09, 1.62), and 1st tertile was 1.22 (95% CI: 0.92, 1.60). We also found that participants under 60 year old had an OR=1.63 (95% CI: 1.20, 2.22), those 60 to 80 years old had an OR=1.18 (95% CI: 1.02, 1.36), and those over 80 years old had an OR=1.05 (0.80, 1.37). Lastly, we found that males had an OR=1.43 (95% CI: 1.22, 1.69), and females had an OR=1.02 (0.87, 1.20).
We found that lower levels of solar radiation were associated with increased odds of incident cognitive impairment.
PMCID: PMC3665728  PMID: 23340910
Sunlight; Temperature; Weather; Climate; Remote Sensing Technology; Cognition
8.  Predictors of stroke recurrence in patients with recent lacunar stroke and response to interventions according to risk status: Secondary Prevention of Small Subcortical Strokes (SPS3) trial 
Among participants in the Secondary Prevention of Small Subcortical Strokes randomized trial, we sought to identify patients with high vs. low rates of recurrent ischemic stroke and to assess effects of aggressive blood pressure control and dual antiplatelet therapy according to risk status.
Multivariable analyses of 3020 participants with recent MRI-defined lacunar strokes followed for a mean of 3.7 years with 243 recurrent ischemic strokes. Results: Prior symptomatic lacunar stroke or TIA (HR 2.2, 95%CI 1.6,2.9), diabetes (HR 2.0, 95%CI 1.5,2.5), Black race (HR 1.7, 95%CI 1.3,2.3) and male sex (HR 1.5, 95%CI 1.1,1.9) were each independently predictive of recurrent ischemic stroke. Recurrent ischemic stroke occurred at a rate of 4.3%/yr (95% CI 3.3, 5.5) in patients with prior symptomatic lacunar stroke or TIA (15% of the cohort), 3.1%/yr (95%CI 2.6, 3.9) in those with >1 of the other 3 risk factors (27% of the cohort), and 1.3%/yr (95%CI 1.0,1.7) in those with 0 to 1 risk factors (58% of the cohort). There were no significant interactions between treatment effects and stroke risk status.
In this large, carefully followed cohort of patients with recent lacunar stroke and aggressive blood pressure management, prior symptomatic lacunar ischemia, diabetes, Black race and male sex independently predicted ischemic stroke recurrence. The effects of blood pressure targets and dual antiplatelet therapy were similar across the spectrum of independent risk factors and recurrence risk.
PMCID: PMC3858405  PMID: 23800503
lacunar infarct; cerebral small vessel disease; prognosis; recurrent stroke
9.  Usability and Feasibility of an Internet-Based Virtual Pedestrian Environment to Teach Children to Cross Streets Safely 
Virtual reality  2013;18(1):5-11.
Child pedestrian injury is a preventable global health challenge. Successful training efforts focused on child behavior, including individualized streetside training and training in large virtual pedestrian environments, are laborious and expensive. This study considers the usability and feasibility of a virtual pedestrian environment “game” application to teach children safe street-crossing behavior via the internet, a medium that could be broadly disseminated at low cost. Ten 7- and 8-year-old children participated. They engaged in an internet-based virtual pedestrian environment and completed a brief assessment survey. Researchers rated children's behavior while engaged in the game. Both self-report and researcher observations indicated the internet-based system was readily used by the children without adult support. The youth understood how to engage in the system and used it independently and attentively. The program also was feasible. It provided multiple measures of pedestrian safety that could be used for research or training purposes. Finally, the program was rated by children as engaging and educational. Researcher ratings suggested children used the program with minimal fidgeting or boredom. The pilot test suggests an internet-based virtual pedestrian environment offers a usable, feasible, engaging, and educational environment for child pedestrian safety training. If future research finds children learn the cognitive and perceptual skills needed to cross streets safely within it, internet-based training may provide a low-cost medium to broadly disseminate child pedestrian safety training. The concept may be generalized to other domains of health-related functioning such as teen driving safety, adolescent sexual risk-taking, and adolescent substance use.
