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1.  Relationship between Enhanced Intensity of Contrast Enhanced Ultrasound and Microvessel Density of Aortic Atherosclerostic Plaque in Rabbit Model 
PLoS ONE  2014;9(4):e92445.
The aim of this study was to evaluate the relationship between enhanced intensity of contrast enhanced ultrasound and microvessel density of aortic atherosclerotic plaque in rabbit model. The abdominal aortas of thirty-six male New Zealand rabbits were damaged by balloon expansion and the animals were then fed a high fat diet for 12 weeks. Twenty-seven plaques on the near aortic wall were detected using conventional ultrasound examination. The maximum thickness of each plaque was recorded. CEUS was performed on these 27 plaques and the time-intensity curves (TICs) were analyzed offline. Using the quantitative ACQ software, features such as the arrival time (AT), time to peak (TTP), baseline intensity (BI), peak intensity (PI) and enhanced intensity (EI) (EI = PI-BI) were assessed. Inter- and intra-observer agreement of EI were assessed using the Bland-Altman test. After CEUS examination, the rabbits were sacrificed for pathological examination and CD34 monoclonal antibody immunohistochemical detection. Microvessel density (MVD) was counted under the microscope. The relationship between indexes of CEUS and the level of MVD was analyzed. There was a good positive linear correlation between EI and MVD (γ = 0. 854, P<0. 001), the intraclass correlations for inter- and intra-observer agreement for EI were 0.73 and 0.82 respectively, suggesting that EI may be act as a useful index for plaque risk stratification in animal models.
doi:10.1371/journal.pone.0092445
PMCID: PMC3979663  PMID: 24713618
2.  Relationship between Serum Ferritin Levels and Sarcopenia in Korean Females Aged 60 Years and Older Using the Fourth Korea National Health and Nutrition Examination Survey (KNHANES IV-2, 3), 2008–2009 
PLoS ONE  2014;9(2):e90105.
Context
It has been suggested that elevated serum ferritin is associated with several metabolic disorders. However, there is no reported study assessing any association between serum ferritin and sarcopenia despite the close relationship between sarcopenia and metabolic disorders.
Objective
We investigated whether serum ferritin was associated with sarcopenia in older Koreans.
Design and Setting
We conducted a cross-sectional study based on data acquired in the second and third years (2008–9) of the fourth Korean National Health and Nutrition Examination Survey.
Participants
In total, 952 men (mean age 69.0 years) and 1,380 women (mean age 69.3 years) aged 60 years and older completed a body composition study using dual energy X-ray absorptiometry.
Measurements
Serum ferritin levels were measured. Sarcopenia was defined as an appendicular skeletal mass as a percentage of body weight that was less than two standard deviations below the gender-specific mean for young adults.
Results
Serum ferritin levels were lower in women than in men. Women with sarcopenia showed a higher level of serum ferritin than women without sarcopenia (men: without sarcopenia 115.7 ng/mL and with sarcopenia 134.4 ng/mL vs. women: without sarcopenia 70.7 ng/mL and with sarcopenia 85.4 ng/mL). The prevalence of sarcopenia increased as the tertile of serum ferritin increased. However, statistical significance was only seen in elderly women (1st tertile 6.3%, 2nd tertile 8.0%, 3rd tertile 12.0%; p = 0.008). Without adjustment, compared with those in the lowest tertile of serum ferritin level, participants in the highest tertile had an odds ratio of 2.02 (95% confidence interval = 1.26–3.23) for sarcopenia in women. After adjusting for known risk factors, the OR for sarcopenia was 1.74 (95% CI = 1.02–2.97) in women. There was no statistically significant association between sarcopenia and serum ferritin tertiles in men.
Conclusions
Elevated serum ferritin levels were associated with an increased prevalence of sarcopenia in women but not in men from a representative sample of elderly Koreans.
doi:10.1371/journal.pone.0090105
PMCID: PMC3934984  PMID: 24587226
3.  Association between Vitamin D Status and Risk of Metabolic Syndrome among Korean Postmenopausal Women 
PLoS ONE  2014;9(2):e89721.
This study aimed to investigate the association between serum levels of 25-hydroxyvitamin D [25(OH)D] and metabolic syndrome along with its associated risk factors in Korean postmenopausal women. This study was performed using data from the KNHANES 2008–2010 study and included 4,364 postmenopausal Korean women. Clinical and other objective characteristics, seasonality, and presence of metabolic syndrome with its five components were evaluated and correlated with the serum levels of 25(OH)D. Although no statistically significant associations were observed between the levels of serum 25(OH)D and the prevalence of metabolic syndrome, the adjusted OR for elevated blood pressure, elevated triglycerides (TGs), and reduced high-density lipoprotein cholesterol (HDL-C) showed tendency to decrease sequentially as tertiles of serum 25(OH)D levels increased (p for trends  = 0.066, 0.043, and 0.010, respectively). Women in the highest tertile of serum 25(OH)D showed a significant decrease in the prevalence of elevated blood pressure, elevated TGs, and reduced HDL-C as compared with those in the lowest tertile of serum 25(OH)D (p = 0.020, 0.014, and 0.002, respectively). Based on these results, we consider that adequate serum levels of 25(OH)D in Korean postmenopausal women may not entirely indicate a lower risk of developing metabolic syndrome. However, adequate serum levels of 25(OH)D are significantly associated with a decrease in elevated blood pressure, elevated TGs, and reduced HDL-C levels in postmenopausal women.
doi:10.1371/journal.pone.0089721
PMCID: PMC3931824  PMID: 24586986
4.  Carotid intima-media thickness progression to predict cardiovascular events in the general population (the PROG-IMT collaborative project): a meta-analysis of individual participant data 
Lancet  2012;379(9831):2053-2062.
Summary
Background
Carotid intima-media thickness (cIMT) is related to the risk of cardiovascular events in the general population. An association between changes in cIMT and cardiovascular risk is frequently assumed but has rarely been reported. Our aim was to test this association.
Methods
We identified general population studies that assessed cIMT at least twice and followed up participants for myocardial infarction, stroke, or death. The study teams collaborated in an individual participant data meta-analysis. Excluding individuals with previous myocardial infarction or stroke, we assessed the association between cIMT progression and the risk of cardiovascular events (myocardial infarction, stroke, vascular death, or a combination of these) for each study with Cox regression. The log hazard ratios (HRs) per SD difference were pooled by random effects meta-analysis.
