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1.  Developmental Outcomes in Young Children Born to Mothers with West Nile Illness during Pregnancy 
Background
West Nile virus (WNV) infection is associated with acute morbidity and mortality in adults and children. Information on the effects of maternal WNV illness during pregnancy on early childhood development is limited. This study was designed to examine the relationship between maternal WNV illness during pregnancy and birth and developmental outcomes at age 3 years.
Methods
Mother-child participants were identified using a national surveillance registry for women with WNV illness during pregnancy. Maternal and infant health data and relevant family characteristics were obtained through medical record reviews and maternal questionnaires. All infants received ophthalmologic examinations. Child development was evaluated at age 3 years using the Bayley Scales of Infant and Toddler Development–Third Edition (Bayley-III).
Results
As a group, the children’s (N = 11) birth weight, head circumference, and infant ophthalmologic examination results were within age expectations; one child was born preterm (gestational age 36 weeks). Mean (SD) age at the time of Bayley-III testing was 36.7 (3.8) months. The group’s mean performance on the Bayley-III was at or above age level in all domains, but one child showed a mild delay in the Adaptive domain. The variability observed in this sample (1/53 [1.9%] Domain scores < −2.0 SDs) was consistent with expectations based upon the distribution of Bayley-III Domain scores in the general population.
Conclusion
Maternal WNV infection does not appear to be associated with global developmental delays in young children. These results are preliminary, however, and require confirmation in future research.
doi:10.1002/bdra.23297
PMCID: PMC4573576  PMID: 25196266
West Nile virus; pregnancy; infancy; early childhood development
2.  Associations of common carotid intima-media thickness (IMT) with coronary heart disease risk factors and events vary with distance from the carotid bulb 
Background
Common carotid artery (CCA) intima-media thickness (IMT) can be measured by ultrasound near to or below the carotid bulb. This might affect associations of IMT with coronary heart disease (CHD) risk factors and events.
Methods
We performed IMT measurements near and below the divergence of the CCA bulb, in 279 white individuals, aged 45–54 years, free of CHD at baseline and a subset of the Multi-Ethnic Study of Atherosclerosis (MESA), a cohort composed of Whites, Blacks, Chinese and Hispanics. Participants were followed for an average of 8.2 years. Far wall mean of the maximum IMT (MMaxIMT) and mean of the mean IMT (MMeanIMT) of the right and left CCA were averaged. Framingham risk factors were used in multivariable linear regression models. Parsimonious Cox proportional regression models included first time CHD as outcome.
Results
MMeanIMT below the bulb was smaller than near the bulb (0.51 mm +/− 0.078 mm versus 0.56 +/− 0.088 mm; p < 0.001) and had similar associations with risk factors (model R2 of 0.215 versus 0.186). MMaxIMT below the bulb was associated with risk factors (model R2: 0.211), MMaxIMT near to the bulb was not (R2: 0.025). MMeanIMT and MMaxIMT below the bulb were associated with CHD events (HR 1.67; p = 0.047 and 1.72; p= 0.037, respectively) but not when measured near the bulb.
Conclusions
CCA IMT measurements made below the bulb are smaller but have more consistent associations with CHD risk factors and outcomes as compared to IMT measured near the bulb.
doi:10.1016/j.echo.2014.04.019
PMCID: PMC4149919  PMID: 24944141
risk factors; common carotid artery; ultrasound; coronary heart disease; intima media thickness; carotid artery bifurcation
3.  What Do Carotid Intima-Media Thickness and Plaque Add to Prediction of Stroke and Cardiovascular Disease Risk in Older Adults? The Cardiovascular Health Study 
Background
We evaluated whether addition of carotid ultrasound intima-media thickness (CIMT) measurements and risk categories of plaque help predict incident stroke and CVD in older adults.
Methods
Carotid ultrasound studies were recorded in the multicenter Cardiovascular Health Study (CHS). Cardiovascular disease (CVD) was defined as coronary heart disease plus heart failure plus stroke. Ten-year risk prediction Cox proportional hazards models for stroke and CVD were calculated using CHS-specific coefficients for Framingham Risk Score (FRS) factors. Categories of CIMT and CIMT plus plaque were added to FRS prediction models and categorical net reclassification improvement (NRI) and Harrell’s c-statistic were calculated.
Results
In 4,384 CHS participants (61% women, 14% black, baseline age 72 ± 5 yrs) without CVD at baseline, higher CIMT category and presence of plaque were both associated with higher incidence rates for stroke and CVD. Addition of CIMT improved ability of FRS-type risk models to discriminate cases from non-cases of incident stroke and CVD (NRI = 0.062, p=0.015 and NRI=0.027, p<0.001 respectively), with no further improvement by adding plaque. For both outcomes, NRI was driven by down-classifying those without incident disease. Although addition of plaque to CIMT did not result in a significant NRI for either outcome, it was significant among those without incident disease.
Conclusion
In older adults, addition of CIMT modestly improves 10-year risk prediction for stroke and CVD beyond a traditional risk factor model, mainly by down-classifying risk in those without stroke or CVD; addition of plaque to CIMT adds no statistical benefit in the overall cohort, although there is evidence of down-classification in those without events.
doi:10.1016/j.echo.2014.06.013
PMCID: PMC4158921  PMID: 25172401
4.  Z-Selective Olefin Metathesis on Peptides: Investigation of Side-Chain Influence, Preorganization, and Guidelines in Substrate Selection 
Journal of the American Chemical Society  2014;136(35):12469-12478.