PMCID: PMC3963181  PMID: 24678263
pedestrian; safety; injury; evaluation; Internet
10.  C-reactive Protein as a Prognostic Marker after Lacunar Stroke: The Levels of Inflammatory Markers in the Treatment of Stroke (LIMITS) Study 
Background and Purpose
Inflammatory biomarkers predict incident and recurrent cardiac events, but their relationship to stroke prognosis is uncertain. We hypothesized that high-sensitivity C-reactive protein (hsCRP) predicts recurrent ischemic stroke after recent lacunar stroke.
Levels of Inflammatory Markers in the Treatment of Stroke (LIMITS) was an international, multicenter, prospective ancillary biomarker study nested within Secondary Prevention of Small Subcortical Strokes (SPS3), a Phase III trial in patients with recent lacunar stroke. Patients were assigned in factorial design to aspirin versus aspirin plus clopidogrel, and higher versus lower blood pressure targets. Patients had blood samples collected at enrollment, and hsCRP measured using nephelometry at a central laboratory. Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals (HR, 95%CI) for recurrence risks before and after adjusting for demographics, comorbidities, and statin use.
Among 1244 lacunar stroke patients (mean 63.3 ± 10.8 years), median hsCRP was 2.16 mg/L. There were 83 recurrent ischemic strokes (including 45 lacunes), and 115 major vascular events (stroke, myocardial infarction, vascular death). Compared with the bottom quartile, those in the top quartile (hsCRP >4.86 mg/L) were at increased risk of recurrent ischemic stroke (unadjusted HR 2.54, 95%CI 1.30–4.96), even after adjusting for demographics and risk factors (adjusted HR 2.32, 95%CI 1.15–4.68). HsCRP predicted increased risk of major vascular events (top quartile adjusted HR 2.04, 95%CI 1.14–3.67). There was no interaction with randomized antiplatelet treatment.
Among recent lacunar stroke patients, hsCRP levels predict risk of recurrent strokes and other vascular events. HsCRP did not predict response to dual antiplatelets.
PMCID: PMC4114338  PMID: 24523037
stroke; lacune; inflammation; C-reactive protein; prognosis
11.  American Heart Association's Life's Simple 7 and Risk of Venous Thromboembolism: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study 
The American Heart Association's Life's Simple 7 metric is being used to track the population's cardiovascular health (CVH) toward a 2020 goal for improvement. The metric includes body mass index (BMI), blood pressure, cholesterol, glucose, physical activity (PA), cigarette smoking, and diet. We hypothesized a lower risk of venous thromboembolism (VTE) with favorable Life's Simple 7 scores.
Methods and Results
REGARDS recruited 30 239 black and white participants ≥45 years of age across the United States in 2003–2007. A 14‐point summary score for Life's Simple 7 classified participants into inadequate (0 to 4 points), average (5 to 9 points), and optimal (10 to 14 points) categories. Hazard ratios (HRs) of incident VTE were calculated for these categories, adjusting for age, sex, race, income, education, and region of residence. For comparison, HRs of VTE were calculated using the Framingham 10‐year coronary risk score. There were 263 incident VTE cases over 5.0 years of follow‐up; incidence rates per 1000 person‐years declined from 2.9 (95% confidence interval [CI], 2.3 to 3.7) among those in the inadequate category to 1.8 (95% CI, 1.4 to 2.4) in the optimal category. Compared to the inadequate category, participants in the average category had a 38% lower VTE risk (95% CI, 11 to 57) and participants in the optimal category had a 44% lower risk (95% CI, 18 to 62). The individual score components related to lower VTE risk were ideal PA and BMI. There was no association of Framingham Score with VTE.
Life's Simple 7, a CVH metric, was associated with reduced VTE risk. Findings suggest that efforts to improve the population's CVH may reduce VTE incidence.
PMCID: PMC4392432  PMID: 25725088
epidemiology; risk; thrombosis
12.  Age Differences in the Association of Obstructive Sleep Apnea Risk with Cognition and Quality of Life 
Journal of sleep research  2013;23(1):69-76.