Findings
Of 21 eligible studies, 16 with 36 984 participants were included. During a mean follow-up of 7·0 years, 1519 myocardial infarctions, 1339 strokes, and 2028 combined endpoints (myocardial infarction, stroke, vascular death) occurred. Yearly cIMT progression was derived from two ultrasound visits 2–7 years (median 4 years) apart. For mean common carotid artery intima-media thickness progression, the overall HR of the combined endpoint was 0·97 (95% CI 0·94–1·00) when adjusted for age, sex, and mean common carotid artery intima-media thickness, and 0·98 (0·95–1·01) when also adjusted for vascular risk factors. Although we detected no associations with cIMT progression in sensitivity analyses, the mean cIMT of the two ultrasound scans was positively and robustly associated with cardiovascular risk (HR for the combined endpoint 1·16, 95% CI 1·10–1·22, adjusted for age, sex, mean common carotid artery intima-media thickness progression, and vascular risk factors). In three studies including 3439 participants who had four ultrasound scans, cIMT progression did not correlate between occassions (reproducibility correlations between r=−0·06 and r=−0·02).
Interpretation
The association between cIMT progression assessed from two ultrasound scans and cardiovascular risk in the general population remains unproven. No conclusion can be derived for the use of cIMT progression as a surrogate in clinical trials.
Funding
Deutsche Forschungsgemeinschaft.
doi:10.1016/S0140-6736(12)60441-3
PMCID: PMC3918517  PMID: 22541275
5.  Body Water Distribution and Risk of Cardiovascular Morbidity and Mortality in a Healthy Population: A Prospective Cohort Study  
PLoS ONE  2014;9(2):e87466.
Background
Early alterations in the cardiovascular structure and function may change normal body water distribution. The resulting fluid shifts may thus serve as an early marker for cardiovascular disease. However, studies examining this in healthy populations are absent.
Objective
This study examined the association between the proportion of total body water that is extracellular water and subsequent development of non-fatal or fatal cardiovascular disease in a healthy population.
Method
Bioelectrical impedance spectroscopy is an easy-to-use, non-invasive and relatively inexpensive technique to evaluate changes in body water distribution. A random subset (n = 2120) of Danes aged 41-71 years, examined in 1993–1994 for body water distribution by bioelectrical impedance spectroscopy was included. Cox-proportional hazard models and linear splines were performed. The ratio between resistance estimates from an infinite-frequency and from no-frequency (R∞/R0) was used as a surrogate measure of ratio between extracellular water and total body water. The outcome was 13.5 years of follow-up for cardiovascular morbidity and mortality.
Results
A high proportion of total body water that is extracellular water was associated with increased risk of incident cardiovascular disease. A threshold effect was evident, with greatly increased risk of cardiovascular morbidity and mortality above R∞/R0 = 0.68. Below the threshold there seemed to be no additional benefit of having a low ratio.
Conclusion
Our findings suggest that non-clinically evident oedema, measured as an increased proportion of total body water that is extracellular, above a threshold of 0.68, may be an early marker of pre-clinical cardiovascular disease. This simple, safe, cheap and easily obtainable measure of R∞/R0 from bioelectrical impedance may help the early identification of these otherwise clinically healthy individuals who are at an increased risk of future cardiovascular disease. However, more studies are needed before it can be concluded that bioelectrical impedance spectroscopy improves clinical risk prediction.
doi:10.1371/journal.pone.0087466
PMCID: PMC3911994  PMID: 24498327
6.  Diabetes Is an Independent Predictor for Severe Osteoarthritis 
Diabetes Care  2013;36(2):403-409.
OBJECTIVE
To evaluate if type 2 diabetes is an independent risk predictor for severe osteoarthritis (OA).
RESEARCH DESIGN AND METHODS
Population-based cohort study with an age- and sex-stratified random sample of 927 men and women aged 40–80 years and followed over 20 years (1990–2010).
RESULTS
Rates of arthroplasty (95% CI) were 17.7 (9.4–30.2) per 1,000 person-years in patients with type 2 diabetes and 5.3 (4.1–6.6) per 1,000 person-years in those without (P < 0.001). Type 2 diabetes emerged as an independent risk predictor for arthroplasty: hazard ratios (95% CI), 3.8 (2.1–6.8) (P < 0.001) in an unadjusted analysis and 2.1 (1.1–3.8) (P = 0.023) after adjustment for age, BMI, and other risk factors for OA. The probability of arthroplasty increased with disease duration of type 2 diabetes and applied to men and women, as well as subgroups according to age and BMI. Our findings were corroborated in cross-sectional evaluation by more severe clinical symptoms of OA and structural joint changes in subjects with type 2 diabetes compared with those without type 2 diabetes.
CONCLUSIONS
Type 2 diabetes predicts the development of severe OA independent of age and BMI. Our findings strengthen the concept of a strong metabolic component in the pathogenesis of OA.
doi:10.2337/dc12-0924
PMCID: PMC3554306  PMID: 23002084
7.  Reaction Time and Mortality from the Major Causes of Death: The NHANES-III Study 
PLoS ONE  2014;9(1):e82959.
Objective
Studies examining the relation of information processing speed, as measured by reaction time, with mortality are scarce. We explored these associations in a representative sample of the US population.
Methods
Participants were 5,134 adults (2,342 men) aged 20–59 years from the Third National Health and Nutrition Examination Survey (NHANES III, 1988–94).
Results
Adjusted for age, sex, and ethnic minority status, a 1 SD slower reaction time was associated with a raised risk of mortality from all-causes (HR = 1.25, 95% CI 1.12, 1.39) and cardiovascular disease (CVD) (HR = 1.36, 95% CI 1.17, 1.58). Having 1 SD more variable reaction time was also associated with greater risk of all-cause (HR = 1.36, 95% CI 1.19, 1.55) and CVD (HR = 1.50, 95% CI 1.33, 1.70) mortality. No associations were observed for cancer mortality. The magnitude of the relationships was comparable in size to established risk factors in this dataset, such as smoking.
