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1.  Distribution, size, shape, growth potential and extent of abdominal aortic calcified deposits predict mortality in postmenopausal women 
Aortic calcification is a major risk factor for death from cardiovascular disease. We investigated the relationship between mortality and the composite markers of number, size, morphology and distribution of calcified plaques in the lumbar aorta.
308 postmenopausal women aged 48-76 were followed for 8.3 ± 0.3 years, with deaths related to cardiovascular disease, cancer, or other causes being recorded. From lumbar X-rays at baseline the number (NCD), size, morphology and distribution of aortic calcification lesions were scored and combined into one Morphological Atherosclerotic Calcification Distribution (MACD) index. The hazard ratio for mortality was calculated for the MACD and for three other commonly used predictors: the EU SCORE card, the Framingham Coronary Heart Disease Risk Score (Framingham score), and the gold standard Aortic Calcification Severity score (AC24) developed from the Framingham Heart Study cohorts.
All four scoring systems showed increasing age, smoking, and raised triglyceride levels were the main predictors of mortality after adjustment for all other metabolic and physical parameters. The SCORE card and the Framingham score resulted in a mortality hazard ratio increase per standard deviation (HR/SD) of 1.8 (1.51-2.13) and 2.6 (1.87-3.71), respectively. Of the morphological x-ray based measures, NCD revealed a HR/SD >2 adjusted for SCORE/Framingham. The MACD index scoring the distribution, size, morphology and number of lesions revealed the best predictive power for identification of patients at risk of mortality, with a hazard ratio of 15.6 (p < 0.001) for the 10% at greatest risk of death.
This study shows that it is not just the extent of aortic calcification that predicts risk of mortality, but also the distribution, shape and size of calcified lesions. The MACD index may provide a more sensitive predictor of mortality from aortic calcification than the commonly used AC24 and SCORE/Framingham point card systems.
PMCID: PMC2996339  PMID: 21067610
2.  One-year follow-up of a therapeutic lifestyle intervention targeting cardiovascular disease risk 
In this study, we tested the efficacy of a low-intensity lifestyle intervention aimed at reducing the risk of cardiovascular disease among mid-life individuals.
We conducted a randomized controlled trial in which participants were randomly assigned either to receive a health report card with counselling (from a Telehealth nurse) on smoking, exercise, nutrition and stress or to receive usual care. The patients were divided into 2 groups on the basis of risk: the primary prevention group, with a Framingham risk score of 10% or higher (intervention, n = 157; control, n = 158), and the secondary prevention group, who had a diagnosis of coronary artery disease (intervention, n = 153; control, n = 143). The primary outcome was a change in the Framingham global risk score between baseline and 1-year follow-up. Data were analyzed separately for the 2 prevention groups using an intention-to-treat analysis controlling for covariates.
Within the primary prevention group, there were statistically significant changes for the treatment group relative to the controls, from baseline to year 1, in Framingham score (intervention, –3.10 [95% confidence interval (CI) –3.98 to –2.22]; control, –1.30 [95% CI –2.18 to –0.42]; p < 0.01) and scores for total cholesterol (intervention, –0.41 [95% CI –0.59 to –0.23]; control, –0.14 [95% CI –0.32 to 0.04]; p < 0.05), systolic blood pressure (intervention, –7.49 [95% CI –9.97 to –5.01]; control, –3.58 [95% CI –6.08 to –1.08]; p < 0.05), nutrition level (intervention, 0.30 [95% CI 0.13 to 0.47]; control, –0.05 [95% CI –0.22 to 0.12]; p < 0.01), and health confidence (intervention, 0.20 [95% CI 0.09 to 0.31]; control, 0.04 [95% CI –0.07 to 0.15]; p < 0.05), with adjustment for covariates. No significant changes in outcome variables were found for the secondary prevention group.
We found evidence for the efficacy of an intervention addressing multiple risk factors for primary prevention at 1 year using Framingham risk score report cards and telephone counselling. (Requirement for clinical trial registration waived [enrolment completed before requirement became applicable].)
PMCID: PMC1995136  PMID: 17923653
3.  Healthy Hearts – A community-based primary prevention programme to reduce coronary heart disease 
The ten year probability of cardiovascular events can be calculated, but many people are unaware of their risk and unclear how to reduce it. The aim of this study was to assess whether a community based intervention, for men and women aged between 45 and 64 years without pre-existing coronary heart disease, would reduce their Framingham scores when reassessed one year later.
Individuals in the relevant age group from a defined geographical area were sent an invitation to attend for an assessment of their cardiovascular risk. Individuals with pre-existing cardiovascular disease or terminal illness were excluded. The invitation was in the form of a "Many Happy Returns" card with a number of self-screening questions including the question, "If you put the enclosed string around your waist, is it too short?" The card contained a red 80 cm piece of string in the case of women, or a green 90 cm piece of string in the case of men. At the assessment appointment, Framingham scores were calculated and a printout was given to each individual. Advice was provided for relevant risk factors identified using agreed guidelines. If appropriate, onward referral was also made to a GP, dietician, an exercise referral scheme, or to smoking cessation services, using a set of guidelines. Individuals were sent a second invitation one year later to return for re-assessment.
Results and discussion
2031 individuals were asked to self-assess their eligibility to participate, 596 individuals attended for assessment and 313 of these attended for follow-up one year later. The mean reduction in the Framingham risk score, was significantly lower at one year (0.876, 95% CI 0.211 to 1.541, p = 0.01). The mean 10-year risk of CHD at baseline was 13.14% (SD 9.18) and had fallen at follow-up to 12.34% (SD 8.71), a mean reduction of 6.7% of the initial 10-year Framingham risk. If sustained, the estimated NNT to prevent each year of CHD would be 1141 (95% CI 4739 to 649) individual appointments.
This community intervention for primary prevention of CHD reduces Framingham risk scores at one year in those who engage with the programme.
PMCID: PMC2518127  PMID: 18655720
4.  CARD8 rs2043211 (p.C10X) Polymorphism Is Not Associated with Disease Susceptibility or Cardiovascular Events in Spanish Rheumatoid Arthritis Patients 
DNA and Cell Biology  2013;32(1):28-33.
Rheumatoid arthritis (RA) is a complex polygenic inflammatory disease associated with accelerated atherosclerosis, which is the main cause of increased cardiovascular (CV) morbidity and mortality in RA patients. CARD8 is a constituent of inflammasome, which regulates interleukin 1-beta production, and has been associated with a worse disease course in early RA. One thousand six hundred twenty-one patients fulfilling the 1987 ACR classification criteria for RA and 1300 matched controls, were genotyped for the CARD8 rs2043211 (30T>A, p.C10X) single-nucleotide polymorphism (SNP) using predesigned TaqMan SNP genotyping assay. The genotyping success rate in our study was greater than 94%. We assessed CARD8 rs2043211 gene polymorphism results in 1530 Spanish RA patients in whom information on CV disease and CV risk factors was available at the time of the study. Also, a subgroup of patients with no history of CV events (n=276) was assessed for the potential influence of the rs2043211 variant in the development of subclinical atherosclerosis, by measurement of carotid intima-media thickness (IMT) and presence of carotid plaques. No statistically significant differences in allele or genotype frequencies for the rs2043211 CARD8 gene variant between patients with RA and controls were seen. Similarly, CARD8 rs2043211 (30T>A, p.C10X) SNP did not influence the development of CV events or the risk of CV events throughout the time. Likewise, no significant association between this gene variant and carotid IMT or the presence of plaques was found. In summary, our results do not support a role of the CARD8 rs2043211 gene variant in susceptibility to RA or in the development of CV disease in patients with RA.
Rheumatoid arthritis, an autoimmune disease, results from a complex polygenic cascade of proinflammatory pathways, and is associated with an increased frequency of cardiovascular disease and mortality. In this study of Spanish RA patients, the role of one polymorphism of the CARD8 gene, a component of the inflammasome, was evaluated.
PMCID: PMC3530932  PMID: 23088220
5.  Al Pie De La Letra 
Background and Purpose
Ethnic minorities are at higher stroke risk than non-Hispanic whites yet are less likely to have optimal vascular risk factor control. There is a need to develop culturally sensitive strategies for enhancing vascular risk reduction in minority patients with stroke. This study aimed to develop a postdischarge report card to boost treatment adherence among elderly Spanish-speaking patients with stroke within an urban health system.
