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Aim To examine possible sex differences in the excess risk of myocardial infarction (MI) consequent to a range of conventional risk factors in a large-scale international cohort of patients with diabetes, and to quantify these potential differences both on the relative and absolute scales. Materials and methods Eleven thousand and sixty-five participants (42% women) with type 2 diabetes in the ADVANCE trial and its post-trial follow-up study, ADVANCE-ON, were included. Cox regression models were used to estimate hazard ratios (HRs) for associations between risk factors and MI (fatal and non-fatal) by sex, and the women-to-men ratio of HRs (RHR). Results Over a median of 9.6 years of follow-up, 719 patients experienced MI. Smoking status, smoking intensity, higher systolic blood pressure (SBP), HbA1c, total and LDL cholesterol, duration of diabetes, triglycerides, body mass index (BMI) and lower HDL cholesterol were associated with an increased risk of MI in both sexes. Furthermore, some variables were associated with a greater relative risk of MI in women than men: RHRs were 1.75 (95% CI: 1.05-2.91) for current smoking, 1.53 (1.00-2.32) for former smoking, 1.18 (1.02-1.37) for SBP, and 1.13 (95% CI, 1.003-1.26) for duration of diabetes. Although incidence rates of MI were higher in men (9.3 per 1000 person-years) compared with women (5.8 per 1000 person-years), rate differences associated with risk factors were greater in women than men, except for HDL cholesterol and BMI. Conclusions In patients with type 2 diabetes, smoking, higher SBP and longer duration of diabetes had a greater relative and absolute effect in women than men, highlighting the importance of routine sex-specific approaches and early interventions in women with diabetes.

Aims: The association between diabetes and cognitive decline (CD) and dementia has been well-documented. This study estimated the associations between risk factors and CD/dementia, and the sex differences in these risk factors in individuals with type 2 diabetes, while accounting for the competing risk of death.\ud \ud Materials and methods: The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial of 11,140 individuals with type 2 diabetes was used to estimate the odds of CD/dementia using multinomial logistic regression.\ud \ud Results: During a median five-year follow-up, 1,827 participants (43.2% women) had CD/dementia (1,718 with CD only; 21 with dementia only; 88 with CD and dementia), and 929 (31.0% women) died without CD/dementia. Women had a lower odds of CD/dementia than men (Odds Ratio (OR) (95% confidence interval), 0.88 (0.77, 1.00)); older age, higher total cholesterol, HbA1c , waist circumference, waist-to-height ratio, moderately increased ACR (Albumin-Creatinine Ratio), stroke/transient ischemic attack and retinal disease were each associated with greater odds of CD/dementia; higher years at education completion, baseline cognitive function, taller stature and current alcohol use were inversely associated. Higher waist circumference (women-to-men Ratio of Odds Ratios (ROR), 1.05 (1.00, 1.10) per 5 cm) and presence of anxiety/depression (ROR, 1.28 (1.01, 1.63)) were associated with greater OR for CD/dementia in women than men.\ud \ud Conclusions: Several risk factors were associated with CD/dementia. Higher waist circumference and mental health symptoms were more strongly associated with CD/dementia in women than men. Further studies should examine the mechanisms which underlie these sex differences. This article is protected by copyright. All rights reserved.

A variable is 'systematically missing' if it is missing for all individuals within particular studies in an individual participant data meta-analysis. When a systematically missing variable is a potential confounder in observational epidemiology, standard methods either fail to adjust the exposure-disease association for the potential confounder or exclude studies where it is missing. We propose a new approach to adjust for systematically missing confounders based on multiple imputation by chained equations. Systematically missing data are imputed via multilevel regression models that allow for heterogeneity between studies. A simulation study compares various choices of imputation model. An illustration is given using data from eight studies estimating the association between carotid intima media thickness and subsequent risk of cardiovascular events. Results are compared with standard methods and also with an extension of a published method that exploits the relationship between fully adjusted and partially adjusted estimated effects through a multivariate random effects meta-analysis model. We conclude that multiple imputation provides a practicable approach that can handle arbitrary patterns of systematic missingness. Bias is reduced by including sufficient between-study random effects in the imputation model.