Olefin metathesis has emerged as a promising strategy for modulating the stability and activity of biologically relevant compounds; however, the ability to control olefin geometry in the product remains a challenge. Recent advances in the design of cyclometalated ruthenium catalysts has led to new strategies for achieving such control with high fidelity and Z selectivity, but the scope and limitations of these catalysts on substrates bearing multiple functionalities, including peptides, remained unexplored. Herein, we report an assessment of various factors that contribute to both productive and nonproductive Z-selective metathesis on peptides. The influence of sterics, side-chain identity, and preorganization through peptide secondary structure are explored by homodimerization, cross metathesis, and ring-closing metathesis. Our results indicate that the amino acid side chain and identity of the olefin profoundly influence the activity of cyclometalated ruthenium catalysts in Z-selective metathesis. The criteria set forth for achieving high conversion and Z selectivity are highlighted by cross metathesis and ring-closing metathesis on diverse peptide substrates. The principles outlined in this report are important not only for expanding the scope of Z-selective olefin metathesis to peptides but also for applying stereoselective olefin metathesis in general synthetic endeavors.
doi:10.1021/ja507166g
PMCID: PMC4156862  PMID: 25102124
5.  Common Carotid Intima-Media Thickness Measurements Do Not Improve Cardiovascular Risk Prediction in Individuals With Elevated Blood Pressure 
Hypertension  2014;63(6):1173-1181.
Carotid intima-media thickness (CIMT) is a marker of cardiovascular risk. It is unclear whether measurement of mean common CIMT improves 10-year risk prediction of first-time myocardial infarction or stroke in individuals with elevated blood pressure. We performed an analysis among individuals with elevated blood pressure (ie, a systolic blood pressure ≥140 mm Hg and a diastolic blood pressure ≥ 90 mm Hg) in USE-IMT, a large ongoing individual participant data meta-analysis. We refitted the risk factors of the Framingham Risk Score on asymptomatic individuals (baseline model) and expanded this model with mean common CIMT (CIMT model) measurements. From both models, 10-year risks to develop a myocardial infarction or stroke were estimated. In individuals with elevated blood pressure, we compared discrimination and calibration of the 2 models and calculated the net reclassification improvement (NRI). We included 17 254 individuals with elevated blood pressure from 16 studies. During a median follow-up of 9.9 years, 2014 first-time myocardial infarctions or strokes occurred. The C-statistics of the baseline and CIMT models were similar (0.73). NRI with the addition of mean common CIMT was small and not significant (1.4%; 95% confidence intervals, −1.1 to 3.7). In those at intermediate risk (n=5008, 10-year absolute risk of 10% to 20%), the NRI was 5.6% (95% confidence intervals, 1.6–10.4). There is no added value of measurement of mean common CIMT in individuals with elevated blood pressure for improving cardiovascular risk prediction. For those at intermediate risk, the addition of mean common CIMT to an existing cardiovascular risk score is small but statistically significant.
doi:10.1161/HYPERTENSIONAHA.113.02683
PMCID: PMC4523133  PMID: 24614213
atherosclerosis; carotid intima-media thickness; primary prevention; prognosis; risk
6.  Family History of Coronary Heart Disease and the Incidence and Progression of Coronary Artery Calcification: Multi-Ethnic Study of Atherosclerosis (MESA) 
Atherosclerosis  2013;232(2):369-376.
Objective
We evaluated family history as a predictor of incident and progressive coronary artery calcium (CAC) using data from the Multi-Ethnic Study of Atherosclerosis (MESA).
Background
MESA is a multi-center prospective study of 6,814 asymptomatic individuals. The relationship between family history of coronary heart disease (CHD) and CAC incidence or progression has not been described previously.
Methods
A total of 5,099 participants had detailed information about family history of CHD (late versus premature and parental versus sibling history). The mean time between CAC scans was 3.1 ± 1.3 years. The association of late versus premature family history was assessed against CAC change using multivariate regression model adjusted for demographics and cardiac risk factors.
Results
A family history of premature CHD was associated with an odds ratio (OR) of 1.55 (p < 0.01) for incident development of CAC after adjusting for risk factors and demographics. A premature family history was associated with 14.4 units (p < 0.01) greater volume scores compared to those with no family history in similarly adjusted models by median regression analysis. A combined parental and sibling family history was associated with the greatest incidence and progression in demographic-adjusted models. Caucasians demonstrated the most consistent predictive relationship between family history of premature CHD and incidence (p < 0.01) and progression (p < 0.05) of CAC, though no significant interaction with ethnicity was noted.
Conclusions
Family history of premature CHD is associated with enhanced development and progression of subclinical disease, independent of other risk factors, in a multiethnic, population-based study.
doi:10.1016/j.atherosclerosis.2013.11.042
PMCID: PMC4491495  PMID: 24468150
Subclinical atherosclerosis; coronary calcium; family history
7.  Race/Ethnic Differences in the Associations of the Framingham Risk Factors with Carotid IMT and Cardiovascular Events 
PLoS ONE  2015;10(7):e0132321.
Background
Clinical manifestations and outcomes of atherosclerotic disease differ between ethnic groups. In addition, the prevalence of risk factors is substantially different. Primary prevention programs are based on data derived from almost exclusively White people. We investigated how race/ethnic differences modify the associations of established risk factors with atherosclerosis and cardiovascular events.
Methods
We used data from an ongoing individual participant meta-analysis involving 17 population-based cohorts worldwide. We selected 60,211 participants without cardiovascular disease at baseline with available data on ethnicity (White, Black, Asian or Hispanic). We generated a multivariable linear regression model containing risk factors and ethnicity predicting mean common carotid intima-media thickness (CIMT) and a multivariable Cox regression model predicting myocardial infarction or stroke. For each risk factor we assessed how the association with the preclinical and clinical measures of cardiovascular atherosclerotic disease was affected by ethnicity.
