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1.  Low blood pressure, antihypertensive treatment, and physical and mental health status in patients with arterial disease. The SMART-Study 
Journal of internal medicine  2013;274(3):10.1111/joim.12069.
Objective
To investigate the independent effects of antihypertensive treatment and blood pressure (BP) levels on physical and mental health status in patients with arterial disease.
Design
Cross-sectional analyses within the Secondary Manifestations of ARTerial disease (SMART) study, a single centre cohort study.
Setting
Hospitalized care.
Subjects
5,877 patients (mean age 57) with symptomatic and asymptomatic arterial disease who underwent a standardized vascular screening.
Main outcome measure
Self-rated physical and mental health assessed with the Short Form (SF)-36.
Results
In the total population, antihypertensive drug use and increased intensity of antihypertensive treatment was associated with poorer health status independent of important confounders including BP levels; adjusted mean differences (95%CI) in physical and mental health between 0 and ≥3 antihypertensives were -1.2 (-2.1, -0.3) and -3.5 (-4.4; -2.6). Furthermore, lower systolic and lower diastolic BP levels were related to poorer physical and mental health status independently of antihypertensive treatment. Mean differences (95%CI) in physical and mental health status per SD decrease in systolic BP were -0.56 (-0.84; -0.27) and -0.32 (-0.61; -0.03), and per SD decrease in diastolic BP -0.50 (-0.78; -0.23) and -0.08 (-0.36; 0.20). The association between low BP and poor health status was particularly present in patients with coronary artery disease.
Conclusions
In a population of patients with asymptomatic and symptomatic arterial disease, antihypertensive treatment and lower BP levels are independently associated with poorer self-rated physical and mental health. These results might indicate that there are different underlying mechanisms explaining these independent associations.
doi:10.1111/joim.12069
PMCID: PMC3750200  PMID: 23527863
antihypertensive treatment; blood pressure; physical health; mental health; cardiovascular disease
2.  Rs964184 (APOA5-A4-C3-A1) Is Related to Elevated Plasma Triglyceride Levels, but Not to an Increased Risk for Vascular Events in Patients with Clinically Manifest Vascular Disease 
PLoS ONE  2014;9(6):e101082.
Background
Single nucleotide polymorphisms in the APOA5-A4-C3-A1 gene complex are associated with elevated plasma triglycerides and elevated vascular risk in healthy populations. In patients with clinically manifest vascular disease, hypertriglyceridemia and metabolic syndrome are frequently present, but the contribution of these single nucleotide polymorphisms to plasma triglycerides, effect modification by obesity and risk of recurrent vascular events is unknown in these patients.
Methods
Prospective cohort study of 5547 patients with vascular disease. Rs964184 (APOA5-A4-C3-A1 gene complex) was genotyped, and we evaluated the relation with plasma lipid levels, presence of metabolic syndrome and the risk for new vascular events.
Results
The minor allele of rs964184 was strongly associated with log plasma triglycerides (β 0.12; 95%CI 0.10-0.15, p = 1.1*10−19), and was also associated with 0.03 mmol/L lower high-density lipoprotein-cholesterol (95%CI 0.01–0.04), and 0.14 mmol/L higher non-high-density lipoprotein-cholesterol (95%CI 0.09–0.20). The minor allele frequency increased from 10.9% in patients with plasma triglycerides <1 mmol/L to 24.6% in patients with plasma triglycerides between 4 and 10 mmol/L. The relation between rs964184 and plasma triglycerides was modified by body mass index in patients with one minor allele (β 0.02; (95%CI −0.04–0.09) if body mass index <24 kg/m2, β 0.17 (95%CI 0.12–0.22) if body mass index >27 kg/m2, p for interaction = 0.02). The prevalence of the metabolic syndrome increased from 52% for patients with two copies of the major allele to 62% for patients with two copies of the minor allele (p = 0.01). Rs964184 was not related with recurrent vascular events (HR 0.99; 95%CI 0.86–1.13).
Conclusion
The single nucleotide polymorphism rs964184 (APOA5-A4-C3-A1) is associated with elevated plasma triglycerides concentrations in patients with clinically manifest vascular disease. In carriers of one minor allele, the effect on plasma triglycerides was modified by body mass index. There is no relation between rs964184 and recurrent vascular events in these patients.
doi:10.1371/journal.pone.0101082
PMCID: PMC4076225  PMID: 24979386
3.  Awareness, agreement, adoption and adherence to type 2 diabetes mellitus guidelines: a survey of Indonesian primary care physicians 
BMC Family Practice  2014;15:72.
Background
To assess the degree of awareness, agreement, adoption and adherence of physicians in Indonesia to type 2 diabetes mellitus guidelines, and their association with characteristics of the responders.
Methods
Questionnaire survey among General Practitioners (GPs) attending the Indonesian Association of Family Practitioners annual conference in November 2012. The proportion of GPs who were aware of, agreed with, adopted and adhered to the seven recommendations in the guidelines (screening for diabetes, diagnosis, lifestyle modification, use of sulfonylurea, target blood glucose, target blood pressure and use of statin) were calculated in the total number of responders.
Results
Of the 399 GPs participating, 383 (89%) were aware of the existence of Indonesian type 2 diabetes guidelines. Awareness for each recommendation varied from 66 to 91%. The recommendation to use a random blood glucose test for diagnosing patients with classic diabetes symptoms had the least awareness (265/399, 66%) and least agreement (163/399, 41%). The recommendation on statin use was the least adopted (192/399, 48%), while the least adherence (7/399, 2%) was found for the recommendation on screening for diabetes for patients with risk factors. Years of practice experience and proportion of diabetes patients seen in their practice were independently related with adherence to statin prescription.