Interpretation
Alongside better-established risk factors, reaction time is associated with increased risk of premature death and cardiovascular disease. It is a candidate risk factor for all-cause and cause-specific mortality.
doi:10.1371/journal.pone.0082959
PMCID: PMC3906008  PMID: 24489645
8.  Lipoprotein-Associated Phospholipase A2 Is Associated with Atherosclerotic Stroke Risk: The Northern Manhattan Study 
PLoS ONE  2014;9(1):e83393.
Background
Lipoprotein-associated phospholipase A2 (LpPLA2) levels are associated with stroke, though whether this extends to all populations and stroke subtypes is unknown.
Methods
Serum samples from stroke-free community participants in the Northern Manhattan Study were assayed for LpPLA2 mass and activity. Participants were followed annually for stroke. Cox-proportional-hazard models were fitted to estimate hazard-ratios and 95% confidence intervals (HR, 95% CI) for the association of LpPLA2 levels with ischemic stroke (IS), after adjusting for demographic and medical risk factors.
Results
Serum samples were available in 1946 participants, of whom 151 (7.8%) experienced a first IS during median follow-up 11 years. Mean age was 69 (SD 10), 35.6% were men, 20% non-Hispanic Whites, 22% non-Hispanic Blacks, and 55% Hispanics. LpPLA2 mass and activity levels were not associated with overall IS risk.
LpPLA2 mass but not activity levels were associated with strokes due to large artery atherosclerosis (LAA; adjusted HR per SD 1.55, 95% CI 1.17–2.04). There was a dose-response relationship with LAA (compared to first quartile, 2nd quartile HR = 1.43, 95% CI 0.23–8.64; 3rd quartile HR = 4.47, 95% CI 0.93–21.54; 4th quartile HR = 5.07, 95% CI 1.07–24.06). The associations between LpPLA2-mass and LAA-stroke risk differed by race-ethnicity (p = 0.01); LpPLA2-mass was associated with increased risk of LAA among non-Hispanic Whites (adjusted HR per SD 1.44, 95% CI 0.98–2.11), but not other race-ethnic groups.
Conclusion
LpPLA2-mass levels were associated with risk of atherosclerotic stroke among non-Hispanic White participants, but not in other race-ethnic groups in the cohort. Further study is needed to confirm these race-ethnic differences and the reasons for them.
doi:10.1371/journal.pone.0083393
PMCID: PMC3886969  PMID: 24416164
9.  Assessing Risk Prediction Models Using Individual Participant Data From Multiple Studies 
Pennells, Lisa | Kaptoge, Stephen | White, Ian R. | Thompson, Simon G. | Wood, Angela M. | Tipping, Robert W. | Folsom, Aaron R. | Couper, David J. | Ballantyne, Christie M. | Coresh, Josef | Goya Wannamethee, S. | Morris, Richard W. | Kiechl, Stefan | Willeit, Johann | Willeit, Peter | Schett, Georg | Ebrahim, Shah | Lawlor, Debbie A. | Yarnell, John W. | Gallacher, John | Cushman, Mary | Psaty, Bruce M. | Tracy, Russ | Tybjærg-Hansen, Anne | Price, Jackie F. | Lee, Amanda J. | McLachlan, Stela | Khaw, Kay-Tee | Wareham, Nicholas J. | Brenner, Hermann | Schöttker, Ben | Müller, Heiko | Jansson, Jan-Håkan | Wennberg, Patrik | Salomaa, Veikko | Harald, Kennet | Jousilahti, Pekka | Vartiainen, Erkki | Woodward, Mark | D'Agostino, Ralph B. | Bladbjerg, Else-Marie | Jørgensen, Torben | Kiyohara, Yutaka | Arima, Hisatomi | Doi, Yasufumi | Ninomiya, Toshiharu | Dekker, Jacqueline M. | Nijpels, Giel | Stehouwer, Coen D. A. | Kauhanen, Jussi | Salonen, Jukka T. | Meade, Tom W. | Cooper, Jackie A. | Cushman, Mary | Folsom, Aaron R. | Psaty, Bruce M. | Shea, Steven | Döring, Angela | Kuller, Lewis H. | Grandits, Greg | Gillum, Richard F. | Mussolino, Michael | Rimm, Eric B. | Hankinson, Sue E. | Manson, JoAnn E. | Pai, Jennifer K. | Kirkland, Susan | Shaffer, Jonathan A. | Shimbo, Daichi | Bakker, Stephan J. L. | Gansevoort, Ron T. | Hillege, Hans L. | Amouyel, Philippe | Arveiler, Dominique | Evans, Alun | Ferrières, Jean | Sattar, Naveed | Westendorp, Rudi G. | Buckley, Brendan M. | Cantin, Bernard | Lamarche, Benoît | Barrett-Connor, Elizabeth | Wingard, Deborah L. | Bettencourt, Richele | Gudnason, Vilmundur | Aspelund, Thor | Sigurdsson, Gunnar | Thorsson, Bolli | Kavousi, Maryam | Witteman, Jacqueline C. | Hofman, Albert | Franco, Oscar H. | Howard, Barbara V. | Zhang, Ying | Best, Lyle | Umans, Jason G. | Onat, Altan | Sundström, Johan | Michael Gaziano, J. | Stampfer, Meir | Ridker, Paul M. | Michael Gaziano, J. | Ridker, Paul M. | Marmot, Michael | Clarke, Robert | Collins, Rory | Fletcher, Astrid | Brunner, Eric | Shipley, Martin | Kivimäki, Mika | Ridker, Paul M. | Buring, Julie | Cook, Nancy | Ford, Ian | Shepherd, James | Cobbe, Stuart M. | Robertson, Michele | Walker, Matthew | Watson, Sarah | Alexander, Myriam | Butterworth, Adam S. | Angelantonio, Emanuele Di | Gao, Pei | Haycock, Philip | Kaptoge, Stephen | Pennells, Lisa | Thompson, Simon G. | Walker, Matthew | Watson, Sarah | White, Ian R. | Wood, Angela M. | Wormser, David | Danesh, John
American Journal of Epidemiology  2013;179(5):621-632.