Results
Ethnicity appeared to significantly modify the associations between risk factors and CIMT and cardiovascular events. The association between age and CIMT was weaker in Blacks and Hispanics. Systolic blood pressure associated more strongly with CIMT in Asians. HDL cholesterol and smoking associated less with CIMT in Blacks. Furthermore, the association of age and total cholesterol levels with the occurrence of cardiovascular events differed between Blacks and Whites.
Conclusion
The magnitude of associations between risk factors and the presence of atherosclerotic disease differs between race/ethnic groups. These subtle, yet significant differences provide insight in the etiology of cardiovascular disease among race/ethnic groups. These insights aid the race/ethnic-specific implementation of primary prevention.
doi:10.1371/journal.pone.0132321
PMCID: PMC4489855  PMID: 26134404
8.  Systemic inflammation and cardiovascular risk factors predict rapid progression of atherosclerosis in rheumatoid arthritis 
Annals of the rheumatic diseases  2014;74(6):1118-1123.
Objective
To estimate atherosclerosis progression and identify influencing factors in rheumatoid arthritis (RA).
Methods
We used carotid ultrasound to measure intima-media thickness (IMT) in RA patients, and ascertained cardiovascular (CV) risk factors, inflammation markers and medications. A second ultrasound was performed approximately 3 years later. We calculated the progression rate by subtracting the baseline from the follow-up IMT, divided by the time between the two scans. We used logistic regression to identify baseline factors predictive of rapid progression. We tested for interactions of erythrocyte sedimentation rate (ESR) with CV risk factors and medication use.
Results
Results were available for 487 RA patients. The mean (SD) common carotid IMT at baseline was 0.571 mm (0.151). After a mean of 2.8 years, the IMT increased by 0.050 mm (0.055), p≤0.001, a progression rate of 0.018 mm/year (95% CI 0.016 to 0.020). Baseline factors associated with rapid progression included the number of CV risk factors (OR 1.27 per risk factor, 95% CI 1.01 to 1.61), and the ESR (OR 1.12 per 10 mm/h, 95% CI 1.02 to 1.23). The ESR×CV risk factor and ESR×medication product terms were significant, suggesting these variables modify the association between the ESR and IMT progression.
Conclusions
Systemic inflammation and CV risk factors were associated with rapid IMT progression. CV risk factors may modify the role of systemic inflammation in determining IMT progression over time. Methotrexate and antitumour necrosis factor agents may influence IMT progression by reducing the effect of the systemic inflammation on the IMT.
doi:10.1136/annrheumdis-2013-205058
PMCID: PMC4239202  PMID: 24845391
9.  Edge-Detected Common Carotid Artery Intima–Media Thickness and Incident Coronary Heart Disease in the Multi-Ethnic Study of Atherosclerosis 
Background
Common carotid artery intima–media thickness (IMT) can be measured either by hand or with an automated edge detector. We performed a direct comparison of these 2 approaches and studied their respective associations with coronary heart disease outcomes.
Methods and Results
We studied 5468 participants of the Multi-Ethnic Study of Atherosclerosis, composed of white, Chinese, Hispanic, and black participants with an average age of 61.9 years (47.8% men) and who were free of coronary heart disease at baseline. Manual-traced and edge-detected IMT measurements were made in the same location on ultrasound images of the right common carotid artery far wall in an area free of plaque. Manual-traced and edge-detected common carotid artery IMT measurements were added separately to multivariable Cox proportional hazards models with time to incident coronary heart disease as the outcome and adjusted for traditional coronary heart disease Framingham risk factors, lipid-lowering therapy, blood pressure–lowering therapy, and race or ethnicity. Additional models were generated after adding clinic site and reader. There were 349 events during a median follow-up of 10.2 years. In adjusted models, the hazard ratio was not significant (1.31; 95% CI 0.84 to 2.06) for each millimeter increase in manual-traced IMT but was significant for edge-detected IMT (hazard ratio 1.63; 95% CI 1.12 to 2.37). Edge-detected IMT remained statistically associated with outcomes after additional adjustment for clinic site and reader performing the IMT measurement (hazard ratio 1.59; 95% CI 1.07 to 2.35).
Conclusions
Edge-detected common carotid artery far wall IMT has similar if not stronger associations with coronary heart disease outcomes when compared with manual-traced IMT.
Clinical Trial Registration
URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00063440.
doi:10.1161/JAHA.114.001492
PMCID: PMC4599522  PMID: 26077584
atherosclerosis; carotid arteries; epidemiology; risk factors; ultrasonics
10.  Incident stroke is associated with common carotid artery diameter and not common carotid artery intima-media thickness 
Background and Purpose
The common carotid artery (CCA) inter-adventitial diameter (IAD) is measured on ultrasound images as the distance between the media-adventitia interfaces of the near and far walls. It is associated with common carotid intima-media thickness (IMT) and left ventricular mass and might therefore also have an association with incident stroke.
Methods
We studied 6255 individuals free of coronary heart disease and stroke at baseline with mean age of 62.2 years (47.3% men), members of a multi-ethnic community based cohort of whites, blacks, Hispanics, and Chinese. Ischemic stroke events were centrally adjudicated. CCA IAD and IMT were measured. Cases with incident atrial fibrillation (n = 385) were excluded. Multivariable Cox proportional hazards models were generated with time to ischemic event as outcome, adjusting for risk factors.