This study included a total of 13 Spanish-only speaking participants aged ≥60 years discharged from a local government hospital in Los Angeles within 18 months of an index ischemic stroke and 6 caregivers engaged in focus groups and interviews. Structured interviews were conducted with 11 care providers and 9 administrators at the hospital. Framework analysis examined the data and elicited themes to adapt a pre-existing patient report card tool.
Spontaneously using the same phrase, “Al pie de la letra,” several participants expressed a need to follow medical instructions accurately to prevent recurrent stroke and identified barriers/facilitators for doing so. They made comments about the pre-existing report card, advising several changes, including the clarification of phrases, and written instructions to explain the need for the card and how to fill it out. The providers and administrators recommended avenues for successfully using the card at the hospital. A new report card was created that incorporated all major perspectives.
Crafting a culturally sensitive tool for promoting treatment adherence in elderly Spanish-only-speaking patients with stroke within an urban health system using a participatory methodology is feasible. The efficacy of this new report card should be tested in a randomized controlled trial.
PMCID: PMC4160819  PMID: 20167904
adherence; elderly; focus groups; health services research; interviews; ischemic; outcomes; prevention; quality improvement; Spanish; stroke
6.  Incidence of cardiovascular events after kidney transplantation and cardiovascular risk scores: study protocol 
Cardiovascular disease (CVD) is the major cause of death after renal transplantation. Not only conventional CVD risk factors, but also transplant-specific risk factors can influence the development of CVD in kidney transplant recipients.
The main objective of this study will be to determine the incidence of post-transplant CVD after renal transplantation and related factors. A secondary objective will be to examine the ability of standard cardiovascular risk scores (Framingham, Regicor, SCORE, and DORICA) to predict post-transplantation cardiovascular events in renal transplant recipients, and to develop a new score for predicting the risk of CVD after kidney transplantation.
Observational prospective cohort study of all kidney transplant recipients in the A Coruña Hospital (Spain) in the period 1981-2008 (2059 transplants corresponding to 1794 patients).
The variables included will be: donor and recipient characteristics, chronic kidney disease-related risk factors, pre-transplant and post-transplant cardiovascular risk factors, routine biochemistry, and immunosuppressive, antihypertensive and lipid-lowering treatment. The events studied in the follow-up will be: patient and graft survival, acute rejection episodes and cardiovascular events (myocardial infarction, invasive coronary artery therapy, cerebral vascular events, new-onset angina, congestive heart failure, rhythm disturbances and peripheral vascular disease).
Four cardiovascular risk scores were calculated at the time of transplantation: the Framingham score, the European Systematic Coronary Risk Evaluation (SCORE) equation, and the REGICOR (Registre Gironí del COR (Gerona Heart Registry)), and DORICA (Dyslipidemia, Obesity, and Cardiovascular Risk) functions.
The cumulative incidence of cardiovascular events will be analyzed by competing risk survival methods. The clinical relevance of different variables will be calculated using the ARR (Absolute Risk Reduction), RRR (Relative Risk Reduction) and NNT (Number Needed to Treat).
The ability of different cardiovascular risk scores to predict cardiovascular events will be analyzed by using the c index and the area under ROC curves. Based on the competing risks analysis, a nomogram to predict the probability of cardiovascular events after kidney transplantation will be developed.
This study will make it possible to determine the post-transplant incidence of cardiovascular events in a large cohort of renal transplant recipients in Spain, to confirm the relationship between traditional and transplant-specific cardiovascular risk factors and CVD, and to develop a score to predict the risk of CVD in these patients.
PMCID: PMC3022886  PMID: 21639867
7.  Personalized Prediction of Lifetime Benefits with Statin Therapy for Asymptomatic Individuals: A Modeling Study 
PLoS Medicine  2012;9(12):e1001361.
In a modeling study conducted by Myriam Hunink and colleagues, a population-based cohort from Rotterdam is used to predict the possible lifetime benefits of statin therapy, on a personalized basis.
Physicians need to inform asymptomatic individuals about personalized outcomes of statin therapy for primary prevention of cardiovascular disease (CVD). However, current prediction models focus on short-term outcomes and ignore the competing risk of death due to other causes. We aimed to predict the potential lifetime benefits with statin therapy, taking into account competing risks.
Methods and Findings
A microsimulation model based on 5-y follow-up data from the Rotterdam Study, a population-based cohort of individuals aged 55 y and older living in the Ommoord district of Rotterdam, the Netherlands, was used to estimate lifetime outcomes with and without statin therapy. The model was validated in-sample using 10-y follow-up data. We used baseline variables and model output to construct (1) a web-based calculator for gains in total and CVD-free life expectancy and (2) color charts for comparing these gains to the Systematic Coronary Risk Evaluation (SCORE) charts. In 2,428 participants (mean age 67.7 y, 35.5% men), statin therapy increased total life expectancy by 0.3 y (SD 0.2) and CVD-free life expectancy by 0.7 y (SD 0.4). Age, sex, smoking, blood pressure, hypertension, lipids, diabetes, glucose, body mass index, waist-to-hip ratio, and creatinine were included in the calculator. Gains in total and CVD-free life expectancy increased with blood pressure, unfavorable lipid levels, and body mass index after multivariable adjustment. Gains decreased considerably with advancing age, while SCORE 10-y CVD mortality risk increased with age. Twenty-five percent of participants with a low SCORE risk achieved equal or larger gains in CVD-free life expectancy than the median gain in participants with a high SCORE risk.
We developed tools to predict personalized increases in total and CVD-free life expectancy with statin therapy. The predicted gains we found are small. If the underlying model is validated in an independent cohort, the tools may be useful in discussing with patients their individual outcomes with statin therapy.
Please see later in the article for the Editors' Summary
Editors' Summary
Cardiovascular disease (CVD) affects the heart and/or the blood vessels and is a major cause of illness and death worldwide. In the US, for example, coronary heart disease—a CVD in which narrowing of the heart's blood vessels by fatty deposits slows the blood supply to the heart and may eventually cause a heart attack—is the leading cause of death, and stroke—a CVD in which the brain's blood supply is interrupted—is the fourth leading cause of death. Established risk factors for CVD include smoking, high blood pressure, obesity, and high blood levels of a fat called low-density lipoprotein (“bad cholesterol”). Because many of these risk factors can be modified by lifestyle changes and by drugs, CVD can be prevented. Thus, physicians can assess a healthy individual's risk of developing CVD using a CVD prediction model (equations that take into account the CVD risk factors to which the individual is exposed) and can then recommend lifestyle changes and medications to reduce that individual's CVD risk.
Why Was This Study Done?
Current guidelines recommend that asymptomatic (healthy) individuals whose likely CVD risk is high should be encouraged to take statins—cholesterol-lowering drugs—as a preventative measure. Statins help to prevent CVD in healthy people with a high predicted risk of CVD, but, like all medicines, they have some unwanted side effects, so it is important that physicians can communicate both the benefits and drawbacks of statins to their patients in a way that allows them to make an informed decision about taking these drugs. Telling a patient that statins will reduce his or her short-term risk of CVD is not always helpful—patients really need to know the potential lifetime benefits of statin therapy. That is, they need to know how much longer they might live if they take statins. Here, the researchers use a mathematical model to predict the personalized lifetime benefits (increased total and CVD-free life expectancy) of statin therapy for individuals without a history of CVD.
What Did the Researchers Do and Find?
The researchers used the Rotterdam Ischemic Heart Disease & Stroke Computer Simulation (RISC) model, which simulates the life courses of individuals through six health states, from well through to CVD or non-CVD death, to estimate lifetime outcomes with and without statin therapy in a population of healthy elderly individuals. They then used these outcomes and information on baseline risk factors to develop a web-based calculator suitable for personalized prediction of the lifetime benefits of statins in routine clinical practice. The model estimated that statin therapy increases average life expectancy in the study population by 0.3 years and average CVD-free life expectancy by 0.7 years. The gains in total and CVD-free life expectancy associated with statin therapy increased with blood pressure, unfavorable cholesterol levels, and body mass index (an indicator of body fat) but decreased with age. Notably, the web-based calculator predicted that some individuals with a low ten-year CVD risk might achieve a similar or larger gain in CVD-free life expectancy with statin therapy than some individuals with a high ten-year risk. So, for example, both a 55-year-old non-smoking woman with a ten-year CVD mortality risk of 2% (a two in a hundred chance of dying of CVD within ten years) and a 65-year-old male smoker with a ten-year CVD mortality risk of 15% might both gain one year of CVD-free life expectancy with statin therapy.