Individual participant time-to-event data from multiple prospective epidemiologic studies enable detailed investigation into the predictive ability of risk models. Here we address the challenges in appropriately combining such information across studies. Methods are exemplified by analyses of log C-reactive protein and conventional risk factors for coronary heart disease in the Emerging Risk Factors Collaboration, a collation of individual data from multiple prospective studies with an average follow-up duration of 9.8 years (dates varied). We derive risk prediction models using Cox proportional hazards regression analysis stratified by study and obtain estimates of risk discrimination, Harrell's concordance index, and Royston's discrimination measure within each study; we then combine the estimates across studies using a weighted meta-analysis. Various weighting approaches are compared and lead us to recommend using the number of events in each study. We also discuss the calculation of measures of reclassification for multiple studies. We further show that comparison of differences in predictive ability across subgroups should be based only on within-study information and that combining measures of risk discrimination from case-control studies and prospective studies is problematic. The concordance index and discrimination measure gave qualitatively similar results throughout. While the concordance index was very heterogeneous between studies, principally because of differing age ranges, the increments in the concordance index from adding log C-reactive protein to conventional risk factors were more homogeneous.
doi:10.1093/aje/kwt298
PMCID: PMC3927974  PMID: 24366051
C index; coronary heart disease; D measure; individual participant data; inverse variance; meta-analysis; risk prediction; weighting
10.  Rating of Everyday Arm-Use in the Community and Home (REACH) Scale for Capturing Affected Arm-Use after Stroke: Development, Reliability, and Validity 
PLoS ONE  2013;8(12):e83405.
Objective
To develop a brief, valid and reliable tool [the Rating of Everyday Arm-use in the Community and Home (REACH) scale] to classify affected upper limb use after stroke outside the clinical setting.
Methods
Focus groups with clinicians, patients and caregivers (n = 33) and a literature review were employed to develop the REACH scale. A sample of community-dwelling individuals with stroke was used to assess the validity (n = 96) and inter-rater reliability (n = 73) of the new scale.
Results
The REACH consists of separate scales for dominant and non-dominant affected upper limbs, and takes five minutes to administer. Each scale consists of six categories that capture ‘no use’ to ‘full use’. The intraclass correlation coefficient and weighted kappa for inter-rater reliability were 0.97 (95% confidence interval: 0.95–0.98) and 0.91 (0.89–0.93) respectively. REACH scores correlated with external measures of upper extremity use, function and impairment (rho = 0.64–0.94).
Conclusions
The REACH scale is a reliable, quick-to-administer tool that has strong relationships to other measures of upper limb use, function and impairment. By providing a rich description of how the affected upper limb is used outside of the clinical setting, the REACH scale fills an important gap among current measures of upper limb use and is useful for understanding the long term effects of stroke rehabilitation.
doi:10.1371/journal.pone.0083405
PMCID: PMC3865179  PMID: 24358282
11.  The Relationship of Walking Intensity to Total and Cause-Specific Mortality. Results from the National Walkers’ Health Study 
PLoS ONE  2013;8(11):e81098.
Purpose
Test whether: 1) walking intensity predicts mortality when adjusted for walking energy expenditure, and 2) slow walking pace (≥24-minute mile) identifies subjects at substantially elevated risk for mortality.
Methods
Hazard ratios from Cox proportional survival analyses of all-cause and cause-specific mortality vs. usual walking pace (min/mile) in 7,374 male and 31,607 female recreational walkers. Survival times were left censored for age at entry into the study. Other causes of death were treated as a competing risk for the analyses of cause-specific mortality. All analyses were adjusted for sex, education, baseline smoking, prior heart attack, aspirin use, diet, BMI, and walking energy expenditure. Deaths within one year of baseline were excluded.
Results
The National Death Index identified 1968 deaths during the average 9.4-year mortality surveillance. Each additional minute per mile in walking pace was associated with an increased risk of mortality due to all causes (1.8% increase, P=10-5), cardiovascular diseases (2.4% increase, P=0.001, 637 deaths), ischemic heart disease (2.8% increase, P=0.003, 336 deaths), heart failure (6.5% increase, P=0.001, 36 deaths), hypertensive heart disease (6.2% increase, P=0.01, 31 deaths), diabetes (6.3% increase, P=0.004, 32 deaths), and dementia (6.6% increase, P=0.0004, 44 deaths). Those reporting a pace slower than a 24-minute mile were at increased risk for mortality due to all-causes (44.3% increased risk, P=0.0001), cardiovascular diseases (43.9% increased risk, P=0.03), and dementia (5.0-fold increased risk, P=0.0002) even though they satisfied the current exercise recommendations by walking ≥7.5 metabolic equivalent (MET)-hours per week.
Conclusions
The risk for mortality: 1) decreases in association with walking intensity, and 2) increases substantially in association for walking pace ≥24 minute mile (equivalent to <400m during a six-minute walk test) even among subjects who exercise regularly.
doi:10.1371/journal.pone.0081098
PMCID: PMC3834211  PMID: 24260542
12.  Sex and age interaction with genetic association of atherogenic uric acid concentrations 
Atherosclerosis  2009;210(2):474-478.
Background
High serum uric acid levels are associated with gout, atherosclerosis and cardiovascular disease. Three genes (SLC2A9, ABCG2, and SLC17A3) were reported to be involved in the regulation of uric acid levels.
Research
Design and Methods: SNPs rs2231142 (ABCG2) and rs1165205 (SLC17A3) were genotyped in three cohorts (n = 4492) and combined with previously genotyped SNPs within SLC2A9 (rs6855911, rs7442295, rs6449213, rs12510549).
Results
Each copy of the minor allele decreased uric acid levels by 0.30–0.38 mg/dL for SLC2A9 (p values: 10−20–10−36) and increased levels by 0.34 mg/dL for ABCG2 (p = 1.1×10−16). SLC17A3 influenced uric acid levels only modestly. Together the SNPs showed graded associations with uric acid levels of 0.111 mg/dL per risk allele (p = 3.8×10−42). In addition, we observed a sex-specific interaction of age with the association of SLC2A9 SNPs with uric acid levels, where increasing age strengthened the association of SNPs in women and decreased the association in men.