Using a sample of 2925 stroke-free participants drawn from a national population-based study, we examined cross-sectional associations of obstructive sleep apnea risk (OSA) with cognition and quality of life and whether these vary with age, while controlling for demographics and co-morbidities. Included participants from the REasons for Geographic And Racial Differences in Stroke Study were aged 47-93. OSA risk was categorized as high or low based on responses to the Berlin Sleep Questionnaire. Cognitive function was assessed with standardized fluency and recall measures. Depressive symptoms were assessed with the four-item Center for Epidemiologic Studies Depression Scale. Health-related Quality of Life (HRQoL) was assessed with the Medical Outcomes Study Short Form-12 (SF-12). MANCOVA statistics were applied separately to the cognitive and quality of life dependent variables while accounting for potential confounders (demographics, co-morbidities). In fully adjusted models, those at high risk for OSA had significantly lower cognitive scores (Wilks’ Lambda = 0.996, F(3, 2786) = 3.31, p < .05) and lower quality of life (depressive symptoms and HRQoL) (Wilks’ Lambda = 0.989, F(3, 2786) = 10.02, p < .0001). However, some of the associations were age-dependent. Differences in cognition and quality of life between those at high and low obstructive sleep apnea risk were most pronounced during middle age, with attenuated effects after age 70.
PMCID: PMC4147721  PMID: 24033751
Obstructive sleep apnea; Berlin Sleep Questionnaire; cognitive function; depression; health related quality life; age differences
13.  Testing for clustering at many ranges inflates family-wise error rate (FWE) 
Testing for clustering at multiple ranges within a single dataset is a common practice in spatial epidemiology. It is not documented whether this approach has an impact on the type 1 error rate.
We estimated the family-wise error rate (FWE) for the difference in Ripley’s K functions test, when testing at an increasing number of ranges at an alpha-level of 0.05. Case and control locations were generated from a Cox process on a square area the size of the continental US (≈3,000,000 mi2). Two thousand Monte Carlo replicates were used to estimate the FWE with 95% confidence intervals when testing for clustering at one range, as well as 10, 50, and 100 equidistant ranges.
The estimated FWE and 95% confidence intervals when testing 10, 50, and 100 ranges were 0.22 (0.20 - 0.24), 0.34 (0.31 - 0.36), and 0.36 (0.34 - 0.38), respectively.
Testing for clustering at multiple ranges within a single dataset inflated the FWE above the nominal level of 0.05. Investigators should construct simultaneous critical envelopes (available in spatstat package in R), or use a test statistic that integrates the test statistics from each range, as suggested by the creators of the difference in Ripley’s K functions test.
PMCID: PMC4326498  PMID: 25588612
Ripley’s K function; Overall clustering; Point process; Family wise error rate (FWE); Multiple testing
14.  Cognitive Function in Adults Aging with Fabry Disease: A Case–Control Feasibility Study Using Telephone-Based Assessments 
JIMD Reports  2015;18:41-50.
We examined the feasibility of recruiting US adults ≥45 years old with Fabry disease (FD) for telephone assessments of cognitive functioning. A case–control design matched each FD participant on age, sex, race, and education to four participants from a population-based study. Fifty-four participants with FD age 46–72 years were matched to 216 controls. Standardized cognitive assessments, quality of life (QOL), and medical histories were obtained by phone, supplemented by objective indices of comorbidities. Normalized scores on six cognitive tasks were calculated. On the individual tasks, scores on list recall and semantic fluency were significantly lower among FD participants (p-values < 0.05), while scores on the other four tasks did not differ. After averaging each participant’s normalized scores to form a cognitive composite, we examined group differences in composite scores, before and after adjusting for multiple covariates using generalized estimating equations. The composite scores of FD cases were marginally lower than controls before covariate adjustments (p = 0.08). QOL and mental health variables substantially attenuated this finding (p = 0.75), highlighting the influence of these factors on cognition in FD. Additional adjustment for cardiovascular comorbidities, kidney function, and stroke had negligible impact, despite higher prevalence in the FD sample. Telephone-based cognitive assessment methods are feasible among adults with FD, affording access to a geographically dispersed sample. Although decrements in discrete cognitive domains were observed, the overall cognitive function of older adults with FD was equivalent to that of well-matched controls before and after accounting for multiple confounding variables.
PMCID: PMC4361921  PMID: 25567791
15.  Environmental Public Health Applications Using Remotely Sensed Data 
Geocarto international  2012;29(1):85-98.