What Do These Findings Mean?
These findings suggest that statin therapy can lead on average to small gains in total life expectancy and slightly larger gains in CVD-free life expectancy among healthy individuals, and show that life expectancy benefits can be predicted using an individual's risk factor profile. The accuracy and generalizability of these findings is limited by the assumptions included in the model (in particular, the model did not allow for the known side effects of statin therapy) and by the data fed into it—importantly, the risk prediction model needs to be validated using an independent dataset. If future research confirms the findings of this study, the researchers' web-based calculator could provide complementary information to the currently recommended ten-year CVD mortality risk assessment. Whether communication of personalized outcomes will ultimately result in better clinical outcomes remains to be seen, however, because patients may be less likely to choose statin therapy when provided with more information about its likely benefits.
Additional Information
Please access these websites via the online version of this summary at
The web-based calculator for personalized prediction of lifetime benefits with statin therapy is available (after agreement to software license)
The American Heart Association provides information about many types of cardiovascular disease for patients, carers, and professionals, including information about drug therapy for cholesterol and a heart attack risk calculator
The UK National Health Service Choices website provides information about cardiovascular disease and about statins
Information is available from the British Heart Foundation on heart disease and keeping the heart healthy; information is also available on statins, including personal stories about deciding to take statins
The US National Heart Lung and Blood Institute provides information on a wide range of cardiovascular diseases
The European Society of Cardiology's cardiovascular disease risk assessment model (SCORE) is available
MedlinePlus provides links to many other sources of information on heart diseases, vascular diseases, stroke, and statins (in English and Spanish)
PMCID: PMC3531501  PMID: 23300388
8.  Correlation between Progetto Cuore risk score and early cardiovascular damage in never treated subjects 
Global cardiovascular risk is a new approach which allows the physicians to quantitate the prognosis of the patients. It is therefore possible that a score, based on the major cardiovascular risk factors, is correlated with some degree of cardiovascular anatomic damage. Since this hypothesis has been demonstrated with the Framingham risk score, we decided to verify it using another score (Progetto Cuore risk score), which is probably more precise in a european low-risk population, such as the italian one.
We studied 84 italian caucasian subjects (50 males and 34 females) with elevated blood pressure and/or dyslipidemia plus other possible cardiovascular risk factors.
The subjects have never been treated for these reasons. The following evaluations were performed: history, clinical and laboratory determinations, echocardiogram, carotid echodoppler.
The recruited people were on the whole characterized by a low cardiovascular risk, as confirmed by the low scores of the Progetto Cuore. Simple linear regression analysis showed significant associations between some parameters of early cardiovascular damage (left ventricular mass, intima-media thickness, and an integrated measure of both the carotid wall thickness and the presence of a plaque, called Carotid score) and some predictors. The highest significance was found between the cardiovascular structural results and the Progetto Cuore score. In a multivariate regression analysis our model, which included factors potentially linked to the cardiovascular anatomic changes, demonstrated that the Carotid score was significantly associated with age, sex and pulse pressure; intima-media thickness with the same factors and, in addition, with the body mass index; left ventricular mass with sex, pulse pressure and body mass index.
Our paper confirms previous studies about the association between a comprehensive risk score and signs of early cardiovascular damage. A temporally limited exposure to cardiovascular risk factors, in particular to blood pressure, is already able to induce significant changes in both the heart structure and the vascular wall. Also in a european low-risk population the use of a cardiovascular risk score program, such as the Progetto Cuore in Italy, allows a quite precise estimation of the possible cardiovascular damage.
PMCID: PMC2556661  PMID: 18808666
9.  Efficacy of a strategy for implementing a guideline for the control of cardiovascular risk in a primary healthcare setting: the SIRVA2 study a controlled, blinded community intervention trial randomised by clusters 
BMC Family Practice  2011;12:21.
This work describes the methodology used to assess a strategy for implementing clinical practice guidelines (CPG) for cardiovascular risk control in a health area of Madrid.
The results on clinical practice of introducing CPGs have been little studied in Spain. The strategy used to implement a CPG is known to influence its final use. Strategies based on the involvement of opinion leaders and that are easily executed appear to be among the most successful.
The main aim of the present work was to compare the effectiveness of two strategies for implementing a CPG designed to reduce cardiovascular risk in the primary healthcare setting, measured in terms of improvements in the recording of calculated cardiovascular risk or specific risk factors in patients' medical records, the control of cardiovascular risk factors, and the incidence of cardiovascular events.
This study involved a controlled, blinded community intervention in which the 21 health centres of the Number 2 Health Area of Madrid were randomly assigned by clusters to be involved in either a proposed CPG implementation strategy to reduce cardiovascular risk, or the normal dissemination strategy. The study subjects were patients ≥ 45 years of age whose health cards showed them to belong to the studied health area. The main variable examined was the proportion of patients whose medical histories included the calculation of their cardiovascular risk or that explicitly mentioned the presence of variables necessary for its calculation. The sample size was calculated for a comparison of proportions with alpha = 0.05 and beta = 0.20, and assuming that the intervention would lead to a 15% increase in the measured variables. Corrections were made for the design effect, assigning a sample size to each cluster proportional to the size of the population served by the corresponding health centre, and assuming losses of 20%. This demanded a final sample size of 620 patients. Data were analysed using summary measures for each cluster, both in making estimates and for hypothesis testing. Analysis of the variables was made on an intention-to-treat basis.
Trial Registration NCT01270022
PMCID: PMC3103435  PMID: 21504570
Primary healthcare; Randomised clinical trial; Cluster analysis; Clinical practice guidelines; Cardiovascular disease
10.  Development and evaluation of a patient centered cardiovascular health education program for insured patients in rural Nigeria (QUICK - II) 
BMC Public Health  2011;11:171.
In Sub Saharan Africa, the incidence of hypertension and other modifiable cardiovascular risk factors is growing rapidly. Poor adherence to prescribed prevention and treatment regimens by patients can compromise treatment outcomes. Patient-centered cardiovascular health education is likely to improve shortcomings in adherence. This paper describes a study that aims to develop a cardiovascular health education program for patients participating in a subsidized insurance plan in Nigeria and to evaluate the applicability and effectiveness in patients at increased risk for cardiovascular disease.
Design: The study has two parts. Part 1 will develop a cardiovascular health education program, using qualitative interviews with stakeholders. Part 2 will evaluate the effectiveness of the program in patients, using a prospective (pre-post) observational design.
Setting: A rural primary health center in Kwara State, Nigeria.
Population: For part 1: 40 patients, 10 healthcare professionals, and 5 insurance managers. For part 2: 150 patients with uncontrolled hypertension or other cardiovascular risk factors after one year of treatment.
Intervention: Part 2: patient-centered cardiovascular health education program.
Measurements: Part 1: Semi-structured interviews to identify stakeholder perspectives. Part 2: Pre- and post-intervention assessments including patients' demographic and socioeconomic data, blood pressure, body mass index and self-reporting measures on medication adherence and perception of care. Feasibility of the intervention will be measured using process data.
Outcomes: For program development (part 1): overview of healthcare professionals' perceptions on barriers and facilitators to care, protocol for patient education, and protocol implementation plan.
For program evaluation (part 2): changes in patients' scores on adherence to medication and life style changes, blood pressure, and other physiological and self-reporting measures at six months past baseline.
Analysis: Part 1: content analytic technique utilizing MAXQDA software. Part 2: univariate and multilevel analysis to assess outcomes of intervention.
Diligent implementation of patient-centered education should enhance adherence to cardiovascular disease prevention and management programs in low income countries.
Trial Registration
PMCID: PMC3073901  PMID: 21418629
11.  Are statin trials in diabetes representative of real-world diabetes care: a population-based study on statin initiators in Finland 
BMJ Open  2014;4(6):e005402.