Conclusions
Genetic variants within SLC2A9, ABCG2 and SLC17A3 show highly significant associations with uric acid levels, and for SNPs within SLC2A9 this association is strongly modified by age and sex.
doi:10.1016/j.atherosclerosis.2009.12.013
PMCID: PMC3793203  PMID: 20053405
Epidemiology; Genetics; Uric acid; Copy number variation; Sex-specific effect; Genetic risk score
13.  C-Reactive Protein and B-Type Natriuretic Peptide Yield Either a Non-Significant or a Modest Incremental Value to Traditional Risk Factors in Predicting Long-Term Overall Mortality in Older Adults 
PLoS ONE  2013;8(9):e75809.
Background
New biomarkers may aid in preventive and end-of-life decisions in older adults if they enhance the prognostic ability of traditional risk factors. We investigated whether C-reactive protein (CRP) and/or B-type natriuretic peptide (BNP) improve the ability to predict overall mortality among the elderly of the Bambuí, Brazil Study of Aging when added to traditional risk factors.
Methods
From 1997 to 2007, 1,470 community-dwelling individuals (≥60 years) were followed-up. Death was ascertained by continuous verification of death certificates. We calculated hazard ratios per 1 standard deviation change (HR) of death for traditional risk factors only (old model), and traditional risk factors plus CRP and/or BNP (new models) and assessed calibration of the models. Subsequently, we compared c-statistic of each of the new models to the old one, and calculated integrated discriminative improvement (IDI) and net reclassification improvement (NRI).
Results
544 (37.0%) participants died in a mean follow-up time of 9.0 years. CRP (HR 1.28, 95% CI 1.17-1.40), BNP (HR 1.31 95% CI 1.19-1.45), and CRP plus BNP (HR 1.26, 95% CI 1.15-1.38, and HR 1.29, 95% CI 1.16-1.42, respectively) were independent determinants of mortality. All models were well-calibrated. Discrimination was similar among the old (c-statistic 0.78 [0.78-0.81]) and new models (p=0.43 for CRP; p=0.57 for BNP; and p=0.31 for CRP plus BNP). Compared to the old model, CRP, BNP, and CRP plus BNP models led to an IDI of 0.009 (p<0.001), -0.005 (p<0.001) and -0.003 (p=0.84), and a NRI of 0.04 (p=0.24), 0.07 (p=0.08) and 0.06 (p=0.10), respectively.
Conclusions
Despite being independent predictors of long-term risk of death, compared to traditional risk factors CRP and/or BNP led to either a modest or non-significant improvement in the ability of predicting all-cause mortality in older adults.
doi:10.1371/journal.pone.0075809
PMCID: PMC3815403  PMID: 24244755
14.  A common variant in the adiponutrin gene influences liver enzyme levels 
Journal of medical genetics  2009;47(2):116-119.
Background
Two recent genome-wide association studies identified the liver-expressed transmembrane protein adiponutrin to be associated with liver-related phenotypes such as nonalcoholic fatty liver disease and liver function enzymes. These associations were not uniformly reported for various ethnicities. The aim of this study was to investigate a common nonsynonymous variant within adiponutrin (rs738409, exon 3) with parameters of liver function in three independent West-Eurasian study populations including a total of 4290 participants.
Methods
The study was performed in 1) the population-based Bruneck Study (n=783), 2) the SAPHIR Study from Austria based on a healthy working population (n=1705), and the Utah Obesity Case-Control Study including a group of 1019 severely obese individuals (average BMI 46.0 kg/m2) and 783 controls from the same geographical region of Utah. Liver enzymes measured were alanine-aminotransferase (ALT), aspartate-aminotransferase (AST) and gamma-glutamyl transferase (GGT).
Results and Discussion
We found a strong recessive association of this polymorphism with age- and gender-adjusted ALT and AST levels: being homozygous for the minor allele resulted in a highly significant increase of ALT levels of 3.53 U/L (p=1.86×10−9) and of AST levels of 2.07 U/L (p=9.58×10−6), respectively. The associations were consistently found in all three study populations. In conclusion, the highly significant associations of this transversion polymorphism within the adiponutrin gene with increased ALT and AST levels support a role for adiponutrin as a susceptibility gene for hepatic dysfunction.
doi:10.1136/jmg.2009.066597
PMCID: PMC3759243  PMID: 19542081
PNPLA3; rs738409; genetic association; hepatic dysfunction
15.  Long-Term Effects of Statin Treatment in Elderly People: Extended Follow-Up of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) 
PLoS ONE  2013;8(9):e72642.
Background
The PROspective Study of Pravastatin in the Elderly at Risk (PROSPER), a placebo-controlled trial of pravastatin, demonstrated a 19% reduction in coronary outcomes (p = 0.006) after a mean of 3.2 years, with no impact on stroke outcomes or all-cause mortality. However, there was a suggestion of increased cancer risk. Our aim is to determine the long-term benefits and safety of pravastatin treatment in older people using post-trial follow-up of the PROSPER participants.
Methods
5,804 (2,520 Scottish) men and women aged 70–82 years with either pre-existing vascular disease or increased risk of such disease because of smoking, hypertension or diabetes, were randomised to 40 mg pravastatin or matching placebo. Using record linkage to routinely collected health records, all participants (full cohort) were linked to death and cancer registries, and the Scottish cohort additionally to hospital admissions, to provide composite fatal/non-fatal cardiovascular outcomes (total mean follow-up 8.6 years).
Results
Pravastatin treatment for 3.2 years reduced CHD death in the full cohort, hazard ratio (HR) 0.80, 95% confidence interval (CI) 0.68–0.95, p = 0.0091 and fatal coronary events or coronary hospitalisations in the Scottish cohort (HR 0.81, 95% CI 0.69–0.95, p = 0.0081) over 8.6 years. There was no reduction in stroke or all-cause mortality. Cancer risk was not increased in the full cohort (HR 1.08, 95% CI 0.96–1.21, p = 0.22).
Conclusions
Pravastatin treatment of elderly high-risk subjects for 3.2 years provided long-term protection against CHD events and CHD mortality. However, this was not associated with any increase in life expectancy, possibly due to competing mortality with deaths from other causes. There was no evidence of long-term increased risk of cancer.
Trial registration
ISRCTN40976937.
doi:10.1371/journal.pone.0072642
PMCID: PMC3759378  PMID: 24023757
16.  Plasma Lipid Composition and Risk of Developing Cardiovascular Disease 
PLoS ONE  2013;8(8):e71846.