Conclusions
High awareness of the Indonesian type 2 diabetes guideline does not necessary lead to adoption or adherence to recommendations important for outcomes and quality of care. The awareness-to-adherence model helps in identifying barriers for the use of guidelines.
doi:10.1186/1471-2296-15-72
PMCID: PMC4000317  PMID: 24755412
Awareness; Adoption; Adherence; Diabetes; Guidelines; General practitioners
5.  Prediction of outcome in patients with suspected acute ischaemic stroke with CT perfusion and CT angiography: the Dutch acute stroke trial (DUST) study protocol 
BMC Neurology  2014;14:37.
Background
Prediction of clinical outcome in the acute stage of ischaemic stroke can be difficult when based on patient characteristics, clinical findings and on non-contrast CT. CT perfusion and CT angiography may provide additional prognostic information and guide treatment in the early stage. We present the study protocol of the Dutch acute Stroke Trial (DUST). The DUST aims to assess the prognostic value of CT perfusion and CT angiography in predicting stroke outcome, in addition to patient characteristics and non-contrast CT. For this purpose, individualised prediction models for clinical outcome after stroke based on the best predictors from patient characteristics and CT imaging will be developed and validated.
Methods/design
The DUST is a prospective multi-centre cohort study in 1500 patients with suspected acute ischaemic stroke. All patients undergo non-contrast CT, CT perfusion and CT angiography within 9 hours after onset of the neurological deficits, and, if possible, follow-up imaging after 3 days. The primary outcome is a dichotomised score on the modified Rankin Scale, assessed at 90 days. A score of 0–2 represents good outcome, and a score of 3–6 represents poor outcome. Three logistic regression models will be developed, including patient characteristics and non-contrast CT (model A), with addition of CT angiography (model B), and CT perfusion parameters (model C). Model derivation will be performed in 60% of the study population, and model validation in the remaining 40% of the patients. Additional prognostic value of the models will be determined with the area under the curve (AUC) from the receiver operating characteristic (ROC) curve, calibration plots, assessment of goodness-of-fit, and likelihood ratio tests.
Discussion
This study will provide insight in the added prognostic value of CTP and CTA parameters in outcome prediction of acute stroke patients. The prediction models that will be developed in this study may help guide future treatment decisions in the acute stage of ischaemic stroke.
doi:10.1186/1471-2377-14-37
PMCID: PMC3939816  PMID: 24568540
Stroke; Ischaemia; Infarct; Prediction; CT perfusion; CT angiography
6.  Extracellular vesicle markers in relation to obesity and metabolic complications in patients with manifest cardiovascular disease 
Background
Alterations in extracellular vesicles (EVs), including exosomes and microparticles, contribute to cardiovascular disease. We hypothesized that obesity could favour enhanced release of EVs from adipose tissue, and thereby contribute to cardiovascular risk via obesity-induced metabolic complications. The objectives of this study were: 1) to investigate the relation between the quantity, distribution and (dys) function of adipose tissue and plasma concentrations of atherothrombotic EV-markers; 2) to determine the relation between these EV-markers and the prevalence of the metabolic syndrome; and 3) to assess the contribution of EV markers to the risk of incident type 2 diabetes.
Methods
In 1012 patients with clinically manifest vascular disease, subcutaneous and visceral fat thickness was measured ultrasonographically. Plasma EVs were isolated and levels of cystatin C, serpin G1, serpin F2 and CD14 were measured, as well as fasting metabolic parameters, hsCRP and adiponectin. The association between adiposity, EV-markers, and metabolic syndrome was tested by multivariable linear and logistic regression analyses. As sex influences body fat distribution, sex-stratified analyses between adipose tissue distribution and EV-markers were performed. The relation between EV-markers and type 2 diabetes was assessed with Cox regression analyses.
Results
Higher levels of hsCRP (β 5.59; 95% CI 3.00–8.18) and lower HDL-cholesterol levels (β-11.26; 95% CI −18.39 – -4.13) were related to increased EV-cystatin C levels, and EV-cystatin C levels were associated with a 57% higher odds of having the metabolic syndrome (OR 1.57; 95% CI 1.19–2.27). HDL-cholesterol levels were positively related to EV-CD14 levels (β 5.04; 95% CI 0.07–10.0), and EV-CD14 levels were associated with a relative risk reduction of 16% for development of type 2 diabetes (HR 0.84, 95% CI 0.75–0.94), during a median follow up of 6.5 years in which 42 patients developed type 2 diabetes.
Conclusions
In patients with clinically manifest vascular disease, EV-cystatin C levels were positively related, and EV-CD14 levels were negatively related to metabolic complications of obesity.
doi:10.1186/1475-2840-13-37
PMCID: PMC3918107  PMID: 24498934
Extracellular vesicle markers; Obesity; hsCRP; Metabolic syndrome; Type 2 diabetes
7.  Extracellular vesicle protein levels are related to brain atrophy and cerebral white matter lesions in patients with manifest vascular disease: the SMART-MR study 
BMJ Open  2014;4(1):e003824.
Objectives
Extracellular vesicles (EVs) and their protein levels have been identified as a potential risk marker for the development of vascular disease. In the present study, we assessed whether levels of four previously identified EV proteins (cystatin C, serpin G1, serpin F2 and CD14) are associated with cerebral white matter lesions (WMLs) and brain atrophy.
Design
Cohort study; cross-sectional and prospective.
Setting
Single centre, secondary and tertiary setting.
Participants
1309 patients with manifest vascular disease from the Second Manifestations of ARTerial disease-MR (SMART-MR) study, of which 994 had successful brain MRI and EV protein level measurements.
Outcomes
WML and brain parenchymal fraction (BPF), as parameter for brain atrophy, at baseline and follow-up.
Statistical methods
The relationship between EV protein levels and WML volume (expressed as log transformed percentage of intracranial volume) and BPF (expressed percentage of intracranial volume) on 1.5 T brain MRI was assessed with multivariable linear regression modelling. Subsequently, the relationship between baseline EV protein levels and progression of atrophy and WML was analysed in 534 patients, in whom a follow-up MRI was obtained after 4 years.