To assess the representativeness of the Heart Protection Study (HPS) and the Collaborative Atorvastatin Diabetes Study (CARDS) for incident statin users.
A population-based analysis with linked register data.
56 963 patients with diabetes initiating statin use from 2005 to 2008.
Main outcome measures
We determined the proportions of real-world patients who fulfilled the eligibility criteria for HPS and CARDS trials and assessed the cardiovascular disease (CVD) event rates, assumed to reflect the background CVD risk, for those eligible and ineligible. We used descriptive statistics to identify the patient characteristics, lipid-lowering interventions and adherence to statin therapy.
Of the real-world patients, 57% (N=32 582) fulfilled the eligibility criteria for HPS (DM) and 49% (N=20 499) of those without CVD for CARDS. The patients ineligible for HPS (DM) had a higher cumulative risk for CVD events than those eligible, whereas regarding CARDS the cumulative risks were of similar magnitude. The overall CVD event rates seemed to be comparable to those in the reviewed trials. Both trials were under-representative of women and users of antihypertensive agents and metformin. 27% and 29% of real-world patients had an initial statin dose corresponding to <20 mg of simvastatin. The proportions of patients who were deemed adherent were 57% in the real world and 85% in both trials.
Only half of the real-world patients would have qualified for the HPS (DM) and CARDS, limiting their representativeness for clinical practice. Women and users of antihypertensive agents and metformin were under-represented in both trials. These deviations reflect the changes in diabetes treatment over the years and are not expected to modify the average treatment effects of statins on CVD. Prescribing of lower statin doses in clinical practice than used in the trials and lower adherence may, however, attenuate the benefits in the real world.
PMCID: PMC4067810  PMID: 24948750
adherence; diabetes; representativeness; randomised controlled trial; statin
12.  Improved Response to Disasters and Outbreaks by Tracking Population Movements with Mobile Phone Network Data: A Post-Earthquake Geospatial Study in Haiti 
PLoS Medicine  2011;8(8):e1001083.
Linus Bengtsson and colleagues examine the use of mobile phone positioning data to monitor population movements during disasters and outbreaks, finding that reports on population movements can be generated within twelve hours of receiving data.
Population movements following disasters can cause important increases in morbidity and mortality. Without knowledge of the locations of affected people, relief assistance is compromised. No rapid and accurate method exists to track population movements after disasters. We used position data of subscriber identity module (SIM) cards from the largest mobile phone company in Haiti (Digicel) to estimate the magnitude and trends of population movements following the Haiti 2010 earthquake and cholera outbreak.
Methods and Findings
Geographic positions of SIM cards were determined by the location of the mobile phone tower through which each SIM card connects when calling. We followed daily positions of SIM cards 42 days before the earthquake and 158 days after. To exclude inactivated SIM cards, we included only the 1.9 million SIM cards that made at least one call both pre-earthquake and during the last month of study. In Port-au-Prince there were 3.2 persons per included SIM card. We used this ratio to extrapolate from the number of moving SIM cards to the number of moving persons. Cholera outbreak analyses covered 8 days and tracked 138,560 SIM cards.
An estimated 630,000 persons (197,484 Digicel SIM cards), present in Port-au-Prince on the day of the earthquake, had left 19 days post-earthquake. Estimated net outflow of people (outflow minus inflow) corresponded to 20% of the Port-au-Prince pre-earthquake population. Geographic distribution of population movements from Port-au-Prince corresponded well with results from a large retrospective, population-based UN survey. To demonstrate feasibility of rapid estimates and to identify areas at potentially increased risk of outbreaks, we produced reports on SIM card movements from a cholera outbreak area at its immediate onset and within 12 hours of receiving data.
Results suggest that estimates of population movements during disasters and outbreaks can be delivered rapidly and with potentially high validity in areas with high mobile phone use.
Please see later in the article for the Editors' Summary
Editors' Summary
Every year, millions of people are affected by disasters—sudden calamitous events that disrupt communities and cause major human, material, economic, and environmental losses. Disasters can be natural (for example, earthquakes and infectious disease outbreaks) or man-made (for example, terrorist attacks and industrial accidents). Whenever a disaster strikes, governments, international bodies, and humanitarian agencies swing into action to help the affected population by providing food, water, shelter, and medical assistance. Within days of the earthquake that struck Haiti on January 12, 2010, for instance, many governments pledged large sums of money to help the Haitians, and humanitarian agencies such as Oxfam and the International Federation of Red Cross and Red Crescent Societies sent tons of food and hundreds of personnel into the country. And when a cholera outbreak began in Haiti in October 2010, the world responded by sending further assistance.
Why Was This Study Done?
An instinctive response to any disaster is to flee the affected area, but such population movements after a disaster can increase the loss of human life by complicating the provision of relief assistance, the assessment of needs, and infectious disease surveillance. Unfortunately, there are no rapid or accurate methods available to track population movements after disasters. Relief coordinators currently rely on slow, potentially biased methods such as eye witness accounts and aerial images of shelters to track population movements. In this geospatial analysis, the researchers investigate whether position data from mobile phone SIMs (subscriber identity modules) can be used to estimate the magnitude and trends of population movements by retrospectively following the positions of SIMs in Haiti before and after the earthquake and tracking SIMs during the first few days of the cholera outbreak. Every time a SIM makes a call, the mobile phone network database records which mobile phone tower connected the call. Thus, the database can provide a geographic position for each mobile phone caller.
What Did the Researchers Do and Find?
The researchers obtained anonymized data on the position of 1.9 million SIMs in Haiti from 42 days before the earthquake to 158 days afterwards. Nearly 200,000 SIMs that were present in Haiti's capital Port-au-Prince when the earthquake struck had left 19 days post-earthquake. Just under a third of Port-au-Prince's inhabitants were mobile phone subscribers at the time of the earthquake, so this movement of SIMs equates to the movement of about 630,000 people. Notably, although the SIM-based estimates of numbers leaving Port-au-Prince matched the estimates reported by the Haitian National Civil Protection Agency (NPCA), which were largely based on counting ship and bus movements and which were used during the relief operation, the estimated geographical distribution of displaced people reported by the NPCA was very different to that obtained by analyzing SIM movements. By contrast, the geographical distribution of the population obtained from SIM movements closely matched that reported by a retrospective United Nations Population Fund household survey. Finally, to demonstrate the feasibility of producing rapid estimates of population movements during disasters, the researchers tracked nearly 140,000 SIMs during the first 8 days of the Haitian cholera outbreak and showed that they could distribute analyses of SIM movements within 12 hours of receiving data from the mobile phone company.
What Do These Findings Mean?
These findings suggest that estimates of population movements during disasters and infectious disease outbreaks can be delivered rapidly and accurately in areas of high mobile use by analyzing mobile phone data. 86% of the world's population now has mobile phone network coverage and, in 2009, there were already 3.2 billion mobile phone subscriptions in the developing world, which has a population of 5.5 billion people. Thus, this tracking method could be useful in many parts of the world, including those particularly vulnerable to disasters. However, because mobile phone use varies between sections of society, because some areas have a low density of mobile phone towers, and because disasters can destroy these towers, this approach may not be effective in all disasters. The researchers recommend, therefore, that the use of mobile phone data for tracking population movements is evaluated further and that relationships are built up with mobile phone companies to ensure rapid implementation of the approach after future disasters.
Additional Information
Please access these Web sites via the online version of this summary at
Internal Displacement Monitoring Centre provides information on population displacement during natural disasters
The International Federation of Red Cross and Red Crescent Societies provides information in several languages about disaster management and about the 2010 earthquake in Haiti
Oxfam also has information on conflicts and natural disasters and the Haiti earthquake and cholera outbreak (in several languages)
EM-DAT, the International Disaster Database contains essential core information on 18,000 mass disasters in the world from 1990 until the present
PMCID: PMC3168873  PMID: 21918643
13.  Innate Dysfunction Promotes Linear Growth Failure in Pediatric Crohn Disease and Growth Hormone Resistance in Murine Ileitis 
Inflammatory Bowel Diseases  2011;18(2):236-245.