Aims
We tested whether characteristic changes of the plasma lipidome in individuals with comparable total lipids level associate with future cardiovascular disease (CVD) outcome and whether 23 validated gene variants associated with coronary artery disease (CAD) affect CVD associated lipid species.
Methods and Results
Screening of the fasted plasma lipidome was performed by top-down shotgun analysis and lipidome compositions compared between incident CVD cases (n = 211) and controls (n = 216) from the prospective population-based MDC study using logistic regression adjusting for Framingham risk factors. Associations with incident CVD were seen for eight lipid species (0.21≤q≤0.23). Each standard deviation unit higher baseline levels of two lysophosphatidylcholine species (LPC), LPC16∶0 and LPC20∶4, was associated with a decreased risk for CVD (P = 0.024–0.028). Sphingomyelin (SM) 38∶2 was associated with increased odds of CVD (P = 0.057). Five triglyceride (TAG) species were associated with protection (P = 0.031–0.049). LPC16∶0 was negatively correlated with the carotid intima-media thickness (P = 0.010) and with HbA1c (P = 0.012) whereas SM38∶2 was positively correlated with LDL-cholesterol (P = 0.0*10−6) and the q-values were good (q≤0.03). The risk allele of 8 CAD-associated gene variants showed significant association with the plasma level of several lipid species. However, the q-values were high for many of the associations (0.015≤q≤0.75). Risk allele carriers of 3 CAD-loci had reduced level of LPC16∶0 and/or LPC 20∶4 (P≤0.056).
Conclusion
Our study suggests that CVD development is preceded by reduced levels of LPC16∶0, LPC20∶4 and some specific TAG species and by increased levels of SM38∶2. It also indicates that certain lipid species are intermediate phenotypes between genetic susceptibility and overt CVD. But it is a preliminary study that awaits replication in a larger population because statistical significance was lost for the associations between lipid species and future cardiovascular events when correcting for multiple testing.
doi:10.1371/journal.pone.0071846
PMCID: PMC3744469  PMID: 23967253
17.  Optimal Waist-to-Height Ratio Values for Cardiometabolic Risk Screening in an Ethnically Diverse Sample of South African Urban and Rural School Boys and Girls 
PLoS ONE  2013;8(8):e71133.
Background
The proposed waist-to-height ratio (WHtR) cut-off of 0.5 is less optimal for cardiometabolic risk screening in children in many settings. The purpose of this study was to determine the optimal WHtR for children from South Africa, and investigate variations by gender, ethnicity and residence in the achieved value.
Methods
Metabolic syndrome (MetS) components were measured in 1272 randomly selected learners, aged 10–16 years, comprising of 446 black Africans, 696 mixed-ancestry and 130 Caucasians. The Youden’s index and the closest-top-left (CTL) point approaches were used to derive WHtR cut-offs for diagnosing any two MetS components, excluding the waist circumference.
Results
The two approaches yielded similar cut-off in girls, 0.465 (sensitivity 50.0, specificity 69.5), but two different values in boys, 0.455 (42.9, 88.4) and 0.425 (60.3, 67.7) based on the Youden’s index and the CTL point, respectively. Furthermore, WHtR cut-off values derived differed substantially amongst the regions and ethnic groups investigated, whereby the highest cut-off was observed in semi-rural and white children, respectively, Youden’s index0.505 (31.6, 87.1) and CTL point 0.475 (44.4, 75.9).
Conclusion
The WHtR cut-off of 0.5 is less accurate for screening cardiovascular risk in South African children. The optimal value in this setting is likely gender and ethnicity-specific and sensitive to urbanization.
doi:10.1371/journal.pone.0071133
PMCID: PMC3742786  PMID: 23967160
18.  Light-Intensity Physical Activity and Cardiometabolic Biomarkers in US Adolescents 
PLoS ONE  2013;8(8):e71417.
Background
The minimal physical activity intensity that would confer health benefits among adolescents is unknown. The purpose of this study was to examine the associations of accelerometer-derived light-intensity (split into low and high) physical activity, and moderate- to vigorous-intensity physical activity with cardiometabolic biomarkers in a large population-based sample.
Methods
The study is based on 1,731 adolescents, aged 12–19 years from the 2003/04 and 2005/06 National Health and Nutrition Examination Survey. Low light-intensity activity (100–799 counts/min), high light-intensity activity (800 counts/min to <4 METs) and moderate- to vigorous-intensity activity (≥4 METs, Freedson age-specific equation) were accelerometer-derived. Cardiometabolic biomarkers, including waist circumference, systolic blood pressure, diastolic blood pressure, HDL-cholesterol, and C-reactive protein were measured. Triglycerides, LDL- cholesterol, insulin, glucose, and homeostatic model assessments of β-cell function (HOMA-%B) and insulin sensitivity (HOMA-%S) were also measured in a fasting sub-sample (n = 807).
Results
Adjusted for confounders, each additional hour/day of low light-intensity activity was associated with 0.59 (95% CI: 1.18–0.01) mmHG lower diastolic blood pressure. Each additional hour/day of high light-intensity activity was associated with 1.67 (2.94–0.39) mmHG lower diastolic blood pressure and 0.04 (0.001–0.07) mmol/L higher HDL-cholesterol. Each additional hour/day of moderate- to vigorous-intensity activity was associated with 3.54 (5.73–1.35) mmHG lower systolic blood pressure, 5.49 (1.11–9.77)% lower waist circumference, 25.87 (6.08–49.34)% lower insulin, and 16.18 (4.92–28.53)% higher HOMA-%S.
Conclusions
Time spent in low light-intensity physical activity and high light-intensity physical activity had some favorable associations with biomarkers. Consistent with current physical activity recommendations for adolescents, moderate- to vigorous-intensity activity had favorable associations with many cardiometabolic biomarkers. While increasing MVPA should still be a public health priority, further studies are needed to identify dose-response relationships for light-intensity activity thresholds to inform future recommendations and interventions for adolescents.
doi:10.1371/journal.pone.0071417
PMCID: PMC3739773  PMID: 23951157
19.  Prevalence and Burden of Gait Disorders in Elderly Men and Women Aged 60–97 Years: A Population-Based Study 
PLoS ONE  2013;8(7):e69627.
Background
Although gait disorders are common in the elderly, the prevalence and overall burden of these disorders in the general community is not well defined.
