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OBJECTIVE:--To investigate the association between serum uric acid level and risk of type 2 diabetes. RESEARCH DESIGN AND METHODS--The population for analysis consisted of 4,536 subjects free from diabetes at baseline. During a mean of 10.1 years of follow-up, 462 subjects developed diabetes. RESULTS:--The age- and sex-adjusted hazard ratios (HRs) (95% CIs) for diabetes were 1.30 (0.96-1.76) for the second, 1.63 (1.21-2.19) for the third, and 2.83 (2.13-3.76) for the fourth quartile of serum uric acid, in comparison with the first quartile. After adjustment for BMI, waist circumference, systolic and diastolic blood pressure, and HDL cholesterol, the HRs decreased to 1.08 (0.78-1.49), 1.12 (0.81-1.53), and 1.68 (1.22-2.30), respectively. CONCLUSIONS:--The results of this population-based study suggest that serum uric acid is a strong and independent risk factor for diabetes.

Clinical decision-making often relies on a subject's absolute risk of a disease event of interest. However, in a frail population, competing risk events may preclude the occurrence of the event of interest. We review competing-risk regression models with a view toward predictive modeling. We show how measures of prognostic performance (such as calibration and discrimination) can be adapted to the competing-risks setting. An example of coronary heart disease (CHD) prediction in women aged 55–90 years in the Rotterdam study is used to illustrate the proposed methods, and to compare the Fine and Gray regression model to 2 alternative approaches: (1) a standard Cox survival model, which ignores the competing risk of non-CHD death, and (2) a cause-specific hazards model, which combines proportional hazards models for the event of interest and the competing event. The Fine and Gray model and the cause-specific hazards model perform similarly. However, the standard Cox model substantially overestimates 10-year risk of CHD; it classifies 18% of the individuals as high risk (>20%), compared with only 8% according to the Fine and Gray model. We conclude that competing risks have to be considered explicitly in frail populations such as the elderly.

The prevalence of cardiovascular diseases is rising. Therefore, adequate risk prediction and identification of its determinants is increasingly important. The Rotterdam Study is a prospective population-based cohort study ongoing since 1990 in the city of Rotterdam, The Netherlands. One of the main targets of the Rotterdam Study is to identify the determinants and prognosis of cardiovascular diseases. Case finding in epidemiological studies is strongly depending on various sources of followup and clear outcome definitions. The sources used for collection of data in the Rotterdam Study are diverse and the definitions of outcomes in the Rotterdam Study have changed due to the introduction of novel diagnostics and therapeutic interventions. This article gives the methods for data collection and the up-to-date definitions of the cardiac outcomes based on international guidelines, including the recently adopted cardiovascular disease mortality definitions. In all, detailed description of cardiac outcome definitions enhances the possibility to make comparisons with other studies in the field of cardiovascular research and may increase the strength of collaborations.

There are inconsistent findings on the role of hyperuricemia as an independent risk factor for chronic kidney disease (CKD). Hypertension has been implicated as a factor influencing the association between serum uric acid and CKD. In this population-based study we investigated the association between serum uric acid and decline in renal function and tested whether hypertension moderates this association. We included 2601 subjects aged 55 years and over from the Rotterdam Study. Serum uric acid and estimated glomerular filtration rate (eGFR) were assessed at baseline. After average 6.5 years of follow-up, second eGFR was assessed. CKD was defined as eGFR<60 ml/min/1.73 m(2). All associations were corrected for socio-demographic and cardiovascular factors. Each unit (mg/dL) increase in serum uric acid was associated with 0.19 ml/min per 1.73 m(2) faster annual decline in eGFR. While the association between serum uric acid and incidence of CKD was not significant in our study population (Hazard Ratio: 1.12, 95% confidence interval [CI]: 0.98-1.28), incorporating our results in a meta-analysis with eleven published studies revealed a significant association (Relative Risk: 1.18, 95%CI: 1.15-1.22). In the stratified analyses, we observed that the associations of serum uric acid with eGFR decline and incident CKD were stronger in hypertensive subjects (P for interaction = 0.046 and 0.024, respectively). Our findings suggest that hyperuricemia is independently associated with a decline in renal function. Stronger association in hypertensive individuals may indicate that hypertension mediates the association between serum uric acid and CKD.