Results
Higher EV-cystatin C and EV-CD14 were significantly associated with larger WML volume (linear regression coefficient (95% CI) 0.10 log %/SD (0.04 to 0.17) and 0.14 log %/SD (0.07 to 0.20), respectively. Higher EV-CD14 was associated with more brain atrophy (–0.14%/SD; –0.27 to –0.01). Baseline EV-CD14 was significantly associated with increase of WMLs (0.11 log %/SD (0.04 to 0.18)). No relationship with EV-serpins was observed at baseline or at follow-up.
Conclusions
EV proteins cystatin C and CD14 are related to cerebral WMLs and the progression of brain atrophy in patients with manifest vascular disease, potentially identifying EVs in the aetiology of structural brain changes.
doi:10.1136/bmjopen-2013-003824
PMCID: PMC3902438  PMID: 24430876
extracellular vesicles; White matter lesion; Brain atrophy
8.  Reliability of Visual Assessment of Non-Contrast CT, CT Angiography Source Images and CT Perfusion in Patients with Suspected Ischemic Stroke 
PLoS ONE  2013;8(10):e75615.
Background and Purpose
Good reliability of methods to assess the extent of ischemia in acute stroke is important for implementation in clinical practice, especially between observers with varying experience. Our aim was to determine inter- and intra-observer reliability of the 1/3 middle cerebral artery (MCA) rule and the Alberta Stroke Program Early CT Score (ASPECTS) for different CT modalities in patients suspected of acute ischemic stroke.
Methods
We prospectively included 105 patients with acute neurological deficit due to suspected acute ischemic stroke within 9 hours after symptom onset. All patients underwent non-contrast CT, CT perfusion and CT angiography on admission. All images were evaluated twice for presence of ischemia, ischemia with >1/3 MCA involvement, and ASPECTS. Four observers evaluated twenty scans twice for intra-observer agreement. We used kappa statistics and intraclass correlation coefficient to calculate agreement.
Results
Inter-observer agreement for the 1/3 MCA rule and ASPECTS was fair to good for non-contrast CT, poor to good for CT angiography source images, but excellent for all CT perfusion maps (cerebral blood volume, mean transit time, and predicted penumbra and infarct maps). Intra-observer agreement for the 1/3 MCA rule and ASPECTS was poor to good for non-contrast CT, fair to moderate for CT angiography source images, and good to excellent for all CT perfusion maps.
Conclusion
Between observers with a different level of experience, agreement on the radiological diagnosis of cerebral ischemia is much better for CT perfusion than for non-contrast CT and CT angiography source images, and therefore CT perfusion is a very reliable addition to standard stroke imaging.
doi:10.1371/journal.pone.0075615
PMCID: PMC3792960  PMID: 24116061
9.  Do general practitioners follow treatment recommendations from guidelines in their decisions on heart failure management? A cross-sectional study 
BMJ Open  2013;3(9):e002982.
Objective
To investigate whether general practitioners (GPs) follow treatment recommendations from clinical practice guidelines in their decisions on the management of heart failure patients, and assess whether doctors’ characteristics are related to their decisions.
Design
Cross-sectional vignette study.
Setting
Continuing Medical Education meeting.
Participants
451 Dutch GPs.
Main outcome measures
Answers to four multiple-choice treatment decisions in clinical vignettes of a patient with heart failure and a reduced ejection fraction. With univariable and multivariable regression analyses, respondent characteristics were related to optimal treatment decisions.
Results
Of the 451 GPs, none took four optimal decisions: 7% considered stopping statin treatment, 36% initiated β-blocker treatment at a low-dose and 4% doubled the β-blocker in the up-titration phase. Finally, for our vignette patient now also suffering from chronic obstructive pulmonary disease, 45% of the GPs continued β-blocker therapy even when they considered prescribing a long-acting β2-agonist. While the relation between respondent characteristics and each decision was very different, none was independently associated with all four decisions. Giving priority to evidence-based medicine was independently related to stopping statin treatment and doubling the β-blocker in the up-titration phase.
Conclusions
GPs seem not to follow treatment recommendations from clinical practice guidelines in their decisions on the management of heart failure patients. The recommendations from guidelines may appear counterintuitive when statin treatment needs to be stopped when a patient feels comfortable, or when a β-blocker should be up-titrated in patients who experience more symptoms. Giving priority to evidence-based medicine is possibly positively related to difficult treatment decisions.
doi:10.1136/bmjopen-2013-002982
PMCID: PMC3780330  PMID: 24041845
PRIMARY CARE
10.  Intra and Interobserver Reliability and Agreement of Semiquantitative Vertebral Fracture Assessment on Chest Computed Tomography 
PLoS ONE  2013;8(8):e71204.
Objectives
To evaluate the reliability of semiquantitative Vertebral Fracture Assessment (VFA) on chest Computed Tomography (CT).
Methods
Four observers performed VFA twice upon sagittal reconstructions of 50 routine clinical chest CTs. Intra- and interobserver agreement (absolute agreement or 95% Limits of Agreement) and reliability (Cohen's kappa or intraclass correlation coefficient(ICC)) were calculated for the visual VFA measures (fracture present, worst fracture grade, cumulative fracture grade on patient level) and for percentage height loss of each fractured vertebra compared to the adjacent vertebrae.
Results
Observers classified 24–38% patients as having at least one vertebral fracture, giving rise to kappa's of 0.73–0.84 (intraobserver) and 0.56–0.81 (interobserver). For worst fracture grade we found good intraobserver (76–88%) and interobserver (74–88%) agreement, and excellent reliability with square-weighted kappa's of 0.84–0.90 (intraobserver) and 0.84–0.94 (interobserver). For cumulative fracture grade the 95% Limits of Agreement were maximally ±1,99 (intraobserver) and ±2,69 (interobserver) and the reliability (ICC) varied from 0.84–0.94 (intraobserver) and 0.74–0.94 (interobserver). For percentage height-loss on a vertebral level the 95% Limits of Agreement were maximally ±11,75% (intraobserver) and ±12,53% (interobserver). The ICC was 0.59–0.90 (intraobserver) and 0.53–0–82 (interobserver). Further investigation is needed to evaluate the prognostic value of this approach.