Methods
In a cross-sectional investigation of the population-based Bruneck Study cohort, 488 community-residing elderly aged 60–97 years underwent a thorough neurological assessment including a standardized gait evaluation. Gait disorders were classified according to an accepted scheme and their associations to falls, neuropsychological measures, and quality of life were explored.
Results
Overall, 32.2% (95% confidence interval [CI] 28.2%–36.4%) of participants presented with impaired gait. Prevalence increased with age (p<0.001), but 38.3% (95%CI 30.1%–47.3%) of the subjects aged 80 years or older still had a normally preserved gait. A total of 24.0% (95%CI 20.4%–28.0%) manifested neurological gait disorders, 17.4% (14.3%–21.0%) non-neurological gait problems, and 9.2% (6.9%–12.1%) a combination of both. While there was no association of neurological gait disorders with gender, non-neurological gait disorders were more frequent in women (p = 0.012). Within the group of neurological gait disorders 69.2% (95%CI 60.3%–76.9%) had a single distinct entity and 30.8% (23.1%–39.7%) had multiple neurological causes for gait impairment. Gait disorders had a significant negative impact on quantitative gait measures, but only neurological gait disorders were associated with recurrent falls (odds ratio 3.3; 95%CI 1.4–7.5; p = 0.005 for single and 7.1; 2.7–18.7; p<0.001 for multiple neurological gait disorders). Finally, we detected a significant association of gait disorders, in particular neurological gait disorders, with depressed mood, cognitive dysfunction, and compromised quality of life.
Conclusions
Gait disorders are common in the general elderly population and are associated with reduced mobility. Neurological gait disorders in particular are associated with recurrent falls, lower cognitive function, depressed mood, and diminished quality of life.
doi:10.1371/journal.pone.0069627
PMCID: PMC3722115  PMID: 23894511
20.  Association of Mitochondrial Genetic Variation with Carotid Atherosclerosis 
PLoS ONE  2013;8(7):e68070.
In human pathology, several diseases are associated with somatic mutations in the mitochondrial genome (mtDNA). Even though mitochondrial dysfunction leads to increased oxidative stress, the role of mitochondrial mutations in atherosclerosis has not received much attention so far. In this study we analyzed the association of mitochondrial genetic variation with the severity of carotid atherosclerosis, as assessed by carotid intima-media thickness (cIMT) and the presence of coronary heart disease (CHD) in 190 subjects from Moscow, Russia, a population with high CHD occurrence. cIMT was measured by high-resolution B-mode ultrasonography and mtDNA heteroplasmies by a pyrosequencing-based method. We found that heteroplasmies for several mutations in the mtDNA in leukocytes, including C3256T, T3336C, G12315A, G13513A, G14459A, G14846A, and G15059A mutations, were significantly (p<0.001) associated with both the severity of carotid atherosclerosis and the presence of CHD. These findings indicate that somatic mitochondrial mutations have a role in the development of atherosclerosis.
doi:10.1371/journal.pone.0068070
PMCID: PMC3706616  PMID: 23874496
21.  Association of Body Iron Status with the Risk of Premature Acute Myocardial Infarction in a Pakistani Population 
PLoS ONE  2013;8(6):e67981.
Background
Coronary artery disease is very common in Pakistani population. Some of the studies carried out on Western populations have shown a relationship between body iron status as determined by the ratio of concentrations of serum soluble transferrin receptor (sTfR) to ferritin and the risk of acute myocardial infarction (AMI). In order to investigate whether increased body iron status has any relationship with the risk of premature AMI in Pakistani population, a case-control study was carried out.
Methodology/Principal findings
In this case-control study, 203 consecutive AMI patients [146 males and 57 females; age range 18–45 years] admitted to the National Institute for Cardiovascular Diseases, Karachi, were enrolled with informed consent. In addition, 205 healthy controls whose gender and age (within 3 years) matched the patients, and who had a similar socio-economic background were recruited. Fasting venous blood was obtained and assessed for plasma/serum folate, vitamin B12, homocysteine, total cholesterol, triglycerides, LDL-cholesterol, HDL-cholesterol, sTfR and ferritin and blood lead. It was found that serum concentration of ferritin and blood lead levels were significantly higher in AMI patients compared to their age and gender-matched healthy controls (p value <0.05), while the concentrations of vitamin B12 and HDL-cholesterol were significantly lower in AMI patients compared to controls (p value <0.01). The ratio of sTfR to ferritin was significantly lower in AMI patients compared to controls [mean±SD/median (IQR) values 84.7±295/28.9 (38.4) vs 255±836/49.4 (83.8), respectively; p value <0.001]. Compared with the highest quartile of sTfR/ferritin (low body iron status), the OR for the risk of AMI was 3.29(95% CI, 1.54–7.03) for the lowest quartile (quartile 1) when the model was adjusted for vitamin B12 and HDL-cholesterol (p value for trend <0.01).
Conclusions/Significance
This study shows a positive association between total body iron status and risk of premature AMI in a Pakistani population.
doi:10.1371/journal.pone.0067981
PMCID: PMC3695953  PMID: 23840800
22.  Reconstructive Treatment of Ruptured Intracranial Spontaneous Vertebral Artery Dissection Aneurysms: Long-Term Results and Predictors of Unfavorable Outcomes 
PLoS ONE  2013;8(6):e67169.
Introduction
Few studies focused on predictors of unfavorable outcomes (modified Rankin Scale, 2–6) after reconstructive treatment of the ruptured intracranial spontaneous vertebral artery dissection aneurysms (ris-VADAs), which was evaluated based on 57 reconstructed lesions in this study.
Methods
Results of 57 consecutive patients (M:F = 29∶28; median age, 48 years; range, 27 to 69 years) harboring 57 ris-VADAs, which were treated with coils combined with single stent(n = 32), double overlapping stents (n = 16), and triple overlapping stents (n = 9) between October 2000 to March 2011, were retrospectively reviewed and analyzed.