We describe a remote sensing and GIS-based study that has three objectives: (1) characterize fine particulate matter (PM2.5), insolation and land surface temperature using NASA satellite observations, EPA ground-level monitor data and North American Land Data Assimilation System (NLDAS) data products on a national scale; (2) link these data with public health data from the REasons for Geographic And Racial Differences in Stroke (REGARDS) national cohort study to determine whether these environmental risk factors are related to cognitive decline, stroke and other health outcomes; and (3) disseminate the environmental datasets and public health linkage analyses to end users for decision-making through the Centers for Disease Control and Prevention (CDC) Wide-ranging Online Data for Epidemiologic Research (WONDER) system. This study directly addresses a public health focus of the NASA Applied Sciences Program, utilization of Earth Sciences products, by addressing issues of environmental health to enhance public health decision-making.
PMCID: PMC4044865  PMID: 24910505
remote sensing; GIS; fine particulates; insolation; heat; public health
16.  The Secondary Prevention of Small Subcortical Strokes (SPS3) study 
Small subcortical strokes, also known as lacunar strokes, comprise more than 25% of brain infarcts, and the underlying vasculopathy is the most common cause of vascular cognitive impairment. How to optimally prevent stroke recurrence and cognitive decline in S3 patients is unclear. The aim of the Secondary Prevention of Small Subcortical Strokes study (Trial registration: NCT00059306) is to define strategies for reducing stroke recurrence, cognitive decline, and major vascular events.
Secondary Prevention of Small Subcortical Strokes is a randomised, multicentre clinical trial (n = 3000) being conducted in seven countries, and sponsored by the US NINDS/NIH. Patients with symptomatic small subcortical strokes in the six-months before and an eligible lesion on magnetic resonance imaging are simultaneously randomised, in a 2 × 2 factorial design, to antiplatelet therapy – 325 mg aspirin daily plus 75 mg clopidogrel daily, vs. 325 mg aspirin daily plus placebo, double-blind – and to one of two levels of systolic blood pressure targets –‘intensive’ (<130 mmHg) vs. ‘usual’ (130–149 mmHg). Participants are followed for an average of four-years. Time to recurrent stroke (ischaemic or haemorrhagic) is the primary outcome and will be analysed separately for each intervention. The secondary outcomes are the rate of cognitive decline and major vascular events. The primary and most secondary outcomes are adjudicated centrally by those unaware of treatment assignment.
Secondary Prevention of Small Subcortical Strokes will address several important clinical and scientific questions by testing two interventions in patients with recent magnetic resonance imaging-defined lacunar infarcts, which are likely due to small vessel disease. The results will inform the management of millions of patients with this common vascular disorder.
PMCID: PMC4214141  PMID: 21371282
antiplatelet therapy; hypertension; lacunar stroke; randomised clinical trial; SPS3
17.  Cognitive impairment in lacunar strokes: The Secondary Prevention of Small Subcortical Strokes (SPS3) Trial 
Annals of neurology  2012;72(3):351-362.
Lacunar strokes are a leading cause of cognitive impairment and vascular dementia. However, adequate characterization of cognitive impairment is lacking. The aim of this study was to estimate the prevalence and characterize the neuropsychological impairment in lacunar stroke patients.
All English-speaking participants in the SPS3 trial (NCT: 00059306) underwent neuropsychological testing at baseline. Raw scores were converted to z-scores using published norms. Those with impairment (z≤-1.5) in memory and/or non-memory domains were classified as having Mild Cognitive Impairment (MCI).
Among the 1636 participants, average z scores on all tests were below zero with the largest deficits seen on tests of episodic memory (range of means -0.65 to -0.92), verbal fluency (mean -0.89), and motor dexterity (mean -2.5). Forty-seven percent were classified as having MCI: 36% amnestic, 37% amnestic multidomain, 28% non-amnestic. Of those with Rankin score 0-1 and Barthel score=100, 41% had MCI. Younger age [odds ratio (OR) per 10-yr increase=0.87], male sex (OR 1.3), less education (OR 0.13-0.66 compared to 0-4 yrs education), post-stroke disability (OR 1.4), and impaired activities of daily living (OR 1.8) were independently associated with MCI.
In this large, well characterized cohort of lacunar stroke patients, MCI was present in nearly half, including many with minimal or no physical disabilities. Cognitive dysfunction in lacunar stroke patients may commonly be overlooked in clinical practice but may be as important as motor and sensory sequelae.