Results
There were 115 first time ischemic strokes at 7.8 years of follow-up. CCA IAD was a significant predictor of ischemic stroke (Hazard ratio: 1.86; 95%CI 1.59, 2.17 per mm) and remained so after adjustment for risk factors and common carotid IMT with a hazard ratio of 1.52 per mm (95% CI: 1.22, 1.88). Common carotid IMT was not an independent predictor after adjustment (hazard ratio 0.14; 95% CI: 0.14, 1.19).
Conclusion
While common carotid IMT is not associated with stroke, inter-adventitial diameter of the common carotid artery is independently associated with first time incident ischemic stroke even after adjusting for IMT. Our hypothesis that this is in part due to the effects of exposure to blood pressure needs confirmation by other studies.
doi:10.1161/STROKEAHA.114.004850
PMCID: PMC4270293  PMID: 24643408
11.  Carboxylate-Assisted C(sp3)–H Activation in Olefin Metathesis-Relevant Ruthenium Complexes 
The mechanism of C–H activation at metathesis-relevant ruthenium(II) benzylidene complexes was studied both experimentally and computationally. Synthesis of a ruthenium dicarboxylate at a low temperature allowed for direct observation of the C–H activation step, independent of the initial anionic ligand-exchange reactions. A first-order reaction supports an intramolecular concerted metalation–deprotonation mechanism with ΔG⧧298K = 22.2 ± 0.1 kcal·mol–1 for the parent N-adamantyl-N′-mesityl complex. An experimentally determined ΔS⧧ = −5.2 ± 2.6 eu supports a highly ordered transition state for carboxylate-assisted C(sp3)–H activation. Experimental results, including measurement of a large primary kinetic isotope effect (kH/kD = 8.1 ± 1.7), agree closely with a computed six-membered carboxylate-assisted C–H activation mechanism where the deprotonating carboxylate adopts a pseudo-apical geometry, displacing the aryl ether chelate. The rate of cyclometalation was found to be influenced by both the electronics of the assisting carboxylate and the ruthenium ligand environment.
doi:10.1021/ja5021958
PMCID: PMC4017616  PMID: 24731019
12.  Comparison of Novel Risk Markers for Improvement in Cardiovascular Risk Assessment in Intermediate Risk Individuals. The Multi-Ethnic Study of Atherosclerosis 
Context
Risk markers including coronary artery calcium (CAC), carotid intima-media thickness (CIMT), ankle-brachial Index (ABI), brachial flow-mediated dilation (FMD), high sensitivity C -reactive protein (hs-CRP) and family history (FH) of coronary heart disease (CHD) have been reported to improve on the Framingham risk score (FRS) for prediction of CHD. However, there are no direct comparisons of these markers for risk prediction in a single cohort.
Objective
We compared improvement in prediction of incident CHD/cardiovascular disease (CVD) of these 6 risk markers within intermediate risk participants (5 % < FRS < 20%) in the Multi-Ethnic Study of Atherosclerosis (MESA).
Design, Setting and Participants
Of 6814 MESA participants from 6 US field centers, 1330 were intermediate risk, without diabetes mellitus, and had complete data on all 6 markers. Recruitment spanned July 2000 to September 2002; follow-up extended through May 2011. Probability- weighted Cox proportional hazard models were used to estimate hazard ratios (HR). Area under the receiver operator characteristic curve (AUC) and net reclassification improvement (NRI) were used to compare incremental contributions of each marker when added to the FRS + race/ethnicity.
Main Outcome Measures
Incident CHD defined as MI, angina followed by revascularization, resuscitated cardiac arrest or CHD death. Incident CVD additionally included stroke or CVD death.
Results
After median follow-up of 7.6 years (IQR 7.3 – 7.8 years), 94 CHD and 123 CVD events occurred. CAC, ABI, hs-CRP and FH were independently associated with incident CHD in multivariable analyses [HR (95%CI: 2.60(1.94-3.50), 0.79(0.66-0.95), 1.28(1.00-1.64) and 2.18(1.38-3.42) respectively]. CIMT and FMD were not associated with incident CHD in multivariable analyses [HR (95%CI) 1.17(0.95- 1.45) and 0.95(0.78 −1.14) respectively]. Although the addition of the markers individually to the FRS +race/ethnicity improved the AUC, CAC afforded the highest increment (0.623 vs. 0.784) while FMD afforded the least [0.623 vs. 0.639]. For incident CHD, the NRI with CAC was 0.659, FMD 0.024, ABI 0.036, CIMT 0.102, FH 0.160 and hs-CRP 0.079. Similar results were obtained for incident CVD.
Conclusion
CAC, ABI, hs-CRP and FH are independent predictors of incident CHD/CVD in intermediate risk individuals. CAC provides superior discrimination and risk reclassification compared with other risk markers.
doi:10.1001/jama.2012.9624
PMCID: PMC4141475  PMID: 22910756
13.  Relationship of Carotid Distensibility and Thoracic Aorta Calcification: Multi-Ethnic Study of Atherosclerosis (MESA) 
Hypertension  2009;54(6):1408-1415.