Conclusion
In conclusion, these results demonstrate acceptable reproducibility of VFA on CT.
doi:10.1371/journal.pone.0071204
PMCID: PMC3733867  PMID: 23940719
11.  Impact of Cardiovascular Calcifications on the Detrimental Effect of Continued Smoking on Cardiovascular Risk in Male Lung Cancer Screening Participants 
PLoS ONE  2013;8(6):e66484.
Background
Current smokers have an increased cardiovascular disease (CVD) risk compared to ex-smokers due to reversible as well as irreversible effects of smoking. We investigated if current smokers remain to have an increased CVD risk compared to ex-smokers in subjects with a long and intense smoking history. We in addition studied if the effect of smoking continuation on CVD risk is independent of or modified by the presence of cardiovascular calcifications.
Methods
The cohort used comprised a sample of 3559 male lung cancer screening trial participants. We conducted a case-cohort study using all CVD cases and a random sample of 10% (n = 341) from the baseline cohort (subcohort). A weighted Cox proportional hazards model was used to estimate the hazard ratios for current smoking status in relation to CVD events.
Results
During a median follow-up of 2.6 years (max. 3.7 years), 263 fatal and non-fatal cardiovascular events (cases) were identified. Age, packyears and cardiovascular calcification adjusted hazard ratio of current smokers compared to former smokers was 1.33 (95% confidence interval 1.00–1.77). In additional analyses that incorporated multiplicative interaction terms, neither coronary nor aortic calcifications modified the association between smoking status and cardiovascular risk (P = 0.08).
Conclusions
Current smokers have an increased CVD risk compared to former smokers even in subjects with a long and intense smoking history. Smoking exerts its hazardous effects on CVD risk by pathways partly independent of cardiovascular calcifications.
doi:10.1371/journal.pone.0066484
PMCID: PMC3688769  PMID: 23840486
12.  Association between Subcortical Vascular Lesion Location and Cognition: A Voxel-Based and Tract-Based Lesion-Symptom Mapping Study. The SMART-MR Study 
PLoS ONE  2013;8(4):e60541.
Introduction
Lacunar lesions (LLs) and white matter lesions (WMLs) affect cognition. We assessed whether lesions located in specific white matter tracts were associated with cognitive performance taking into account total lesion burden.
Methods
Within the Second Manifestations of ARTerial disease Magnetic Resonance (SMART-MR) study, cross-sectional analyses were performed on 516 patients with manifest arterial disease. We applied an assumption-free voxel-based lesion-symptom mapping approach to investigate the relation between LL and WML locations on 1.5 Tesla brain MRI and compound scores of executive functioning, memory and processing speed. Secondly, a multivariable linear regression model was used to relate the regional volume of LLs and WMLs within specific white matter tracts to cognitive functioning.
Results
Voxel-based lesion-symptom mapping identified several clusters of voxels with a significant correlation between WMLs and executive functioning, mostly located within the superior longitudinal fasciculus and anterior thalamic radiation. In the multivariable linear regression model, a statistically significant association was found between regional LL volume within the superior longitudinal fasciculus and anterior thalamic radiation and executive functioning after adjustment for total LL and WML burden.
Conclusion
These findings identify the superior longitudinal fasciculus and anterior thalamic radiation as key anatomical structures in executive functioning and emphasize the role of strategically located vascular lesions in vascular cognitive impairment.
doi:10.1371/journal.pone.0060541
PMCID: PMC3620525  PMID: 23593238
13.  Dutch postgraduate GP selection procedure; reliability of interview assessments 
BMC Family Practice  2013;14:43.
Background
Semi- structured interviews are the core of the Dutch selection procedure for postgraduate general practice (GP) training. A staff member, trainer and trainee independently assess personal qualities. Aiming to improve the selection procedure we were interested in the reliability aspects of these interviews. We investigated the inter-rater reliability of the interview for groups of two or three assessors and the degree to which candidates’ characteristics and qualities assessed during interviews explained admission into GP training, controlled for differences between those who apply for the first versus the second or third application.
Methods
An observational study was conducted of all candidates who entered the Utrecht selection procedure between April 2008 and 2010. Candidates’ characteristics and qualities were collected. Inter-rater reliability of different compositions of the interview group per quality was estimated. Factors associated with admission into GP training were assessed.
Results
The study population included 394 candidates. Twenty-six candidates were rejected based on their application letter (4.4%). Three candidates who applied more than 3 times were excluded. Ultimately, 206 of the 365 candidates were admitted to the GP training (56,4%). The inter-rater reliability was satisfactory (ICC: 0.78 – 0 .84). Reduction from three to two assessors slightly reduces the ICC. The candidates’ qualities independently explained admission to GP training, whereas individual characteristics did not. These results did not differ for candidates who applied for the first time versus candidates applying for the second or third time.
Conclusion
Selection interviews with two assessors yielded a satisfactory level of reliability. Individual characteristics were not associated with admission, whereas scores related to candidate qualities did show such an association. The results of those applying for the second or third time were similar.
doi:10.1186/1471-2296-14-43
PMCID: PMC3618184  PMID: 23537312
14.  A gene-centric study of common carotid artery remodelling 
Atherosclerosis  2013;226(2):440-446.
Background
Expansive remodelling is the process of compensatory arterial enlargement in response to atherosclerotic stimuli. The genetic determinants of this process are poorly characterized.
Methods
Genetic association analyses of inter-adventitial common carotid artery diameter (ICCAD) in the IMPROVE study (n = 3427) using the Illumina 200k Metabochip was performed. Single nucleotide polymorphisms (SNPs) that met array-wide significance were taken forward for analysis in three further studies (n = 5704), and tested for association with Abdominal Aortic Aneurysm (AAA).