Growth failure remains a common complication of pediatric Crohn Disease (CD), and has been associated with small bowel involvement and need for surgery. We have reported that patients with elevated (≥ 1.6 mcg/mL) Granulocyte Macrophage Colony Stimulating Factor auto-antibodies (GM-CSF Ab) are more likely to experience complicated ileal disease requiring surgery. We hypothesized that concurrent GM-CSF Ab and CARD15 risk allele carriage (C15+GMAb+) would be associated with growth failure in CD, and growth hormone (GH) resistance in murine ileitis.
We enrolled 229 pediatric CD patients at two sites and determined CARD15 genotype, serum GM-CSF Ab and GH binding protein (GHBP), and height (HTz) and weight (WTz) z scores at diagnosis. Ileitis was induced in card15 deficient mice by gm-csf neutralization and NSAID exposure. Hepatic GH receptor (Ghr) abundance and GH dependent Stat5 activation were determined by western blot, and Igf-I mRNA expression by real-time PCR.
Mean[95th CI] HTz at diagnosis was reduced to −0.48[−4.2,2.3] in C15+GMAb+patients, compared to −0.07[−4.9,3.4] in disease controls, p≤0.05. Circulating GHBP, as a marker for tissue GHR abundance, was reduced in C15+GMAb+ patients. Hepatic Ghr abundance, GH induction of Stat5 tyrosine phosphorylation, and Igf-I mRNA expression were reduced in male card15 deficient mice with ileitis due to gm-csf neutralization and NSAID exposure.
Innate dysfunction due to concurrent genetic variation in CARD15 and neutralizing GM-CSF Ab is associated with linear growth failure in pediatric CD, and hepatic GH resistance in murine ileitis.
PMCID: PMC3057426  PMID: 21337672
granulocyte-macrophage colony stimulating factor; pediatric Crohn disease; linear growth; caspase recruitment domain family member 15; nucleotide-binding oligomerization domain containing 2
14.  Prevalence and Association of Microalbuminuria in Essential Hypertensive Patients 
Microalbuminuria in hypertension has been described as an early sign of kidney damage and a predictor for end stage renal disease and cardiovascular disease. Thus, it is of great importance to study urinary albumin creatinine ratio and progression of kidney disease in hypertensive patients.
The present study was undertaken to find out the prevalence and association of microalbuminuria in newly diagnosed essential hypertension.
Materials and Methods:
Newly diagnosed essential hypertensive cases (n = 106) and normotensive controls (n = 106) were enrolled. Hypertension was defined according to Joint national committee-VII definitions. Microalbuminuria was measured using an U-Albumin (NycoCard, Norway) and adjusted for urine creatinine. Descriptive statistics and testing of hypothesis were used for the analysis using SPSS 16 software.
51.88% of hypertension cases and 13.2% of normotensive controls had microalbuminuria in total population (odds ratio 7.086, P-value <0.001). 46.67% of cases and 12.08% of controls had microalbuminuria in male population (odds ratio 6.375, P-value <0.001). Similarly, 58.7% of cases and 14.58% of controls had microalbuminuria in female population (odds ratio 8.32, P-value <0.001).
By showing strong association between microalbuminuria and hypertension, our findings suggest that microalbuminuria could be a useful marker to assess risk management of cardiovascular disease and renal disease.
PMCID: PMC3421910  PMID: 22912940
Albumin creatinine ratio; Hypertension; Normotension; Microalbuminuria
15.  Longitudinal patterns of gambling activities and associated risk factors in college students 
Addiction (Abingdon, England)  2009;104(7):1219.
To investigate which clusters of gambling activities exist within a longitudinal study of college health, how membership in gambling clusters change over time and whether particular clusters of gambling are associated with unhealthy risk behaviour.
Four-year longitudinal study (2002–2006).
Large, public university.
Undergraduate college students.
Ten common gambling activities were measured during 4 consecutive college years (years 1–4). Clusters of gambling activities were examined using latent class analyses. Relations between gambling clusters and gender, Greek membership, alcohol use, drug use, personality indicators of behavioural undercontrol and psychological distress were examined.
Four latent gambling classes were identified: (1) a low-gambling class, (2) a card gambling class, (3) a casino/slots gambling class and (4) an extensive gambling class. Over the first college years a high probability of transitioning from the low-gambling class and the card gambling class into the casino/slots gambling class was present. Membership in the card, casino/slots and extensive gambling classes were associated with higher scores on alcohol/drug use, novelty seeking and self-identified gambling problems compared to the low-gambling class. The extensive gambling class scored higher than the other gambling classes on risk factors.
Extensive gamblers and card gamblers are at higher risk for problem gambling and other risky health behaviours. Prospective examinations of class membership suggested that being in the extensive and the low gambling classes was highly stable across the 4 years of college.
PMCID: PMC2818490  PMID: 19438422
College student population; gambling; gambling activities; longitudinal; risk factors
16.  CARD15/NOD2, CD14 and Toll-like 4 Receptor Gene Polymorphisms in Saudi Patients with Crohn’s Disease 
Crohn’s disease (CD) is a multifactorial disease with a genetic component and an observed association with genes related to the innate immune response. Polymorphisms in the CARD15/NOD2 gene, in addition to functional variants of the toll-like receptor-4 (TLR4) and CD14 genes, have been associated with the development of Crohn’s disease. There is no information about the frequency of these polymorphisms in the Saudi population. We examined the frequency of the three major CARD15/NOD2 risk alleles (Leu1007fsinsC, Arg702Trp, and Gly908Arg) and the TLR4 (Thr399Il) polymorphism as well as a functional polymorphism in the promoter of the CD14–159C/T in 46 Saudi CD patients and 50 matched controls. Genotyping was performed by allele-specific PCR or by restriction fragment length polymorphism (PCR-RFLP) analysis. The mutant genotype frequencies of the Leu1007fsinsC, Arg702Trp and Gly908Arg in the patient group were 6.5, 21.7 and 6.5%, respectively, compared with frequencies of 0, 4 and 2%, respectively, in the control group. There were 15 patients who carried the mutant alleles for all three CARD15/NOD2 variants, Leu1007fsinsC, Arg702Trp and Gly908Arg, while none of the control candidates carried the three alleles. This genetic study provides evidence that the three major CARD15/NOD2 variant alleles and the CD14 –159C/T polymorphism are associated with Crohn’s disease (CD) susceptibility in the Saudi population; however, there is no evidence that the TLR4 (Thr399Il) or CARD15/NOD2 polymorphisms can be considered risk factors for Crohn’s disease.
PMCID: PMC3344213  PMID: 22605977
inflammatory bowel disease; Crohn’s disease; genetic polymorphism; CARD15/NOD2
17.  The Effect of Chromosome 9p21 Variants on Cardiovascular Disease May Be Modified by Dietary Intake: Evidence from a Case/Control and a Prospective Study 
PLoS Medicine  2011;8(10):e1001106.
Ron Do and colleagues find that a prudent diet high in raw vegetables may modify the increased genetic risk of cardiovascular disease conferred by the chromosome 9p21 SNP.
One of the most robust genetic associations for cardiovascular disease (CVD) is the Chromosome 9p21 region. However, the interaction of this locus with environmental factors has not been extensively explored. We investigated the association of 9p21 with myocardial infarction (MI) in individuals of different ethnicities, and tested for an interaction with environmental factors.
Methods and Findings
We genotyped four 9p21 SNPs in 8,114 individuals from the global INTERHEART study. All four variants were associated with MI, with odds ratios (ORs) of 1.18 to 1.20 (1.85×10−8≤p≤5.21×10−7). A significant interaction (p = 4.0×10−4) was observed between rs2383206 and a factor-analysis-derived “prudent” diet pattern score, for which a major component was raw vegetables. An effect of 9p21 on MI was observed in the group with a low prudent diet score (OR = 1.32, p = 6.82×10−7), but the effect was diminished in a step-wise fashion in the medium (OR = 1.17, p = 4.9×10−3) and high prudent diet scoring groups (OR = 1.02, p = 0.68) (p = 0.014 for difference). We also analyzed data from 19,129 individuals (including 1,014 incident cases of CVD) from the prospective FINRISK study, which used a closely related dietary variable. In this analysis, the 9p21 risk allele demonstrated a larger effect on CVD risk in the groups with diets low or average for fresh vegetables, fruits, and berries (hazard ratio [HR] = 1.22, p = 3.0×10−4, and HR = 1.35, p = 4.1×10−3, respectively) compared to the group with high consumption of these foods (HR = 0.96, p = 0.73) (p = 0.0011 for difference). The combination of the least prudent diet and two copies of the risk allele was associated with a 2-fold increase in risk for MI (OR = 1.98, p = 2.11×10−9) in the INTERHEART study and a 1.66-fold increase in risk for CVD in the FINRISK study (HR = 1.66, p = 0.0026).