Objective To assess fetal growth profiles in an unselected group of pregnant women with either Type-1 diabetes (DM1), Type-2 diabetes (DM2) or gestational diabetes (GDM), with emphasis on intergroup differences and development of disproportionate fetal growth and macrosomia. Methods Second- and third-trimester longitudinal ultrasound measurements of fetal growth were made in 77 women with DM1, 68 women with DM2 and in 99 women with GDM. Altogether 897 ultrasound examinations were performed and 145 uncomplicated pregnancies with 843 ultrasound examinations were included as controls. Ultrasound data included head circumference (HC), abdominal circumference (AC), femur length (FL) and HC/AC ratio. Results The AC, but not HC and FL, evolved differently in diabetic pregnancies, with a smaller AC in early pregnancy and larger AC at term (significant for DM1 and DM2). The most striking differences were found for the HC/AC ratio, especially in DM1 pregnancies. HC/AC growth trajectories of both macrosomic and non-macrosomic fetuses differed from that of the controls, and the HC/AC ratio at term was lower in all diabetic subgroups except in non-macrosomic DM2 cases. Conclusion We found altered (disproportionate) fetal growth in macrosomic and non-macrosomic fetuses of women with DM1, DM2 and GDM. This indicates that the abnormal intrauterine environment affects the majority of these infants. Growth profiles differed among these groups, the most prominent growth deviations being found in the fetuses of women with DM1. The latter was most probably caused by poor glucose control. In monitoring fetal growth in diabetic pregnancies the HC/AC ratio should be used to assess altered fetal growth. Copyright © 2012 ISUOG. Published by John Wiley & Sons, Ltd.

Peters SAE, Lind L, Palmer MK, Grobbee DE,Crouse JR III, O’Leary DH, Evans GW, Raichlen J,Bots ML, den Ruijter HM, on behalf of the METEORstudygroup(UniversityMedicalCenterUtrecht,Utr-echt, The Netherlands; Uppsala University Hospital,Uppsala, Sweden;KeeleUniversity,Keele, UK; WakeForest University School of Medicine, Winston-Salem, NC, USA; Caritas Carney Hospital, Boston,MA, USA; and AstraZeneca, Wilmington, DE, USA).Increasedage,highbodymassindexandlowHDL-Clevels are related to an echolucent carotid intima–media: the METEOR study. J Intern Med 2012;272:257–266.Introduction. Echolucentplaquesarerelatedtoahighercardiovascular risk. Studies to investigate the rela-tionship between echolucency and cardiovascularriskintheearlystages ofatherosclerosisare limited.We studied the relationship between cardiovascularrisk factors and echolucency of the carotid intima–mediainlow-riskindividuals.Methods. Data were analysed from the Measuring Ef-fects on Intima-Media Thickness: an Evaluation ofRosuvastatin (METEOR) study, a randomized pla-cebo-controlledtrialincluding984individualswhichshowed that rosuvastatin attenuated the rate ofchange of carotid intima–media thickness (CIMT). Inthisposthocanalysis,duplicatebaselineultrasoundimagesfromthefarwalloftheleftandrightcommoncarotid arteries were used for the evaluation of theecholucency of the carotid intima–media, measuredbygrey-scalemedian(GSM)onascaleof0–256.LowGSM values reflect echolucent, whereas high valuesreflect echogenic structures. The relationship be-tween baseline GSM and cardiovascular risk factorswasevaluatedusinglinearregressionmodels.Results. MeanbaselineGSM(± SD)was84 ± 29.LowerGSMofthecarotidintima–mediawasassociatedwitholder age, highbodymass index (BMI) andlow levelsof high-density lipoprotein cholesterol (HDL-C) [beta)4.49, 95% confidence interval (CI) )6.50 to )2.49;beta)4.51,95%CI)6.43to)2.60;beta2.45,95%CI0.47to4.42,respectively].CommonCIMTwasinver-selyrelatedtoGSMofthecarotidintima–media(beta)3.94,95%CI)1.98to)5.89).Conclusion. Olderage,highBMIandlowlevelsofHDL-Carerelatedtoecholucencyofthecarotidintima–med-ia. Hence, echolucency of the carotid intima–mediamaybeusedasamarkerofcardiovascularriskprofiletoprovidemoreinformationthanthicknessalone.Keywords: atherosclerosis, carotid intima–mediathickness, carotid ultrasound, echolucency, riskfactors.IntroductionAtherosclerosis is a chronic and progressive diseaseofthe arterial wallandis theunderlyingcause ofthemajority of cardiovascular events worldwide [1, 2].B-modeultrasoundmeasurements of thecarotidar-teryhavecommonlybeenusedtoassessthepresenceand severity of atherosclerotic disease in a safe, reli-able and reproducible way [3]. Histological studieshave shown that plaques that appear echolucent onB-mode ultrasound are rich in lipids, whereas echo-genic plaqueshavea higher contentoffibrous tissue*