Results
rs3768445 on Chromosome 1q24.3, in a cluster of protein coding genes (DNM3, PIGC, C1orf105) was associated with larger ICCAD in the IMPROVE study. For each copy of the rare allele carried, ICCAD was on average 0.13 mm greater (95% CI 0.08–0.18 mm, P = 8.2 × 10−8). A proxy SNP (rs4916251, R2 = 0.99) did not, however, show association with ICCAD in three follow-up studies (P for replication = 0.29). There was evidence of interaction between carotid intima-media thickness (CIMT) and rs4916251 on ICCAD in two of the cohorts studies suggesting that it plays a role in the remodelling response to atherosclerosis. In meta-analysis of 5 case–control studies pooling data from 5007 cases and 43,630 controls, rs4916251 was associated with presence of AAA 1.10, 95% CI 1.03–1.17, p = 2.8 × 10−3, I2 = 18.8, Q = 0.30). A proxy SNP, rs4916251 was also associated with increased expression of PIGC in aortic tissue, suggesting that this may the mechanism by which this locus affects vascular remodelling.
Conclusions
Common variation at 1q24.3 is associated with expansive vascular remodelling and risk of AAA. These findings support a hypothesis that pathways involved in systemic vascular remodelling play a role in AAA development.
Highlights
► In the IMPROVE study (n > 3000) variants at 1q24.3 were strongly associated with larger carotid diameters. ► The lead variant was associated with Abdominal Aortic Aneurysm (AAA) in meta-analysis of 5 studies (n > 50,000). ► Variants at 1q24.3 appear to be associated with vascular remodelling and risk of AAA.
doi:10.1016/j.atherosclerosis.2012.11.002
PMCID: PMC3573227  PMID: 23246012
Abdominal aortic aneurysm; Genome-wide association studies; Vascular remodelling; Carotid artery
15.  The daily 10 kcal expenditure deficit: a before-and-after study on low-cost interventions in the work environment 
BMJ Open  2013;3(1):e002125.
Objectives
To evaluate whether four types of low-cost interventions in the working environment can promote the small everyday lifestyle adaptations that can halt the epidemics of obesity and hypertension when maintained long term.
Design
A single-blind uninterrupted time-series intervention study consisting of four study periods: run-in (2 weeks), baseline (2 weeks), intervention (2 weeks), and after intervention 2 weeks).
Setting
University Medical Centre with over 11 000 employees, over 1000 hospital beds and over 2000 customers visiting the hospital restaurant each day.
Participants
Hospital staff and visitors.
Interventions
(1) Point-of-decision prompts on hospital elevator doors promoting stair use. (2) Point-of-purchase prompts in the hospital restaurant promoting reduced-salt soup. (3) Point-of-purchase prompts in the hospital restaurant promoting lean croissants. (4) Reversal of the accessibility and availability of diet margarine and butter in the hospital restaurant.
Main outcome measures
(1) Number of passages through 15 different parts of the hospital staircases. (2) Number and ratio of normal-salt and reduced-salt soup purchased. (3) Number and ratio of butter croissants and lean croissants purchased. (4) Number and ratio of diet margarine and butter purchased.
Results
Elevator signs increased the mean 24-h number of stair passages per measurement site (baseline: 992 ± 479 on week days and 208 ± 116 on weekend days) by 11.2% (95% CI 8.7% to 13.7%). This effect was maintained at least 2 weeks after the point-of-decision prompts were removed. Point-of-purchase prompts promoting low-salt soup and lean croissants did not result in altered purchase behaviour. The ratio between the purchase of margarine and butter was changed sevenfold (p<0.01) by reversing the positions of these products in the hospital restaurant.
Conclusions
Healthy lifestyle adaptations in the working environment can be effectively promoted by making healthy choices easier than unhealthy ones. Educational prompts at points-of-decision moderately increase stair climbing, but do not affect healthy food choices.
Protocol registration
Clinicaltrials.gov identifier number: NCT01574040.
doi:10.1136/bmjopen-2012-002125
PMCID: PMC3563119  PMID: 23355669
Health Promotion; Occupational & Industrial Medicine; Physical Activity And Exercise Methodology; Preventive Medicine
16.  Aspirin for primary prevention of vascular events in women: individualized prediction of treatment effects 
European Heart Journal  2011;32(23):2962-2969.
Aims
To identify women who benefit from aspirin 100 mg on alternate days for primary prevention of vascular events by using treatment effect prediction based on individual patient characteristics.
Methods and results
Randomized controlled trial data from the Women's Health Study were used to predict treatment effects for individual women in terms of absolute risk reduction for major cardiovascular events (i.e. myocardial infarction, stroke, or cardiovascular death). Predictions were based on existing risk scores, i.e. Framingham (FRS), and Reynolds (RRS), and on a newly developed prediction model. The net benefit of different aspirin treatment-strategies was compared: (i) treat no one, (ii) treat everyone, (iii) treatment according to the current guidelines (i.e. selective treatment of women >65 years of age or having >10% FRS), and (iv) prediction-based treatment (i.e. selective treatment of patients whose predicted treatment effect exceeds a given decision threshold). The predicted reduction in 10-year absolute risk for major cardiovascular events was <1% in 97.8% of 27 939 study subjects when based on the refitted FRS, in 97.0% when based on the refitted RRS, and in 90.0% when based on the newly developed model. Of the treatment strategies considered, only prediction-based treatment using the newly developed model and selective treatment of women >65 years of age yielded more net benefit than treating no one, provided that the 10-year number-willing-to-treat (NWT) to prevent one cardiovascular event was above 50.
Conclusion
Aspirin was ineffective or even harmful in the majority of patients. Age was positively related to treatment effect, whereas current smoking and baseline risk for cardiovascular events were not. When the NWT is 50 or lower, the aspirin treatment strategy that is associated with optimal net benefit in primary prevention of vascular events in women is to treat none.