The risk of MI and CVD conferred by Chromosome 9p21 SNPs appears to be modified by a prudent diet high in raw vegetables and fruits.
Please see later in the article for the Editors' Summary
Editors' Summary
Cardiovascular diseases (CVDs)—diseases that affect the heart and/or the blood vessels—are a leading cause of illness and death worldwide. In the United States, for example, the leading cause of death is coronary heart disease, a CVD in which narrowing of the heart's blood vessels by fatty deposits slows the blood supply to the heart and may eventually cause a heart attack (myocardial infarction, or MI); the third leading cause of death in the US is stroke, a CVD in which the brain's blood supply is interrupted. Environmental factors such as diet, physical activity, and smoking alter a person's risk of developing CVD. In addition, certain genetic variants (alterations in the DNA that forms the body's blueprint; DNA is packed into structures called chromosomes) alter the risk of developing CVD and are passed from parent to child. Thus, in CVD, as in most common diseases, both genetics and the environment play a role.
Why Was This Study Done?
Recent studies have identified several genetic variants that are associated with an increased risk of developing CVD. One of the most robust of these genetic associations is a cluster of single nucleotide polymorphisms (SNPs, differences in a single DNA building block) in a chromosomal region (locus) called 9p21. So far, this association has been mainly studied in European populations. Moreover, the interaction of this locus with environmental factors has not been extensively studied. A better understanding of how 9p21 variants affect CVD risk in people of different ethnicities and of the interaction between this locus and environmental factors could allow the development of targeted strategies for the prevention of CVD. In this study, the researchers investigate the association of 9p21 risk variants with CVD in people of different ethnicities and test for an interaction between this locus and environmental factors.
What Did the Researchers Do and Find?
The researchers assessed four 9p21 SNPs in people enrolled in the INTERHEART study, a global retrospective case-control study that investigated potential MI risk factors by comparing people who had had an acute non-fatal MI with similar people without heart disease. All four SNP risk variants increased the risk of MI by about a fifth. However, the effect of the SNPs on MI was influenced by the “prudent” diet pattern score of the INTERHEART participants, a score that includes fresh fruit and vegetable intake as recorded in food frequency questionnaires. That is, the risk of MI in people carrying SNP risk variants was influenced by their diet. The strongest interaction was seen with an SNP called rs2383206, but although rs2383206 carriers who ate a diet poor in fruits and vegetables had a higher risk of MI than people with a similar diet who did not carry this SNP, rs2383206 carriers and non-carriers who ate a fruit- and vegetable-rich diet had a comparable MI risk. Overall, the combination of the least “prudent” diet and two copies of the risk variant (human cells contain two complete sets of chromosomes) was associated with a two-fold increase in risk for MI in the INTERHEART study. Additionally, data collected in the FINRISK study, which characterized healthy individuals living in Finland at baseline and then followed them to see whether they developed CVD, revealed a similar interaction between diet and 9p21 SNPs.
What Do These Findings Mean?
These findings suggest that the risk of CVD conferred by chromosome 9p21 SNPs may be influenced by diet in multiple ethnic groups. Importantly, they suggest that the deleterious effect of 9p21 SNPs on CVD might be mitigated by consuming a diet rich in fresh fruits and vegetables. The accuracy of these findings may be affected by recall bias in the INTERHEART study (that is, some people may not have remembered their diet accurately) and by the small number of CVD cases in the FINRISK study. Nevertheless, these findings suggest that gene–environment interactions are important drivers of CVD, and they raise the possibility that a sound diet can mediate the effects of 9p21 SNPs.
Additional Information
Please access these websites via the online version of this summary at
The American Heart Association provides information about many types of cardiovascular disease for patients, caregivers, and professionals and tips on keeping the heart healthy
The UK National Health Service Choices website provides information about cardiovascular disease and stroke
Information is available from the British Heart Foundation on heart disease and keeping the heart healthy
The US National Heart Lung and Blood Institute provides information on a wide range of cardiovascular diseases
MedlinePlus provides links to many other sources of information on heart diseases, vascular diseases, and stroke (in English and Spanish)
The US Centers for Disease Control and Prevention has a simple fact sheet on gene-environment interactions; the US National Institute of Environmental Health Sciences provides links to other information on gene-environment interactions
More information is available on the INTERHEART study and on the FINRISK study
PMCID: PMC3191151  PMID: 22022235
18.  Patterns of Relationships between Cardiovascular Disease Risk Factors and Neurocognitive Function in African Americans 
Ethnicity & disease  2008;18(4):471-476.
The association between cardiovascular disease (CVD) risk and neurocognitive function has gathered a good deal of attention in the health and social science literature; however, the relationship among several CVD risk factors and neurocognitive function has not been fully explored in an African American sample. The purpose of this study was to examine the pattern of relationships among four CVD risk factors and five measures of higher cortical functions.
Data were collected from a sample of 106 African American community-dwelling adults in the metropolitan Washington, DC, area. A nurse collected blood pressure, waist circumference, and a blood sample (to assess triglycerides and high-density lipoprotein (HDL) cholesterol) from study participants. Participants completed the Symbol Digit Modalities Test, Trailmaking B, Stroop Colorword Task, California Verbal Learning Test-II, and Wisconsin Card Sorting Test as assessments of neurocognitive function. Canonical analysis and multiple regression analysis were the major statistical methods utilized to assess relationships between CVD risk factors and neurocognitive function.
The results suggest that 1) attentional processes are associated with diastolic blood pressure levels, 2) verbal learning processes are associated with diastolic blood pressure and triglyceride levels, and 3) the ability to shift cognitive set is associated with HDL cholesterol levels.
As cardiovascular health worsens in our society, particularly among ethnic minorities, the neurocognitive consequences must be clearly understood. Future studies should focus on identifying and building awareness of cardiovascular and neurocognitive links through longitudinal research designs and brain imaging technology.
PMCID: PMC3804014  PMID: 19157252
Cognitive Function; African Americans; Cardiovascular Risk; Metabolic Syndrome; Cognition
19.  Differential utilization of CARD9 by Dectin-1 in macrophages and dendritic cells12 
The pattern recognition receptors Toll-like receptor 2 (TLR2) and Dectin-1 play key roles in coordinating the responses of macrophages and dendritic cells (DC) to fungi. Induction of pro-inflammatory cytokines is instructed by signals from both TLR2 and Dectin-1. A recent report identified a role for CARD9 in innate anti-fungal responses, demonstrating CARD9-Bcl10-mediated activation of NF-κB and pro-inflammatory cytokine induction in murine bone marrow-derived DC (bmDC) stimulated via Dectin-1. We now report that Dectin-1-CARD9 signals fail to activate NF-κB and drive TNF-α induction in murine bone marrow-derived macrophages (bmM). However, priming of bmM with GM-CSF or IFN-γ permits Dectin-1-CARD9-mediated TNF-α induction. Analysis of other macrophage/DC populations revealed further variation in the ability of Dectin-1-CARD9 signaling to drive TNF-α production. Resident peritoneal cells and alveolar macrophages produce TNF-α upon Dectin-1 ligation, while thioglycollate-elicited peritoneal macrophages and Flt3L-derived DC do not. We present data demonstrating that CARD9 is recruited to phagosomes via its CARD domain where it enhances TLR-induced cytokine production even in cells in which Dectin-1 is insufficient to drive cytokine production. In such cells, Dectin-1, CARD9 and Bcl10 levels are not limiting, and data indicate that these cells express additional factors that restrict Dectin-1-CARD9 signaling for TNF-α induction.
PMCID: PMC2718573  PMID: 19124758
Dendritic cells; Monocytes/Macrophages; Fungal infection; Phagocytosis; Signal transduction
20.  Genome-wide association analysis confirms and extends the association of SLC2A9 with serum uric acid levels to Mexican Americans 
Frontiers in Genetics  2013;4:279.