Stiffening of the central elastic arteries is one of the earliest detectable manifestations of adverse change within the vessel wall. While an association between carotid artery stiffness and adverse events has been demonstrated, little is known about the relationship between stiffness and atherosclerosis. Even less is known about the impact of age, gender, and race on this association. To elucidate this question, we used baseline data from the Multi-Ethnic Study of Atherosclerosis (MESA, 2000-2002). Carotid artery distensibility coefficient (DC) was calculated after visualization of the instantaneous waveform of common carotid diameter using high resolution B-mode ultrasound. Thoracic aorta calcification (TAC) was identified using non-contrast cardiac CT. We found a strong association between decreasing DC (increasing carotid stiffness) and increasing TAC as well as a graded increase in TAC score (p<0.001). After controlling for age, gender, race, and traditional and emerging cardiovascular risk factors, individuals in the stiffest quartile had a prevalence ratio of 1.52 (95% CI 1.15-2.00) for TAC compared to the least stiff quartile. In exploratory analysis, carotid stiffness was more highly correlated with calcification of the aorta than calcification of the coronary arteries (ρ=0.32 vs. 0.22, p<0.001 for comparison). In conclusion, there is a strong independent association between carotid stiffness and thoracic aorta calcification. Carotid stiffness is more highly correlated with calcification of the aorta, a central elastic artery, than calcification of the coronary arteries. The prognostic significance of these findings requires longitudinal follow-up of the MESA cohort.
doi:10.1161/HYPERTENSIONAHA.109.138396
PMCID: PMC4118641  PMID: 19805639
Carotid stiffness; carotid compliance; subclinical atherosclerosis; thoracic aorta calcification; coronary calcification
14.  Carotid artery plaque and progression of coronary artery calcium: the Multi-Ethnic Study of Atherosclerosis 
Background
Carotid and coronary atherosclerosis are associated to each other in imaging and autopsy studies. We evaluated whether carotid artery plaque seen on carotid ultrasound can predict incident coronary artery calcification (CAC).
Materials and Methods
We repeated Agatston calcium score measurements in 5445 participants of the Multi-Ethnic Study of Atherosclerosis (MESA) (mean age 57.9 years; 62.9% female). Internal carotid artery lesions were graded as 0%, 1-24%, >25% diameter narrowing and intima-media thickness (IMT) was measured. Plaque was present for any stenosis > 0%. CAC progression was evaluated with multivariable relative risk regression in cases with CAC = 0 at baseline and with multivariable linear regression for CAC > 0 adjusting for cardiovascular risk factors, body mass index, ethnicity, and common carotid IMT.
Results
CAC was positive at baseline in 2708/5445 (49.7%) participants and became positive in 458/2837 (16.1%) at mean interval of 2.4 years between repeat examinations. Plaque and ICA IMT were both strongly associated with presence of CAC. After statistical adjustment, presence of carotid artery plaque significantly predicted incident CAC with a relative risk(RR) of 1.37 (95% Confidence Intervals: 1.12, 1.67). Incident CAC was associated with ICA IMT with an RR of 1.13 (95% Confidence Intervals: 1.03, 1.25) for each mm increase. Progression of CAC was also significantly associated (p < 0.001) with plaque and ICA IMT.
Conclusions
In individuals free of cardiovascular disease, subjective and quantitative measures of carotid artery plaques by ultrasound imaging are associated with CAC incidence and progression.
doi:10.1016/j.echo.2013.02.009
PMCID: PMC4084492  PMID: 23522805
15.  The MCIC collection: a shared repository of multi-modal, multi-site brain image data from a clinical investigation of schizophrenia 
Neuroinformatics  2013;11(3):367-388.
Expertly collected, well-curated data sets consisting of comprehensive clinical characterization and raw structural, functional and diffusion-weighted DICOM images in schizophrenia patients and sex and age-matched controls are now accessible to the scientific community through an on-line data repository (coins.mrn.org). The Mental Illness and Neuroscience Discovery Institute, now the Mind Research Network (MRN, www.mrn.org), comprised of investigators at the University of New Mexico, the University of Minnesota, Massachusetts General Hospital, and the University of Iowa, conducted a cross-sectional study to identify quantitative neuroimaging biomarkers of schizophrenia. Data acquisition across multiple sites permitted the integration and cross-validation of clinical, cognitive, morphometric, and functional neuroimaging results gathered from unique samples of schizophrenia patients and controls using a common protocol across sites. Particular effort was made to recruit patients early in the course of their illness, at the onset of their symptoms. There is a relatively even sampling of illness duration in chronic patients. This data repository will be useful to 1) scientists who can study schizophrenia by further analysis of this cohort and/or by pooling with other data; 2) computer scientists and software algorithm developers for testing and validating novel registration, segmentation, and other analysis software; and 3) educators in the fields of neuroimaging, medical image analysis and medical imaging informatics who need exemplar data sets for courses and workshops. Sharing provides the opportunity for independent replication of already published results from this data set and novel exploration. This manuscript describes the inclusion/exclusion criteria, imaging parameters and other information that will assist those wishing to use this data repository.
doi:10.1007/s12021-013-9184-3
PMCID: PMC3727653  PMID: 23760817
Medical Image Data repository; Schizophrenia; fMRI; DWI; mMRI; healthy controls
16.  Eyeblink conditioning in unmedicated schizophrenia patients: A positron emission tomography study 
Psychiatry research  2013;214(3):402-409.