Trial registration information: Clinicaltrials.gov identifier number: NCT00000479.
doi:10.1093/eurheartj/ehr423
PMCID: PMC3227855  PMID: 22090661
Aspirin; Primary prevention; Treatment effect prediction; Net benefit
17.  Interleukin-6 receptor pathways in abdominal aortic aneurysm 
European Heart Journal  2012;34(48):3707-3716.
Methods
We conducted a systematic review and meta-analysis of studies reporting circulating IL-6 in AAA, and new investigations of the association between a common non-synonymous functional variant (Asp358Ala) in the IL-6R gene (IL6R) and AAA, followed the analysis of the variant both in vitro and in vivo.
Inflammation may play a role in the development of abdominal aortic aneurysms (AAA). Interleukin-6 (IL-6) signalling through its receptor (IL-6R) is one pathway that could be exploited pharmacologically. We investigated this using a Mendelian randomization approach.
Results
Up to October 2011, we identified seven studies (869 cases, 851 controls). Meta-analysis demonstrated that AAA cases had higher levels of IL-6 than controls [standardized mean difference (SMD) = 0.46 SD, 95% CI = 0.25–0.66, I2 = 70%, P = 1.1 × 10–5 random effects]. Meta-analysis of five studies (4524 cases/15 710 controls) demonstrated that rs7529229 (which tags the non-synonymous variant Asp358Ala, rs2228145) was associated with a lower risk of AAA, per Ala358 allele odds ratio 0.84, 95% CI: 0.80–0.89, I2 = 0%, P = 2.7 × 10–11). In vitro analyses in lymphoblastoid cell lines demonstrated a reduction in the expression of downstream targets (STAT3, MYC and ICAM1) in response to IL-6 stimulation in Ala358 carriers.
Conclusions
A Mendelian randomization approach provides robust evidence that signalling via the IL-6R is likely to be a causal pathway in AAA. Drugs that inhibit IL-6R may play a role in AAA management.
doi:10.1093/eurheartj/ehs354
PMCID: PMC3869968  PMID: 23111417
Abdominal aortic aneurysm; Mendelian randomization; Interleukin-6; Polymorphism
18.  From west to east; experience with adapting a curriculum in evidence-based medicine 
Perspectives on Medical Education  2012;1(5-6):249-261.
Clinical epidemiology (CE) and evidence-based medicine (EBM) have become an important part of medical school curricula. This report describes the implementation and some preliminary outcomes of an integrated CE and EBM module in the Faculty of Medicine Universitas Indonesia (UI), Jakarta and in the University of Malaya (UM) in Kuala Lumpur. A CE and EBM module, originally developed at the University Medical Center Utrecht (UMCU), was adapted for implementation in Jakarta and Kuala Lumpur. Before the start of the module, UI and UM staff followed a training of teachers (TOT). Student competencies were assessed through pre and post multiple-choice knowledge tests, an oral and written structured evidence summary (evidence-based case report, EBCR) as well as a written exam. All students also filled in a module evaluation questionnaire. The TOT was well received by staff in Jakarta and Kuala Lumpur and after adaptation the CE and EBM modules were integrated in both medical schools. The pre-test results of UI and UM were significantly lower than those of UMCU students (p < 0.001). The post test results of UMCU students were comparable (p = 0.48) with UI, but significantly different (p < 0.001) from UM. Common problems for the modules in both UI and UM were limited access to literature and variability of the tutors’ skills. Adoption and integration of an existing Western CE-EBM teaching module into Asian medical curricula is feasible while learning outcomes obtained are quite similar.
doi:10.1007/s40037-012-0029-9
PMCID: PMC3518799  PMID: 23240103
Curriculum; Medical students; Under-graduate education; Evidence-based medicine
19.  Screening for type 2 diabetes in a high-risk population: study design and feasibility of a population-based randomized controlled trial 
BMC Public Health  2012;12:671.
Background
We describe the design and present the results of the first year of a population-based study of screening for type 2 diabetes in individuals at high risk of developing the disease. High risk is defined as having abdominal obesity.
Methods
Between 2006 and 2007, 79,142 inhabitants of two Dutch municipalities aged 40–74 years were approached to participate in screening. Eligible participants had a self-reported waist circumference of ≥80 cm for women and ≥94 cm for men, and no known pre-existing diabetes. Of the respondents (n = 20,578; response rate 26%), 16,135 were abdominally obese. In total, 10,609 individuals gave written informed consent for participation and were randomized into either the screening (n = 5305) or the control arm (n = 5304). Participants in the screening arm were invited to have their fasting plasma glucose (FPG) measured and were referred to their general practitioner (GP) if it was ≥6.1 mmol/L. In addition, blood lipids were determined in the screening arm, because abdominal obesity is often associated with cardiovascular risk factors. Participants in both arms received written healthy lifestyle information. Between-group differences were analyzed with Chi-square tests and logistic regression (categorical variables) and unpaired t-tests (continuous variables).
Results
The screening attendance rate was 84.1%. Attending screening was associated with age at randomization (OR = 1.03, 95% CI 1.02-1.04), being married (OR = 1.57, 95% CI 1.33-1.83) and not-smoking currently (OR = 0.52, 95% CI 0.44-0.62). Of the individuals screened, 5.6% had hyperglycemia, and a further 11.6% had an estimated absolute cardiovascular disease risk of 5% or higher, according to the Systematic Coronary Risk Evaluation risk model. These participants were referred to their GP.
Conclusions
Self-reported home-assessed waist circumference could feasibly detect persons at high risk of hyperglycemia or cardiovascular disease. Continuation of the large-scale RCT is warranted to test the hypothesis that targeted population-based screening for type 2 diabetes leads to a significant reduction in cardiovascular morbidity and mortality.