Increased serum uric acid (SUA) is a risk factor for gout and renal and cardiovascular disease (CVD). The purpose of this study was to identify genetic factors that affect the variation in SUA in 632 Mexican Americans participants of the San Antonio Family Heart Study (SAFHS). A genome-wide association (GWA) analysis was performed using the Illumina Human Hap 550K single nucleotide polymorphism (SNP) microarray. We used a linear regression-based association test under an additive model of allelic effect, while accounting for non-independence among family members via a kinship variance component. All analyses were performed in the software package SOLAR. SNPs rs6832439, rs13131257, and rs737267 in solute carrier protein 2 family, member 9 (SLC2A9) were associated with SUA at genome-wide significance (p < 1.3 × 10−7). The minor alleles of these SNPs had frequencies of 36.2, 36.2, and 38.2%, respectively, and were associated with decreasing SUA levels. All of these SNPs were located in introns 3–7 of SLC2A9, the location of the previously reported associations in European populations. When analyzed for association with cardiovascular-renal disease risk factors, conditional on SLC2A9 SNPs strongly associated with SUA, significant associations were found for SLC2A9 SNPs with BMI, body weight, and waist circumference (p < 1.4 × 10−3) and suggestive associations with albumin-creatinine ratio and total antioxidant status (TAS). The SLC2A9 gene encodes an urate transporter that has considerable influence on variation in SUA. In addition to the primary association locus, suggestive evidence (p < 1.9 × 10−6) for joint linkage/association (JLA) was found at a previously-reported urate quantitative trait locus (Logarithm of odds score = 3.6) on 3p26.3. In summary, our GWAS extends and confirms the association of SLC2A9 with SUA for the first time in a Mexican American cohort and also shows for the first time its association with cardiovascular-renal disease risk factors.
PMCID: PMC3863993  PMID: 24379826
variance components decomposition approach; joint linkage/association analysis; kinship; hyperuricemia
21.  Social status and cardiovascular disease: a Mediterranean case. Results from the Italian Progetto CUORE cohort study 
BMC Public Health  2010;10:574.
Social factors could offer useful information for planning prevention strategy for cardiovascular diseases. This analysis aims to explore the relationship between education, marital status and major cardiovascular risk factors and to evaluate the role of social status indicators in predicting cardiovascular events and deaths in several Italian cohorts.
The population is representative of Italy, where the incidence of the disease is low. Data from the Progetto CUORE, a prospective study of cohorts enrolled between 1983-1997, were used; 7520 men and 13127 women aged 35-69 years free of previous cardiovascular events and followed for an average of 11 years. Educational level and marital status were used as the main indicators of social status.
About 70% of the studied population had a low or medium level of education (less than high school) and more than 80% was married or cohabitating. There was an inverse relationship between educational level and major cardiovascular risk factors in both genders. Significantly higher major cardiovascular risk factors were detected in married or cohabitating women, with the exception of smoking. Cardiovascular risk score was lower in married or cohabitating men. No relationship between incidence of cardiac events and the two social status indicators was observed. Cardiovascular case-fatality was significantly higher in men who were not married and not cohabitating (HR 3.20, 95%CI: 2.21-4.64). The higher cardiovascular risk observed in those with a low level of education deserves careful attention even if during the follow-up it did not seem to determine an increase of cardiac events.
Preventive interventions on cardiovascular risk should be addressed mostly to people with less education. Cardiovascular risk score and case-fatality resulted higher in men living alone while cardiovascular factors were higher in women married or cohabitating. Such gender differences seem peculiar of our population and require further research on unexpected cultural and behavioural influences.
PMCID: PMC2955692  PMID: 20868471
22.  The association between cardiovascular risk and cardiovascular magnetic resonance measures of fibrosis: the Multi-Ethnic Study of Atherosclerosis (MESA) 
Risk scores for cardiovascular disease (CVD) are in common use to integrate multiple cardiovascular risk factors in order to identify individuals at greatest risk for disease. The purpose of this study was to determine if individuals at greater cardiovascular risk have T1 mapping indices by cardiovascular magnetic resonance (CMR) indicative of greater myocardial fibrosis.
CVD risk scores for 1208 subjects (men, 50.8%) ages 55–94 years old were evaluated in the Multiethnic Study of Atherosclerosis (MESA) at six centers. T1 times were determined at 1.5Tesla before and after gadolinium administration (0.15 mmol/kg) using a modified Look-Locker pulse sequence. The relationship between CMR measures (native T1, 12 and 25 minute post-gadolinium T1, partition coefficient and extracellular volume fraction) and 14 established different cardiovascular risk scores were determined using regression analysis. Bootstrapping analysis with analysis of variance was used to compare different CMR measures. CVD risk scores were significantly different for men and women (p < 0.001).
25 minute post gadolinium T1 time showed more statistically significant associations with risk scores (10/14 scores, 71%) compared to other CMR indices (e.g. native T1 (7/14 scores, 50%) and partition coefficient (7/14, 50%) in men. Risk scores, particularly the new 2013 AHA/ASCVD risk score, did not correlate with any CMR fibrosis index.
Men with greater CVD risk had greater CMR indices of myocardial fibrosis. T1 times at greater delay time (25 minutes) showed better agreement with commonly used risk score indices compared to ECV and native T1 time.
Clinical trial registration, NCT00005487.
PMCID: PMC4326517
Myocardium; Cardiovascular magnetic resonance; Risk factors
23.  Biomarker Profiling by Nuclear Magnetic Resonance Spectroscopy for the Prediction of All-Cause Mortality: An Observational Study of 17,345 Persons 
PLoS Medicine  2014;11(2):e1001606.
In this study, Würtz and colleagues conducted high-throughput profiling of blood specimens in two large population-based cohorts in order to identify biomarkers for all-cause mortality and enhance risk prediction. The authors found that biomarker profiling improved prediction of the short-term risk of death from all causes above established risk factors. However, further investigations are needed to clarify the biological mechanisms and the utility of these biomarkers to guide screening and prevention.
Please see later in the article for the Editors' Summary
Early identification of ambulatory persons at high short-term risk of death could benefit targeted prevention. To identify biomarkers for all-cause mortality and enhance risk prediction, we conducted high-throughput profiling of blood specimens in two large population-based cohorts.
Methods and Findings
106 candidate biomarkers were quantified by nuclear magnetic resonance spectroscopy of non-fasting plasma samples from a random subset of the Estonian Biobank (n = 9,842; age range 18–103 y; 508 deaths during a median of 5.4 y of follow-up). Biomarkers for all-cause mortality were examined using stepwise proportional hazards models. Significant biomarkers were validated and incremental predictive utility assessed in a population-based cohort from Finland (n = 7,503; 176 deaths during 5 y of follow-up). Four circulating biomarkers predicted the risk of all-cause mortality among participants from the Estonian Biobank after adjusting for conventional risk factors: alpha-1-acid glycoprotein (hazard ratio [HR] 1.67 per 1–standard deviation increment, 95% CI 1.53–1.82, p = 5×10−31), albumin (HR 0.70, 95% CI 0.65–0.76, p = 2×10−18), very-low-density lipoprotein particle size (HR 0.69, 95% CI 0.62–0.77, p = 3×10−12), and citrate (HR 1.33, 95% CI 1.21–1.45, p = 5×10−10). All four biomarkers were predictive of cardiovascular mortality, as well as death from cancer and other nonvascular diseases. One in five participants in the Estonian Biobank cohort with a biomarker summary score within the highest percentile died during the first year of follow-up, indicating prominent systemic reflections of frailty. The biomarker associations all replicated in the Finnish validation cohort. Including the four biomarkers in a risk prediction score improved risk assessment for 5-y mortality (increase in C-statistics 0.031, p = 0.01; continuous reclassification improvement 26.3%, p = 0.001).
Biomarker associations with cardiovascular, nonvascular, and cancer mortality suggest novel systemic connectivities across seemingly disparate morbidities. The biomarker profiling improved prediction of the short-term risk of death from all causes above established risk factors. Further investigations are needed to clarify the biological mechanisms and the utility of these biomarkers for guiding screening and prevention.