PMCID: PMC4198173  PMID: 23034910
Small subcortical stroke; lacunar stroke; Vascular cognitive impairment; Neuropsychological tests; Mild Cognitive Impairment
18.  Stroke Genetics Network (SiGN) Study: Design and rationale for a genome-wide association study of ischemic stroke subtypes 
Background and Purpose
Meta-analyses of extant genome-wide data illustrate the need to focus on subtypes of ischemic stroke for gene discovery. The NINDS Stroke Genetics Network (SiGN) contributes substantially to meta-analyses that focus on specific subtypes of stroke.
The NINDS Stroke Genetics Network (SiGN) includes ischemic stroke cases from 24 Genetic Research Centers (GRCs), 13 from the US and 11 from Europe. Investigators harmonize ischemic stroke phenotyping using the web-based Causative Classification of Stroke (CCS) system, with data entered by trained and certified adjudicators at participating GRCs. Through the Center for Inherited Diseases Research (CIDR), SiGN plans to genotype 10,296 carefully phenotyped stroke cases using genome-wide SNP arrays, and add to these another 4,253 previously genotyped cases for a total of 14,549 cases. To maximize power for subtype analyses, the study allocates genotyping resources almost exclusively to cases. Publicly available studies provide most of the control genotypes. CIDR-generated genotypes and corresponding phenotypic data will be shared with the scientific community through dbGaP, and brain MRI studies will be centrally archived.
The SiGN consortium, with its emphasis on careful and standardized phenotyping of ischemic stroke and stroke subtypes, provides an unprecedented opportunity to uncover genetic determinants of ischemic stroke.
PMCID: PMC4056331  PMID: 24021684
ischemic stroke; genetics; genomics
19.  Clinical Features and Racial/Ethnic Differences among the 3020 Participants in the Secondary Prevention of Small Subcortical Strokes (SPS3) Trial 
To describe the baseline characteristics, racial/ethnic differences, and geographic differences among participants in the Secondary Prevention of Small Subcortical Strokes (SPS3) study.
The SPS3 trial enrolled patients with a symptomatic small subcortical stroke (lacunar stroke) within the prior 6 months and an eligible lesion on MRI, who were randomized, in a factorial design, to antiplatelet therapy (aspirin 325 mg daily plus clopidogrel 75 mg daily vs. aspirin 325 mg daily plus placebo) and to one of two levels of systolic blood pressure targets (“intensive” (<130 mmHg) vs. “usual” (130–149 mmHg)).
Among the 3020 participants recruited from 81 clinical sites in 8 countries, the mean age was 63 years, 63% were men, 75% had a history of hypertension, and 37% were diabetic. Fifty-one percent were White, 30% Hispanic, and 16% Black. Black participants were younger (mean age 58 years vs. 64 years, p<0.001) and more often had hypertension (95% vs. 89%, p<0.001) than White participants. Hispanic and Black participants more often had diabetes than White participants (42%, 40% vs. 32% respectively, both p<0.001). Tobacco smoking at the time of qualifying stroke was much more frequent among Spanish participants (32%) than those from North America (22%) or Latin America (8%) (p<0.001); systolic blood pressure at study entry was 5 mmHg lower among Spanish vs. North American participants (p<0.01).
The SPS3 cohort is the largest MRI-defined series of patients with S3. Among the racially/ethnically diverse SPS3 participants, there are important differences in patient features and vascular risk factors could influence prognosis for recurrent stroke and response to interventions.
Clinical Trial Registration Information
The SPS3 study is registered on (NCT00059306).
PMCID: PMC3970545  PMID: 22516427
20.  Racial and Regional Differences in Venous Thromboembolism in the United States in Three Cohorts 
Circulation  2014;129(14):1502-1509.
Blacks are thought to have a higher risk of venous thromboembolism (VTE) than whites however prior studies are limited to administrative databases that lack specific information on VTE risk factors or have limited geographic scope.
Methods and Results
We ascertained VTE from three prospective studies; the Atherosclerosis Risk in Communities study (ARIC), the Cardiovascular Health Study (CHS), and the REasons for Geographic and Racial Differences in Stroke study (REGARDS). We tested the association of race with VTE using Cox proportional hazard models adjusted for VTE risk factors. Over 438,090 person-years, 916 incident VTE events (302 in blacks) occurred in 51,149 individuals (17,318 blacks) followed. In risk factor-adjusted models, blacks had a higher rate of VTE than whites in CHS (HR 1.81; 95% CI 1.20, 2.73) but not ARIC (HR 1.21; 95% CI 0.96, 1.54). In REGARDS, there was a significant region by race interaction (p = 0.01); blacks in the southeast had a significantly higher rate of VTE than blacks in the rest of the US (HR 1.63; 95% CI 1.08, 2.48) which was not seen in whites (HR 0.83; 95% CI 0.61, 1.14).