Trial registration
ISRCTN75983009
doi:10.1186/1471-2458-12-671
PMCID: PMC3497580  PMID: 22900932
Early detection; Screening; Type 2 diabetes; Abdominal obesity; Waist circumference
20.  Clinical outcome of implant removal after fracture healing. Design of a prospective multicentre clinical cohort study 
Background
The clinical results of removal of metal implants after fracture healing are unknown and the question whether to remove or to leave them in is part of discussion worldwide. We present the design of a prospective clinical multicentre cohort study to determine the main indications for and expectations of implant removal, the influence on complaints, the incidence of surgery related complications and the socio-economic consequences of implant removal.
Methods/Design
In a prospective multicentre clinical cohort study at least 200 patients with a healed fracture after osteosynthesis with a metal implant are included for analyzing the outcome after removal. Six hospitals in the Netherlands are participating. Special questionnaires are designed. The follow up after surgery will be at least six months. The primary endpoint is the incidence of surgery related complications. Secondary endpoints are the influence of removal on preoperative symptoms and complaints and the socio-economic consequences.
Discussion
By performing this study we hope to find profound arguments to remove or not to remove metal implants after fracture healing that can help to develop clear guidelines for daily practice.
Trial registration
NTR1297, http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1297
doi:10.1186/1471-2474-13-147
PMCID: PMC3493388  PMID: 22894749
Implant removal; Metal implants; Fracture healing; Fracture surgery; Osteosynthesis; Complications; Complaints
21.  The relationship between walking speed and changes in cardiovascular risk factors during a 12-day walking tour to Santiago de Compostela: a cohort study 
BMJ Open  2012;2(3):e000875.
Objectives
Physical exercise has beneficial effects on cardiovascular risk factors. Knowledge about the effect of exercise intensity, specifically walking speed, on cardiovascular risk factors is limited. We report the relationship between walking speed and changes in cardiovascular risk factors in participants of a 12-day walking tour to Santiago de Compostela.
Design
Prospective cohort study.
Setting
Single-centre study with healthy middle-aged volunteers.
Participants
Healthy middle-aged men (n=15) and women (n=14). Subjects using lipid-lowering medication were excluded.
Intervention
Participants walked 281±10 km of the classical route to Santiago de Compostela in 12 days in 2009.
Primary and secondary outcome measures
Walking speed was recorded and blood pressure, weight, waist circumference, lipids and glucose were measured every other day. Changes in risk factors were compared between gender-pooled groups with faster and slower walking speed. Second, the relationship between walking speed and changes in risk factors was quantified using a linear mixed effects model.
Results
In the faster walking speed (4.6±0.2 km/h) group, high-density lipoprotein cholesterol (HDL-c) increased more than in the slower walking speed (4.1±0.2 km/h) group (difference in change between groups: 0.20; 95% CI −0.02 to 0.42 mmol/l), while low-density lipoprotein cholesterol (LDL-c) and total cholesterol decreased more in the slower walking speed group (differences in changes between groups: LDL-c: −0.50; 95% CI −0.88 to −0.12 mmol/l and total cholesterol: −0.75; 95% CI −1.19 to −0.31 mmol/l). A 1 km/h higher walking speed was related to an increase in HDL-c (0.24; 95% CI 0.12 to 0.30 mmol/l), LDL-c (0.18; 95% CI −0.16 to 0.42 mmol/l) and total cholesterol (0.36; 95% CI 0.12 to 0.60 mmol/l), adjusted for age, gender, smoking, body mass index and heart rate, during the whole walking tour.
Conclusions
Walking the same distance faster improves HDL-c more, while LDL-c and total cholesterol decrease more with lower walking speed independent of changes in body weight in healthy middle-aged subjects.
Article summary
Article focus
Physical exercise has beneficial effects on cardiovascular risk factors; however, the knowledge about the effect of exercise intensity, specifically walking speed, on cardiovascular risk factors is limited.
We report the relationship between walking speed and changes in cardiovascular risk factors in participants of a 12-day walking tour to Santiago de Compostela.
Key messages
In subjects walking a 12-day walking tour to Santiago de Compostela, with long daily stages:walking the same distance with higher walking speed was related to a higher increase in HDL-c, while walking with lower walking speed was related to larger decreases in LDL-c and total cholesterol, adjusted for age, gender, smoking, body mass index and heart rate.there was no relationship between walking speed and changes in weight, waist circumference, blood pressure, triglycerides or glucose.
Strengths and limitations of this study
All subjects walked the same overall distance, walking speed was measured and measurements of cardiovascular risk factors were conducted every other day.
This is a small study with 29 participants walking 281 km in 12 days. Whether the results of this study can be extrapolated to less exercise, and other types of exercise is not known.
doi:10.1136/bmjopen-2012-000875
PMCID: PMC3353125  PMID: 22581795
22.  Unrequested Findings on Cardiac Computed Tomography: Looking Beyond the Heart 
PLoS ONE  2012;7(4):e32184.
Objectives
To determine the prevalence of clinically relevant unrequested extra-cardiac imaging findings on cardiac Computed Tomography (CT) and explanatory factors thereof.
Methods
A systematic review of studies drawn from online electronic databases followed by meta-analysis with meta-regression was performed. The prevalence of clinically relevant unrequested findings and potentially explanatory variables were extracted (proportion of smokers, mean age of patients, use of full FOV, proportion of men, years since publication).
Results
Nineteen radiological studies comprising 12922 patients met the inclusion criteria. The pooled prevalence of clinically relevant unrequested findings was 13% (95% confidence interval 9–18, range: 3–39%). The large differences in prevalence observed were not explained by the predefined (potentially explanatory) variables.
Conclusions
Clinically relevant extra-cardiac findings are common in patients undergoing routine cardiac CT, and their prevalence differs substantially between studies. These differences may be due to unreported factors such as different definitions of clinical relevance and differences between populations. We present suggestions for basic reporting which may improve the interpretability and comparability of future research.
doi:10.1371/journal.pone.0032184
PMCID: PMC3334960  PMID: 22536315
23.  Direct short-term effects of EBP teaching: change in knowledge, not in attitude; a cross-cultural comparison among students from European and Asian medical schools 
Medical Education Online  2012;17:10.3402/meo.v17i0.19623.