Previous studies suggest that patients with schizophrenia exhibit dysfunctions in a widely distributed circuit—the cortico-cerebellar-thalamic-cortical circuit, or CCTCC—and that this may explain the multiple cognitive deficits observed in the disorder. This study uses positron emission tomography (PET) with O15 H2O to measure regional cerebral blood flow (rCBF) in response to a classic test of cerebellar function, the associative learning that occurs during eyeblink conditioning, in a sample of 20 unmedicated schizophrenia patients and 20 closely matched healthy controls. The PET paradigm examined three phases of acquisition and extinction (early, middle and late). The patients displayed impaired behavioral performance during both acquisition and extinction. The imaging data indicate that, compared to the control subjects, the patients displayed decreases in rCBF in all three components of the CCTCC during both acquisition and extinction. Specifically, patients had less rCBF in the middle and medial frontal lobes, anterior cerebellar lobules I/V and VI, as well as the thalamus during acquisition and although similar areas were found in the frontal lobe, ipsilateral cerebellar lobule IX showed consistently less activity in patients during extinction. Thus this study provides additional support for the hypothesis that patients with schizophrenia have a cognitive dysmetria—an inability to smoothly coordinate many different types of mental activity—that affects even a very basic cognitive task that taps into associative learning.
doi:10.1016/j.pscychresns.2013.07.006
PMCID: PMC3980571  PMID: 24090512
Eyeblink; Positron emissions tomography (PET); Cerebellum; Schizophrenia; Cognitive dysmetria
17.  Genetic Architecture of Carotid Artery Intima-Media Thickness in Mexican Americans 
Circulation. Cardiovascular genetics  2013;6(2):10.1161/CIRCGENETICS.113.000079.
Background
Intima-media thickness (IMT) of the common and internal carotid arteries is an established surrogate for atherosclerosis and predicts risk of stroke and myocardial infarction. Often IMT is measured as the average of these two arteries, yet they are believed to result from separate biological mechanisms. The aim of this study was to conduct a family-based genome-wide association study (GWAS) for IMT to identify polymorphisms influencing IMT and to determine if distinct carotid artery segments are influenced by different genetic components.
Methods and Results
IMT for the common and internal carotid arteries was determined through B-mode ultrasound in 772 Mexican Americans from the San Antonio Family Heart Study. A GWAS utilizing 931,219 single nucleotide polymorphisms (SNPs) was undertaken with six internal and common carotid artery IMT phenotypes utilizing an additive measured genotype model. The most robust association detected was for two SNPs (rs16983261, rs6113474, p=1.60e−7) in complete linkage disequilibrium on chromosome 20p11 for the internal carotid artery near wall, next to the gene PAX1. We also replicated previously reported GWAS regions on chromosomes 19q13 and 7q22. We found no overlapping associations between internal and common carotid artery phenotypes at p<5.0e0−6. The genetic correlation between the two carotid IMT arterial segments was 0.51.
Conclusions
This study represents the first large scale GWAS of carotid IMT in a non-European population and identified several novel loci. We do not detect any shared GWAS signals between common and internal carotid arterial segments but the moderate genetic correlation implies both common and unique genetic components.
doi:10.1161/CIRCGENETICS.113.000079
PMCID: PMC3865281  PMID: 23487405
intima-media thickness; carotid artery; GWAS; Hispanics
18.  Eyeblink Conditioning in Healthy Adults: A Positron Emission Tomography Study 
Cerebellum (London, England)  2012;11(4):10.1007/s12311-012-0377-3.
Eyeblink conditioning is a paradigm commonly used to investigate the neural mechanisms underlying motor learning. It involves the paired presentation of a toneconditioning stimulus which precedes and co-terminates with an airpuff unconditioned stimulus. Following repeated paired presentations a conditioned eyeblink develops which precedes the airpuff. This type of learning has been intensively studied and the cerebellum is known to be essential in both humans and animals. The study presented here was designed to investigate the role of the cerebellum during eyeblink conditioning in humans using positron emission tomography (PET). The sample includes 20 subjects (10 male and 10 female) with an average age of 29.2 years. PET imaging was used to measure regional cerebral blood flow (rCBF) changes occurring during the first, second, and third blocks of conditioning. In addition, stimuli-specific rCBF to unpaired tones and airpuffs (“pseudoconditioning”) was used as a baseline level that was subtracted from each block. Conditioning was performed using three, 15-trial blocks of classical eyeblink conditioning with the last five trials in each block imaged. As expected, subjects quickly acquired conditioned responses. A comparison between the conditioning tasks and the baseline task revealed that during learning there was activation of the cerebellum and recruitment of several higher cortical regions. Specifically, large peaks were noted in cerebellar lobules IV/V, the frontal lobes, and cingulate gyri.
doi:10.1007/s12311-012-0377-3
PMCID: PMC3835594  PMID: 22430943
Eyeblink conditioning; Motor learning; PET imagining; Frontal lobe; Extinction
19.  Prospective Study of Particulate Air Pollution Exposures, Subclinical Atherosclerosis, and Clinical Cardiovascular Disease 
American Journal of Epidemiology  2012;176(9):825-837.
The Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air) was initiated in 2004 to investigate the relation between individual-level estimates of long-term air pollution exposure and the progression of subclinical atherosclerosis and the incidence of cardiovascular disease (CVD). MESA Air builds on a multicenter, community-based US study of CVD, supplementing that study with additional participants, outcome measurements, and state-of-the-art air pollution exposure assessments of fine particulate matter, oxides of nitrogen, and black carbon. More than 7,000 participants aged 45–84 years are being followed for over 10 years for the identification and characterization of CVD events, including acute myocardial infarction and other coronary artery disease, stroke, peripheral artery disease, and congestive heart failure; cardiac procedures; and mortality. Subcohorts undergo baseline and follow-up measurements of coronary artery calcium using computed tomography and carotid artery intima-medial wall thickness using ultrasonography. This cohort provides vast exposure heterogeneity in ranges currently experienced and permitted in most developed nations, and the air monitoring and modeling methods employed will provide individual estimates of exposure that incorporate residence-specific infiltration characteristics and participant-specific time-activity patterns. The overarching study aim is to understand and reduce uncertainty in health effect estimation regarding long-term exposure to air pollution and CVD.
doi:10.1093/aje/kws169
PMCID: PMC3571256  PMID: 23043127
air pollution; atherosclerosis; cardiovascular diseases; environmental exposure; epidemiologic methods; particulate matter
20.  Genetics of coronary artery calcification among African Americans, a meta-analysis 
BMC Medical Genetics  2013;14:75.