Results
The available (n = 54) mean durations of angiographic and clinical follow-ups were 27 months (range, 12 to 78) and 62 months (range, 12 to 132), respectively. The involvement of PICA (p = 0.004), size of lesions (p = 0.000), quantity of stent (p = 0.001), and coil type (p = 0.002) affected the immediate obliteration grade, which was only risk factor for angiographic recurrences (p = 0.031). Although the post-treatment outcomes did not differ between single stent and multiple stents (p = 0.434), 5 angiographic recurrences, 1 rebleeding and 1 suspected rebleeding, all occurred in partial obliteration after single-stent-assisted coiling. Progressive thrombosis and in-stent obliteration were not detected on follow-up angiograms. Older age (odds ratio [OR] = 1.090; 95% confidence interval [CI], 1.004–1.184; p = 0.040) and unfavorable Hunt-Hess scale (OR = 4.289; 95%CI, 1.232–14.933; p = 0.022) were independent predictors of unfavorable outcomes in the reconstructed ris-VADAs.
Conclusions
Immediate obliteration grade was only risk factor for angiographic recurrence after reconstructive treatment. Unfavorable Hunt-Hess grade and older age were independent predictors of unfavorable outcomes in ris-VADAs.
doi:10.1371/journal.pone.0067169
PMCID: PMC3693966  PMID: 23840616
23.  Thrombin Generation in the Glasgow Myocardial Infarction Study 
PLoS ONE  2013;8(6):e66977.
Background
Thrombin is a key protease in coagulation also implicated in complex pathology including atherosclerosis. To address the role of thrombin in relation to myocardial infarction (MI) we explored thrombin generation analysis in plasma from patients and controls that had participated in the Glasgow MI Study (GLAMIS).
Methods
Thrombin generation at 1 and 2 pM TF and with and without thrombomodulin (TM) was performed on plasmas from 356 subjects (171 cases, 185 age and sex matched controls) from GLAMIS collected between 3 and 9 months after the MI event.
Results
Although thrombin generation was slightly delayed in cases (lag time increased from 3.3 to 3.6 min) at the highest trigger, the overall potential to generate thrombin was increased by 7% for the ETP and by 15% for the peak height (both at the 1 pM TF trigger) in cases. Addition of TM did not reveal differences. Furthermore, an increased thrombin generation was associated with MI [normalized ETP: adjusted OR for the highest percentile = 2.4 (95% CI 1.3–4.5) and normalized peak height: adjusted OR = 2.6 (1.3–5.0)] at the lowest trigger; normalized ETP and peak height being 2.1 (1.1–3.8) and 2.0 (1.0–4.1) at the higher 2 pM trigger.
Conclusion
In GLAMIS, patients with a previous MI had an increased thrombin generation compared to controls. The absence of a clear difference in TM reduction suggests an unaltered anticoagulant activity in these patients. Further research is needed in order to unravel the underlying mechanisms of enhanced thrombin generation after MI.
doi:10.1371/journal.pone.0066977
PMCID: PMC3691168  PMID: 23826181
24.  Increasing Prevalence of Metabolic Syndrome in a Chinese Elderly Population: 2001–2010 
PLoS ONE  2013;8(6):e66233.
Objective
The information on the changes of prevalence of MetS in China is limited. Our objective was to assess a 10-year’s change of the prevalence of MetS in a Chinese elderly population between 2001 and 2010.
Methods
We conducted two cross-sectional surveys in a representative sample of elderly population aged 60 to 95 years in Beijing in 2001 and 2010 respectively. MetS was defined according to the 2009 harmonizing definition.
Results
A total of 2,334 participants (943 male, 1,391 female) in 2001 and 2,102 participants (848 male, 1,254 female) in 2010 completed the survey. The prevalence of MetS was 50.4% (95%CI: 48.4%–52.4%) in 2001 and 58.1% (95%CI: 56.0%–60.2%) in 2010. The absolute change of prevalence of MetS was 7.7% over the 10-year’s period (p<0.001). The syndrome was more common in female than male in both survey years. Among the five components, hypertriglyceridemia and low HDL-C had increased most, with an increase of 14.8% (from 29.4% to 44.2%) and 9.9% (from 28.3% to 38.2%) respectively. The adjusted ORs of MetS for CHD, stroke and CVD were 1.67(95%CI: 1.39–1.99), 1.50(95%CI: 1.19–1.88) and 1.70(95%CI: 1.43–2.01) respectively in 2001, and were 1.74(95%CI: 1.40–2.17), 1.25(95%CI: 0.95–1.63) and 1.52(95%CI: 1.25–1.86) respectively in 2010.
Conclusion
The prevalence of MetS is high and increasing rapidly in this Chinese elderly population. Participants with Mets and its individual components are at significantly elevated ORs for CVD. Urgent public health actions are needed to control MetS and its components, especially for dislipidemia.
doi:10.1371/journal.pone.0066233
PMCID: PMC3688874  PMID: 23824753
25.  Plasma Processing Conditions Substantially Influence Circulating microRNA Biomarker Levels 
PLoS ONE  2013;8(6):e64795.
Circulating, cell-free microRNAs (miRNAs) are promising candidate biomarkers, but optimal conditions for processing blood specimens for miRNA measurement remain to be established. Our previous work showed that the majority of plasma miRNAs are likely blood cell-derived. In the course of profiling lung cancer cases versus healthy controls, we observed a broad increase in circulating miRNA levels in cases compared to controls and that higher miRNA expression correlated with higher platelet and particle counts. We therefore hypothesized that the quantity of residual platelets and microparticles remaining after plasma processing might impact miRNA measurements. To systematically investigate this, we subjected matched plasma from healthy individuals to stepwise processing with differential centrifugation and 0.22 µm filtration and performed miRNA profiling. We found a major effect on circulating miRNAs, with the majority (72%) of detectable miRNAs substantially affected by processing alone. Specifically, 10% of miRNAs showed 4–30x variation, 46% showed 30-1,000x variation, and 15% showed >1,000x variation in expression solely from processing. This was predominantly due to platelet contamination, which persisted despite using standard laboratory protocols. Importantly, we show that platelet contamination in archived samples could largely be eliminated by additional centrifugation, even in frozen samples stored for six years. To minimize confounding effects in microRNA biomarker studies, additional steps to limit platelet contamination for circulating miRNA biomarker studies are necessary. We provide specific practical recommendations to help minimize confounding variation attributable to plasma processing and platelet contamination.
doi:10.1371/journal.pone.0064795
PMCID: PMC3676411  PMID: 23762257

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