Introduction
We report about the direct short-term effects of a Clinical Epidemiology and Evidence-based Medicine (CE-EBM) module on the knowledge, attitude, and behavior of students in the University Medical Center Utrecht (UMCU), Universitas Indonesia (UI), and University of Malaya (UM).
Methods
We used an adapted version of a 26-item validated questionnaire, including four subscales: knowledge, attitude, behavior, and future use of evidence-based practice (EBP). The four components were compared among the students in the three medical schools before the module using one-way ANOVA. At the end of the module, we measured only knowledge and attitudes. We computed Cronbach's α to assess the reliability of the responses in our population. To assess the change in knowledge and attitudes, we used the paired t-test in the comparison of scores before and after the module.
Results
In total, 526 students (224 UI, 202 UM, and 100 UMCU) completed the questionnaires. In the three medical schools, Cronbach's α for the pre-module total score and the four subscale scores always exceeded 0.62. UMCU students achieved the highest pre-module scores in all subscales compared to UI and UM with the comparison of average (SD) score as the following: knowledge 5.04 (0.4) vs. 4.73 (0.69) and 4.24 (0.74), p<0.001; attitude 4.52 (0.64) vs. 3.85 (0.68) and 3.55 (0.63), p<0.001; behavior 2.62 (0.55) vs. 2.35 (0.71) and 2.39 (0.92), p=0.016; and future use of EBP 4.32 (0.59) vs. 4.08 (0.62) and 3.7 (0.71), p<0.01. The CE-EBM module increased the knowledge of the UMCU (from average 5.04±0.4 to 5.35±0.51; p<0.001) and UM students (from average 4.24±0.74 to 4.53±0.72; p<0.001) but not UI. The post-module scores for attitude did not change in the three medical schools.
Conclusion
EBP teaching had direct short-term effects on knowledge, not on attitude. Differences in pre-module scores are most likely related to differences in the system and infrastructure of both medical schools and their curriculum.
doi:10.3402/meo.v17i0.19623
PMCID: PMC3487025  PMID: 23121993
Evidence Based Medicine; knowledge; attitude; behavior; medical students
24.  Insulin resistance increases the occurrence of new cardiovascular events in patients with manifest arterial disease without known diabetes. The SMART study 
Background
Insulin resistance is accompanied by a cluster of metabolic changes, often referred to as metabolic syndrome. Metabolic syndrome is associated with an increased cardiovascular risk in patients with manifest arterial disease. We investigated whether insulin resistance is associated with an increased risk for cardiovascular events in patients with manifest arterial disease without known diabetes and whether this can be explained by the components of the metabolic syndrome or by inflammation.
Methods
Prospective cohort study in 2611 patients with manifest arterial disease without known diabetes. Homeostasis model of insulin resistance (HOMA-IR) was used to quantify insulin resistance. The relation of HOMA-IR with cardiovascular events (vascular death, myocardial infarction or stroke) and all cause mortality was assessed with Cox regression analysis. In additional models adjustments were performed for the single components constituting the metabolic syndrome and for inflammation.
Results
HOMA-IR increases with the number of metabolic syndrome components (mean HOMA-IR ± SD in groups with 0, 1, 2, 3, 4 and 5 metabolic syndrome components: 1.4 ± 0.7; 1.8 ± 1.2; 2.4 ± 1.5; 3.1 ± 1.8; 4.0 ± 2.6; and 5.6 ± 3.6 respectively). High HOMA-IR was independently associated with an increased risk of cardiovascular events (tertile 2 vs. 1 HR 1.92; 95%CI 1.20-3.08) (tertile 3 vs.1 HR 1.78; 95%CI 1.10-2.89) and with all cause mortality (tertile 2 vs. 1 HR 1.80; 95%CI 1.04-3.10) (tertile 3 vs.1 HR 1.56; 95%CI 0.88-2.75). These relations were not influenced by the individual components of metabolic syndrome or by inflammation.
Conclusions
In patients with manifest arterial disease without known diabetes, insulin resistance increases with the number of metabolic syndrome components, and elevated insulin resistance increases the risk of new cardiovascular events.
doi:10.1186/1475-2840-10-100
PMCID: PMC3268731  PMID: 22098712
Insulin resistance; Manifest arterial disease; Metabolic syndrome
25.  Progression of White Matter Lesion Volume and Health-Related Quality of Life in Patients with Symptomatic Atherosclerotic Disease: The SMART-MR Study 
Journal of Aging Research  2011;2011:280630.
Objectives. Mechanisms influencing the course of physical and mental functioning after an atherosclerotic event are unclear. We examined effects of white matter lesion (WML) activity on changes in functioning in patients with symptomatic atherosclerotic disease. Methods. In 486 patients (58 ± 9 years) of the Second Manifestations of ARTerial disease-Magnetic Resonance (SMART-MR) study, volumetric WML measurements on 1.5T MRI were performed at baseline and 3.9 ± 0.4 years followup. Functioning was assessed with the modified Short-Form 12 (SF-12) questionnaire. Associations of WML progression with changes in functioning were adjusted for age, sex, and vascular risk factors. Results. Physical functioning (baseline: 44, 10th–90th percentile 29–55) improved, whereas mental functioning (baseline: 51, 10th–90th percentile 32–60) declined during followup. WML progression (highest quartile versus rest) contributed to a stronger decline in mental functioning (B = −1.76, 95% CI −3.11 to −0.42), but did not influence changes in physical functioning. Conclusions. Progression of WML volume contributes to a decline in mental functioning in patients with symptomatic atherosclerotic disease.
doi:10.4061/2011/280630
PMCID: PMC3195506  PMID: 22013526

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