Peters SAE, den Ruijter HM, Palmer MK, Grobbee DE, Crouse JR, O’Leary DH, Evans GW, Raichlen JS, Lind L, Bots ML, on behalf of the METEOR Study Group (University Medical Center Utrecht, Utrecht, The Netherlands; Keele University, Keele, UK; Wake Forest University School of Medicine, Winston-Salem, NC, USA; Caritas Carney Hospital, Boston, MA, USA; Wake Forest University School of Medicine, Winston-Salem, NC, USA; AstraZeneca, Wilmington, DE, USA; and Uppsala University Hospital, Uppsala, Sweden). Manual or semi-automated edge detection of the maximal far wall common carotid intima–media thickness: a direct comparison. J Intern Med 2012; 271: 247–256. Background. Automated edge detection is thought to be superior to manual edge detection in quantification of the far wall common carotid intima–media thickness (CIMT), yet published evidence making a direct comparison is not available. Methods. Data were used from the METEOR study, a randomized placebo-controlled trial among 984 individuals showing that rosuvastatin attenuated the rate of change of 2 year change in CIMT among low-risk individuals with subclinical atherosclerosis. For this post hoc analysis, CIMT images of the far wall of the common carotid artery were evaluated using manual and semi-automated edge detection and reproducibility, relation to cardiovascular risk factors, rates of change over time and effects of lipid-lowering therapy were assessed. Results. Reproducibility was high for both reading methods. Direction, magnitude and statistical significance of risk factor relations were similar across methods. Rate of change in CIMT in participants assigned to placebo was 0.0066 mm per year (SE: 0.0027) for manually and 0.0072 mm per year (SE: 0.0029) for semi-automatically read images. The effect of lipid-lowering therapy on CIMT changes was −0.0103 mm per year (SE: 0.0032) for manual reading and −0.0111 mm per year (SE: 0.0034) for semi-automated reading. Conclusion. Manual and semi-automated readings of the maximal far wall of the common CIMT images both result in high reproducibility, show similar risk factor relations, rates of change and treatment effects. Hence, choices between semi-automated and manual reading software for CIMT studies likely should be based on logistical and cost considerations rather than differences in expected data quality when the choice is made to use far wall common CIMT measurements.

Eur J Clin Invest 2012; 42 (1): 110–116 Abstract Background Identification of individuals at high risk for cardiovascular disease (CVD) is important to initiate adequate treatment and to prevent future events. Moreover, identification of low-risk individuals is important to refrain from unneeded therapy. Current risk prediction models do not accurately predict the risk of CVD in individuals, and new markers have been sought to improve the risk assessment in individuals. Coronary artery calcification (CAC) is a marker of atherosclerosis that might improve current risk assessment when added to traditional risk factors. Materials and methods We performed a systematic review on PubMed search (1 February 2011) on studies reporting on the added value of CAC in risk prediction in asymptomatic individuals. Results Of 39 publications on CAC and CVD, nine studies were carried out in asymptomatic individuals. All studies showed an increase in area under the curve ranging from 0·05 to 0·20 when CAC was added to the risk model. Four studies reported on improvements of individuals in low-, intermediate-, and high-risk categories. Addition of CAC to the risk model resulted in a net reclassification improvement ranging from 14% to 30%, meaning that CAC measurement reclassified a substantial proportion of individuals into correct risk categories. This improvement was most pronounced in those at intermediate Framingham risk. Conclusions The available studies consistently showed that CAC scoring improves risk stratification in CVD risk categories when added to traditional risk factors only, especially among individuals at intermediate risk for CVD. Cost-effectiveness analyses together with a randomized controlled trial are needed before widespread introduction of CAC in clinical care.