Background
Coronary heart disease (CHD) is the major cause of death in the United States. Coronary artery calcification (CAC) scores are independent predictors of CHD. African Americans (AA) have higher rates of CHD but are less well-studied in genomic studies. We assembled the largest AA data resource currently available with measured CAC to identify associated genetic variants.
Methods
We analyzed log transformed CAC quantity (ln(CAC + 1)), for association with ~2.5 million single nucleotide polymorphisms (SNPs) and performed an inverse-variance weighted meta-analysis on results for 5,823 AA from 8 studies. Heritability was calculated using family studies. The most significant SNPs among AAs were evaluated in European Ancestry (EA) CAC data; conversely, the significance of published SNPs for CAC/CHD in EA was queried within our AA meta-analysis.
Results
Heritability of CAC was lower in AA (~30%) than previously reported for EA (~50%). No SNP reached genome wide significance (p < 5E-08). Of 67 SNPs with p < 1E-05 in AA there was no evidence of association in EA CAC data. Four SNPs in regions previously implicated in CAC/CHD (at 9p21 and PHACTR1) in EA reached nominal significance for CAC in AA, with concordant direction. Among AA, rs16905644 (p = 4.08E-05) had the strongest association in the 9p21 region.
Conclusions
While we observed substantial heritability for CAC in AA, we failed to identify loci for CAC at genome-wide significant levels despite having adequate power to detect alleles with moderate to large effects. Although suggestive signals in AA were apparent at 9p21 and additional CAC and CAD EA loci, overall the data suggest that even larger samples and an ethnic specific focus will be required for GWAS discoveries for CAC in AA populations.
doi:10.1186/1471-2350-14-75
PMCID: PMC3733595  PMID: 23870195
Atherosclerosis; Coronary artery calcium; Genetics; Meta-analysis; African-American
21.  Function Biomedical Informatics Research Network Recommendations for Prospective Multi-Center Functional Magnetic Resonance Imaging Studies 
This report provides practical recommendations for the design and execution of Multi-Center functional Magnetic Resonance Imaging (MC-fMRI) studies based on the collective experience of the Function Biomedical Informatics Research Network (FBIRN). The paper was inspired by many requests from the fMRI community to FBIRN group members for advice on how to conduct MC-fMRI studies. The introduction briefly discusses the advantages and complexities of MC-fMRI studies. Prerequisites for MC-fMRI studies are addressed before delving into the practical aspects of carefully and efficiently setting up a MC-fMRI study. Practical multi-site aspects include: (1) establishing and verifying scan parameters including scanner types and magnetic fields, (2) establishing and monitoring of a scanner quality program, (3) developing task paradigms and scan session documentation, (4) establishing clinical and scanner training to ensure consistency over time, (5) developing means for uploading, storing, and monitoring of imaging and other data, (6) the use of a traveling fMRI expert and (7) collectively analyzing imaging data and disseminating results. We conclude that when MC-fMRI studies are organized well with careful attention to unification of hardware, software and procedural aspects, the process can be a highly effective means for accessing a desired participant demographics while accelerating scientific discovery.
doi:10.1002/jmri.23572
PMCID: PMC3349791  PMID: 22314879
Functional magnetic resonance imaging; fMRI; multi-center; multi-site; FIRST Biomedica Informatics Research Network; FBIRN
22.  Cholesteryl Ester Transfer Protein Genetic Polymorphisms, HDL Cholesterol, and Subclinical Cardiovascular Disease in the Multi-Ethnic Study of Atherosclerosis 
Atherosclerosis  2008;200(2):359-367.
The cholesteryl ester transport protein (CETP) plays a key role in high-density lipoprotein (HDL) metabolism. Genetic variants that alter CETP activity and concentration may cause significant alterations in HDL-cholesterol (HDL-C) concentration; however, controversies remain about whether these genetic variants are associated with atherosclerosis. We genotyped the CETP R451Q, A373P, -629C/A, Taq1B, and -2505C/A polymorphisms in a cohort of Caucasian, Chinese, African-American, and Hispanic individuals within the Multi-Ethnic Study of Atherosclerosis. Genotypes were examined in relationship to HDL-C, CETP activity, CETP concentration, and three measures of subclinical cardiovascular disease (CVD): coronary artery calcium (CAC) measured by fast CT scanning, and carotid intimal-medial thickness (IMT) and carotid artery plaque, measured by ultrasonography. Carriers of the 451Q and 373P alleles have significantly higher CETP concentration (22.4% and 19.5%, respectively; p<0.001) and activity (13.1% and 9.4%, respectively; p<0.01) and lower HDL-C (5.6% and 6.0%, respectively; p<0.05). The minor alleles of the R451Q and A373P polymorphisms are associated with the presence of CAC, even after adjusting for CVD risk factors and HDL-C (p=0.006 and p=0.01, respectively). The R451Q polymorphism is also associated with presence of carotid artery plaque (p=0.036). Neither polymorphism is associated with common or internal carotid IMT. We confirmed that the -629A, Taq1B B2, and -2505A alleles are significantly associated with lower CETP concentration (20.8%, 25.0%, and 23.7%, respectively; p<0.001) and activity (14.8%, 19.8%, and 18.4%, respectively; p<0.001) and higher HDL-C concentration (9.7%, 11.5%, and 10.4%, respectively; p<0.01). However, we did not find any associations between these non-coding polymorphisms and subclinical CVD.
doi:10.1016/j.atherosclerosis.2007.12.038
PMCID: PMC3612981  PMID: 18243217
CETP; CVD; HDL; MESA
23.  Neural Sensitivity to Absolute and Relative Anticipated Reward in Adolescents 
PLoS ONE  2013;8(3):e58708.