The association of race with VTE differed in each cohort, which may reflect the different time periods of the studies and/or different regional rates of VTE. Further study of environmental and genetic risk factors for VTE are needed to determine which underlie racial and perhaps regional differences in VTE.
PMCID: PMC4098668  PMID: 24508826
Venous Thrombosis; Epidemiology; Race
21.  Report of stroke-like symptoms predicts incident cognitive impairment in a stroke-free cohort 
Neurology  2013;81(2):113-118.
The present study characterizes the relationship between report of stroke symptoms (SS) or TIA and incident cognitive impairment in the large biracial cohort of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study.
The REGARDS Study is a population-based, biracial, longitudinal cohort study that has enrolled 30,239 participants from the United States. Exclusion of those with baseline cognitive impairment, stroke before enrollment, or incomplete data resulted in a sample size of 23,830. Participants reported SS/TIA on the Questionnaire for Verifying Stroke-free Status at baseline and every 6 months during follow-up. Incident cognitive impairment was detected using the Six-item Screener, which was administered annually.
Logistic regression found significant association between report of SS/TIA and subsequent incident cognitive impairment. Among white participants, the odds ratio for incident cognitive impairment was 2.08 (95% confidence interval: 1.81, 2.39) for those reporting at least one SS/TIA compared with those reporting no SS/TIA. Among black participants, the odds ratio was 1.66 (95% confidence interval: 1.45, 1.89) using the same modeling. The magnitude of impact was largest among those with fewer traditional stroke risk factors, particularly among white participants.
Report of SS/TIA showed a strong association with incident cognitive impairment and supports the use of the Questionnaire for Verifying Stroke-free Status as a quick, low-cost instrument to screen for people at increased risk of cognitive decline.
PMCID: PMC3770175  PMID: 23783751
Heart failure (HF) is associated with an overall stroke rate that is too low to justify anticoagulation in all patients. This study was conducted to determine if vascular risk factors can identify a subgroup of individuals with heart failure with a stroke rate high enough to warrant anticoagulation. The REGARDS study is a population-based cohort of US adults aged ≥45 years. Participants are contacted every six months by telephone for self- or proxy-reported stroke and medical records are retrieved and adjudicated by physicians. Participants were characterized into three groups: HF without atrial fibrillation (AF), AF with or without HF, and neither HF nor AF. Cardiovascular risk factors at baseline were compared between participants with and without incident stroke in HF and AF. Stroke incidence was assessed in risk factor subgroups in HF participants. Of the 30,239 participants, those with missing/anomalous data were excluded. Of the remaining 28,832, 1,360 (5%) had HF without AF, 2,528 (9%) had AF, and 24,944 (86%) had neither. Prior stroke/TIA (p=0.0004), diabetes (DM) (p=0.03) and higher systolic blood pressure (p=0.046), were associated with increased stroke risk in participants with HF without AF. In participants with HF without AF, stroke incidence was highest in those with prior stroke/TIA and DM (2.4 [1.1, 4.0] per hundred personyears). The combination of prior stroke/TIA and DM increases the incidence of stroke in participants with HF without AF. No analyzed subgroup had a stroke rate high enough to make it likely that the benefits of warfarin would outweigh the risks.
PMCID: PMC3326204  PMID: 22142776
23.  Sunlight exposure and cardiovascular risk factors in the REGARDS study: a cross-sectional split-sample analysis 
BMC Neurology  2014;14:133.
Previous research has suggested that vitamin D and sunlight are related to cardiovascular outcomes, but associations between sunlight and risk factors have not been investigated. We examined whether increased sunlight exposure was related to improved cardiovascular risk factor status.
Residential histories merged with satellite, ground monitor, and model reanalysis data were used to determine previous-year sunlight radiation exposure for 17,773 black and white participants aged 45+ from the US. Exploratory and confirmatory analyses were performed by randomly dividing the sample into halves. Logistic regression models were used to examine relationships with cardiovascular risk factors.