Please see later in the article for the Editors' Summary
Editors' Summary
A biomarker is a biological molecule found in blood, body fluids, or tissues that may signal an abnormal process, a condition, or a disease. The level of a particular biomarker may indicate a patient's risk of disease, or likely response to a treatment. For example, cholesterol levels are measured to assess the risk of heart disease. Most current biomarkers are used to test an individual's risk of developing a specific condition. There are none that accurately assess whether a person is at risk of ill health generally, or likely to die soon from a disease. Early and accurate identification of people who appear healthy but in fact have an underlying serious illness would provide valuable opportunities for preventative treatment.
While most tests measure the levels of a specific biomarker, there are some technologies that allow blood samples to be screened for a wide range of biomarkers. These include nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry. These tools have the potential to be used to screen the general population for a range of different biomarkers.
Why Was This Study Done?
Identifying new biomarkers that provide insight into the risk of death from all causes could be an important step in linking different diseases and assessing patient risk. The authors in this study screened patient samples using NMR spectroscopy for biomarkers that accurately predict the risk of death particularly amongst the general population, rather than amongst people already known to be ill.
What Did the Researchers Do and Find?
The researchers studied two large groups of people, one in Estonia and one in Finland. Both countries have set up health registries that collect and store blood samples and health records over many years. The registries include large numbers of people who are representative of the wider population.
The researchers first tested blood samples from a representative subset of the Estonian group, testing 9,842 samples in total. They looked at 106 different biomarkers in each sample using NMR spectroscopy. They also looked at the health records of this group and found that 508 people died during the follow-up period after the blood sample was taken, the majority from heart disease, cancer, and other diseases. Using statistical analysis, they looked for any links between the levels of different biomarkers in the blood and people's short-term risk of dying. They found that the levels of four biomarkers—plasma albumin, alpha-1-acid glycoprotein, very-low-density lipoprotein (VLDL) particle size, and citrate—appeared to accurately predict short-term risk of death. They repeated this study with the Finnish group, this time with 7,503 individuals (176 of whom died during the five-year follow-up period after giving a blood sample) and found similar results.
The researchers carried out further statistical analyses to take into account other known factors that might have contributed to the risk of life-threatening illness. These included factors such as age, weight, tobacco and alcohol use, cholesterol levels, and pre-existing illness, such as diabetes and cancer. The association between the four biomarkers and short-term risk of death remained the same even when controlling for these other factors.
The analysis also showed that combining the test results for all four biomarkers, to produce a biomarker score, provided a more accurate measure of risk than any of the biomarkers individually. This biomarker score also proved to be the strongest predictor of short-term risk of dying in the Estonian group. Individuals with a biomarker score in the top 20% had a risk of dying within five years that was 19 times greater than that of individuals with a score in the bottom 20% (288 versus 15 deaths).
What Do These Findings Mean?
This study suggests that there are four biomarkers in the blood—alpha-1-acid glycoprotein, albumin, VLDL particle size, and citrate—that can be measured by NMR spectroscopy to assess whether otherwise healthy people are at short-term risk of dying from heart disease, cancer, and other illnesses. However, further validation of these findings is still required, and additional studies should examine the biomarker specificity and associations in settings closer to clinical practice. The combined biomarker score appears to be a more accurate predictor of risk than tests for more commonly known risk factors. Identifying individuals who are at high risk using these biomarkers might help to target preventative medical treatments to those with the greatest need.
However, there are several limitations to this study. As an observational study, it provides evidence of only a correlation between a biomarker score and ill health. It does not identify any underlying causes. Other factors, not detectable by NMR spectroscopy, might be the true cause of serious health problems and would provide a more accurate assessment of risk. Nor does this study identify what kinds of treatment might prove successful in reducing the risks. Therefore, more research is needed to determine whether testing for these biomarkers would provide any clinical benefit.
There were also some technical limitations to the study. NMR spectroscopy does not detect as many biomarkers as mass spectrometry, which might therefore identify further biomarkers for a more accurate risk assessment. In addition, because both study groups were northern European, it is not yet known whether the results would be the same in other ethnic groups or populations with different lifestyles.
In spite of these limitations, the fact that the same four biomarkers are associated with a short-term risk of death from a variety of diseases does suggest that similar underlying mechanisms are taking place. This observation points to some potentially valuable areas of research to understand precisely what's contributing to the increased risk.
Additional Information
Please access these websites via the online version of this summary at
The US National Institute of Environmental Health Sciences has information on biomarkers
The US Food and Drug Administration has a Biomarker Qualification Program to help researchers in identifying and evaluating new biomarkers
Further information on the Estonian Biobank is available
The Computational Medicine Research Team of the University of Oulu and the University of Bristol have a webpage that provides further information on high-throughput biomarker profiling by NMR spectroscopy
PMCID: PMC3934819  PMID: 24586121
24.  Juvenile Myoclonic Epilepsy (JME): Neuropsychological Profile and Related Factors with Cognitive Dysfunction 
Iranian Journal of Psychiatry  2014;9(1):14-19.
The aim of present study was to verify possible cognitive dysfunction in the patients with Juvenile Myoclonic Epilepsy (JME) and its correlation to factors related to epilepsy and patients demographic variables.
Material and Methods
Thirty two consecutive patients with JME and 32 healthy controls were evaluated in neuropsychological domains including orientation, mental control, logical memory, forward and backward digit spans, visual memory, associative learning, and memory quotient (using Persian version of Wechsler Memory Scale (WMS)-Revised), preservative errors (using Wisconsin Card Sorting Test (WCST)), Stroop Test (color and word), IQ score (using Raven’s Progressive Matrices test), and depression (using the Persian version of Beck Depression Inventory (BDI)). SPSS 11.0 (SPSS Inc., Chicago, Illinois, USA) software was used for statistical analysis. Student’s t-test and the Mann-Whitney U-test were used for independent normally and non-normally distributed continuous variables, respectively.
Our study showed significant differences between patients with JME and control group with respect to scores of mental control (p=0.015), forward digit span (p=0.004), total digit span (p=0.008) and IQ (p=0.003). In addition, age, education level, duration of epilepsy and medication showed an impact on several cognitive functions in the patients with JME.
It is indicated that JME is associated with impairment in specific cognitive domains, despite any evidence in favor of depression.
PMCID: PMC4277602  PMID: 25561943
Juvenile Myoclonic Epilepsy (JME); cognitive dysfunction; neuropsychological asessement, seizure
25.  Patterning in Birthweight in India: Analysis of Maternal Recall and Health Card Data 
PLoS ONE  2010;5(7):e11424.
National data on birthweight from birth certificates or medical records are not available in India. The third Indian National Family Health Survey included data on birthweight of children obtained from health cards and maternal recall. This study aims to describe the population that these data represent and compares the birthweight obtained from health cards with maternal recall data in terms of its socioeconomic patterning and as a risk factor for childhood growth failure.
Methodology/Principal Findings
The analytic sample consisted of children aged 0 to 59 months with birthweight data obtained from health cards (n = 3227) and maternal recall (n = 16787). The difference between the card sample and the maternal recall sample in the distribution across household wealth, parental education, caste, religion, gender, and urban residence was compared using multilevel models. We also assessed the ability of birthweight to predict growth failure in infancy and childhood in the two groups. The survey contains birthweight data from a majority of household wealth categories (>5% in every category for recall), both genders, all age groups, all caste groups, all religion groups, and urban and rural dwellers. However, children from the lowest quintile of household wealth were under-represented (4.73% in card and 8.62% in recall samples). Comparison of data across health cards and maternal recall revealed similar social patterning of low birthweight and ability of birthweight to predict growth failure later in life. Children were less likely to be born with low birthweight if they had mothers with over 12 years of education compared to 1–5 years of education with relative risk (RR) of 0.79 (95% confidence interval [CI]: 0.52, 1.2) in the card sample and 0.70 (95% CI: 0.59, 0.84) in the recall sample. A 100 gram difference in a child's birthweight was associated with a decreased likelihood of underweight in both the card (RR: 0.95; 95% CI: 0.94, 0.96) and recall (RR: 0.96; 95% CI: 0.96, 0.97) samples.
Our results suggest that in the absence of other sources, the data on birthweight in the third Indian National Family Health Survey is valuable for epidemiologic research.
PMCID: PMC2896401  PMID: 20625399

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