Adolescence is associated with a dramatic increase in risky and impulsive behaviors that have been attributed to developmental differences in neural processing of rewards. In the present study, we sought to identify age differences in anticipation of absolute and relative rewards. To do so, we modified a commonly used monetary incentive delay (MID) task in order to examine brain activity to relative anticipated reward value (neural sensitivity to the value of a reward as a function of other available rewards). This design also made it possible to examine developmental differences in brain activation to absolute anticipated reward magnitude (the degree to which neural activity increases with increasing reward magnitude). While undergoing fMRI, 18 adolescents and 18 adult participants were presented with cues associated with different reward magnitudes. After the cue, participants responded to a target to win money on that trial. Presentation of cues was blocked such that two reward cues associated with $.20, $1.00, or $5.00 were in play on a given block. Thus, the relative value of the $1.00 reward varied depending on whether it was paired with a smaller or larger reward. Reflecting age differences in neural responses to relative anticipated reward (i.e., reference dependent processing), adults, but not adolescents, demonstrated greater activity to a $1 reward when it was the larger of the two available rewards. Adults also demonstrated a more linear increase in ventral striatal activity as a function of increasing absolute reward magnitude compared to adolescents. Additionally, reduced ventral striatal sensitivity to absolute anticipated reward (i.e., the difference in activity to medium versus small rewards) correlated with higher levels of trait Impulsivity. Thus, ventral striatal activity in anticipation of absolute and relative rewards develops with age. Absolute reward processing is also linked to individual differences in Impulsivity.
doi:10.1371/journal.pone.0058708
PMCID: PMC3609767  PMID: 23544046
24.  Effects of Chronic Marijuana Use on Brain Activity During Monetary Decision-Making 
Neuropsychopharmacology  2011;37(3):618-629.
Marijuana (MJ) acutely acts on cannabinoid receptors that are found in numerous brain regions, including those involved in reward processing and decision-making. However, it remains unclear how long-term, chronic MJ use alters reward-based decision-making. In the present study, using [15O]water PET imaging, we measured brain activity in chronic MJ users, who underwent monitored abstinence from MJ for approximately 24 h before imaging, and control participants, while they took part in the Iowa Gambling Task (IGT), a monetary decision making task that strongly relies on the ventromedial prefrontal cortex (vmPFC). During PET imaging, participants took part in the standard and a variant version of the IGT as well as a control task. Chronic MJ users performed equally well on the standard IGT, but significantly worse than controls on the variant IGT. Chronic MJ users and control subjects showed increased regional cerebral blood flow (rCBF) in the vmPFC on both versions of the IGT compared to the control task. In the two-group comparison, chronic MJ users showed significantly greater rCBF than controls in the vmPFC on the standard IGT and greater activity in the cerebellum on both versions of the IGT. Furthermore, duration of use, but not age of first use, was associated with greater activity in the vmPFC. Thus, chronic MJ users tend to strongly recruit neural circuitry involved in decision-making and reward processing (vmPFC), and probabilistic learning (cerebellum) when performing the IGT.
doi:10.1038/npp.2011.227
PMCID: PMC3260974  PMID: 21956445
marijuana; decision-making; ventromedial prefrontal cortex; chronic use; cerebellum; PET; addiction & substance abuse; cannabinoids; cognition; decision-making; imaging; clinical or preclinical; PET; prefrontal cortex
25.  Common carotid artery intima-media thickness (IMT) progression as a predictor of stroke in MESA (Multi-Ethnic Study of Atherosclerosis) 
Background
Carotid artery intima-media thickness (IMT) is a marker of cardiovascular disease associated with incident stroke. We study whether IMT rate-of-change is associated with stroke.
Materials and Methods
We studied 5028 participants of the Multi-Ethnic Study of Atherosclerosis (MESA) composed of whites, Chinese, Hispanic and African-Americans free of cardiovascular disease. In this MESA IMT progression study, IMT rate-of-change (mm/year) was the difference in right common carotid artery (CCA) far-wall IMT (mm) divided by the interval between two ultrasound examinations (median interval of 32 months). CCA IMT was measured in a region free of plaque. Cardiovascular risk factors and baseline IMT were determined when IMT rate-of-change was measured. Multivariable Cox proportional hazards models generated Hazard risk Ratios (HR) with cardiovascular risk factors, ethnicity and education level/income as predictors.
Results
There were 42 first time strokes seen during a mean follow-up of 3.22 years (median 3.0 years). Average age was 64.2 years, with 48% males. In multivariable models, age (HR: 1.05 per year), systolic blood pressure (HR 1.02 per mmHg), lower HDL cholesterol levels (HR: 0.96 per mg/dL) and IMT rate-of-change (HR 1.23 per 0.05 mm/year; 95% C.L. 1.02, 1.48) were significantly associated with incident stroke. The upper quartile of IMT rate-of-change had an HR of 2.18 (95% C.L.: 1.07, 4.46) compared to the lower three quartiles combined.
Conclusion
Common carotid artery IMT progression is associated with incident stroke in this cohort free of prevalent cardiovascular disease and atrial fibrillation at baseline.
doi:10.1161/STROKEAHA.111.625186
PMCID: PMC3202068  PMID: 21885840
Ultrasonography; Risk Factors; Carotid Arteries; Carotid Intima Media Thickness; stroke

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