The lowest, compared to the highest quartile of insolation exposure was associated with lower high-density lipoprotein levels in adjusted exploratory (−2.7 mg/dL [95% confidence interval: −4.2, −1.2]) and confirmatory (−1.5 mg/dL [95% confidence interval: −3.0, −0.1]) models. The lowest, compared to the highest quartile of insolation exposure was associated with higher systolic blood pressure levels in unadjusted exploratory and confirmatory, as well as the adjusted exploratory model (2.3 mmHg [95% confidence interval: 0.8, 3.8]), but not the adjusted confirmatory model (1.6 mg/dL [95% confidence interval: −0.5, 3.7]).
The results of this study suggest that lower long-term sunlight exposure has an association with lower high-density lipoprotein levels. However, all associations were weak, thus it is not known if insolation may affect cardiovascular outcomes through these risk factors.
PMCID: PMC4075775  PMID: 24946776
Sunlight; Temperature; Weather; Climate; Environment; Blood pressure; Lipids and lipoproteins
24.  The American Heart Association Life's Simple 7 and Incident Cognitive Impairment: The REasons for Geographic And Racial Differences in Stroke (REGARDS) Study 
Life's Simple 7 is a new metric based on modifiable health behaviors and factors that the American Heart Association uses to promote improvements to cardiovascular health (CVH). We hypothesized that better Life's Simple 7 scores are associated with lower incidence of cognitive impairment.
Methods and Results
For this prospective cohort study, we included REasons for Geographic And Racial Differences in Stroke (REGARDS) participants aged 45+ who had normal global cognitive status at baseline and no history of stroke (N=17 761). We calculated baseline Life's Simple 7 score (range, 0 to 14) based on smoking, diet, physical activity, body mass index, blood pressure, total cholesterol, and fasting glucose. We identified incident cognitive impairment using a 3‐test measure of verbal learning, memory, and fluency obtained a mean of 4 years after baseline. Relative to the lowest tertile of Life's Simple 7 score (0 to 6 points), odds ratios of incident cognitive impairment were 0.65 (0.52, 0.81) in the middle tertile (7 to 8 points) and 0.63 (0.51, 0.79) in the highest tertile (9 to 14 points). The association was similar in blacks and whites, as well as outside and within the Southeastern stroke belt region of the United States.
Compared with low CVH, intermediate and high CVH were both associated with substantially lower incidence of cognitive impairment. We did not observe a dose‐response pattern; people with intermediate and high levels of CVH had similar incidence of cognitive impairment. This suggests that even when high CVH is not achieved, intermediate levels of CVH are preferable to low CVH.
PMCID: PMC4309046  PMID: 24919926
cardiovascular disease prevention; cardiovascular disease risk factors; cognitive impairment; cognitive tests; lifestyle
25.  Effect of duration and age at exposure to the Stroke Belt on incident stroke in adulthood 
Neurology  2013;80(18):1655-1661.
To assess whether there are differences in the strength of association with incident stroke for specific periods of life in the Stroke Belt (SB).
The risk of stroke was studied in 24,544 black and white stroke-free participants, aged 45+, in the Reasons for Geographic and Racial Differences in Stroke study, a national population-based cohort enrolled 2003–2007. Incident stroke was defined as first occurrence of stroke over an average 5.8 years of follow-up. Residential histories (city/state) were obtained by questionnaire. SB exposure was quantified by combinations of SB birthplace and current residence and proportion of years in SB during discrete age categories (0–12, 13–18, 19–30, 31–45, last 20 years) and entire life. Proportional hazards models were used to establish association of incident stroke with indices of exposure to SB, adjusted for demographic, socioeconomic (SES), and stroke risk factors.
In the demographic and SES models, risk of stroke was significantly associated with proportion of life in the SB and with all other exposure periods except birth, ages 31–45, and current residence. The strongest association was for the proportion of the entire life in SB. After adjustment for risk factors, the risk of stroke remained significantly associated only with proportion of residence in SB in adolescence (hazard ratio 1.17, 95% confidence interval 1.00–1.37).
Childhood emerged as the most important period of vulnerability to SB residence as a predictor of future stroke. Improvement in childhood health circumstances should be considered as part of long-term health improvement strategies in the SB.
PMCID: PMC3716470  PMID: 23616168

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