Several studies have associated physical activity with the risk of dementia, but mostly did so during short follow-up. It remains unclear whether physical activity also affects dementia during longer follow-up. We examined the association between physical activity and risk of dementia during a follow-up period up to 14 years. From 1997 to 1999, physical activity was assessed using a validated questionnaire in 4,406 elderly persons (age range 61–97) from the prospective, population-based Rotterdam Study. Follow-up for dementia was complete until January 1, 2011. We used Cox proportional hazards models to assess the association between physical activity and incident dementia. Next, we stratified follow-up time using a cut-off of 4 years. We separately investigated dementia due to Alzheimer disease. During 38,631 person-years, 583 participants developed dementia. When adjusting for age and sex, we found a borderline significant association between higher physical activity and lower risk of dementia (HR 0.95; 95 % CI 0.87–1.04). This association was confined to follow-up up to 4 years (HR 0.82; 95 % CI 0.71–0.95), and not to follow-up of at least 4 years (HR 1.04; 95 % CI 0.93–1.16). Additional adjustments only slightly attenuated the associations. A similar pattern was present for Alzheimer disease. We found a higher level of physical activity to be associated with a lower risk of dementia. This association was confined to follow-up for up to 4 years and not to longer follow-up, suggesting either a role for reverse causality or only a short term effect of late-life physical activity in an elderly population.

Individuals with type 2 diabetes have increased fracture risk despite higher bone mineral density (BMD). Our aim was to examine the influence of glucose control on skeletal complications. Data of 4,135 participants of the Rotterdam Study, a prospective population-based cohort, were available (mean follow-up 12.2 years). At baseline, 420 participants with type 2 diabetes were classified by glucose control (according to HbA1c calculated from fructosamine), resulting in three comparison groups: adequately controlled diabetes (ACD; n = 203; HbA1c <7.5%), inadequately controlled diabetes (ICD; n = 217; HbA1c ≥ 7.5%), and no diabetes (n = 3,715). Models adjusted for sex, age, height, and weight (and femoral neck BMD) were used to test for differences in bone parameters and fracture risk (hazard ratio [HR] [95% CI]). The ICD group had 1.1-5.6% higher BMD, 4.6-5.6% thicker cortices, and -1.2 to -1.8% narrower femoral necks than ACD and ND, respectively. Participants with ICD had 47-62% higher fracture risk than individuals without diabetes (HR 1.47 [1.12-1.92]) and ACD (1.62 [1.09-2.40]), whereas those with ACD had a risk similar to those without diabetes (0.91 [0.67-1.23]). Poor glycemic control in type 2 diabetes is associated with fracture risk, high BMD, and thicker femoral cortices in narrower bones. We postulate that fragility in apparently \"strong\" bones in ICD can result from microcrack accumulation and/or cortical porosity, reflecting impaired bone repair.

The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in The Netherlands. The study targets cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, oncological, and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. The findings of the Rotterdam Study have been presented in over a 1,000 research articles and reports (see www. erasmus-epidemiology. nl/rotterdamstudy).This article gives the rationale of the study and its design. It also presents a summary of the major findings and an update of the objectives and methods.

Genetic Variation, C-Reactive Protein Levels, and Incidence of Diabetes Abbas Dehghan 1 , Isabella Kardys 1 , Moniek P.M. de Maat 2 , Andre G. Uitterlinden 1 3 , Eric J.G. Sijbrands 3 , Aart H. Bootsma 3 , Theo Stijnen 1 , Albert Hofman 1 , Miranda T. Schram 1 4 and Jacqueline C.M. Witteman 1 1 Department of Epidemiology and Biostatistics, Erasmus Medical Center, Rotterdam, the Netherlands 2 Department of Hematology, Erasmus Medical Center, Rotterdam, the Netherlands 3 Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands 4 Department of Gerontology, Leiden University Medical Center, Leiden, the Netherlands Address correspondence and reprint requests to J.C.M. Witteman, PhD, Department of Epidemiology and Biostatistics, Erasmus Medical Center, Rotterdam, P.O. Box 2040, 3000 CA Netherlands. E-mail: j.witteman{at}erasmusmc.nl Abstract C-reactive protein (CRP) has been shown to be associated with type 2 diabetes, but whether CRP has a causal role is not yet clear. We examined the association in the Rotterdam Study, a population-based prospective cohort study. The association of baseline serum CRP and incident diabetes during follow-up was investigated, and a meta-analysis was conducted on the BMI-adjusted relation of CRP and diabetes. Furthermore, the association of CRP haplotypes with serum CRP and risk of diabetes was assessed. The age- and sex-adjusted hazard ratio for diabetes was 1.41 (95% CI 1.29–1.54) per 1 SD increase in natural logarithm of CRP, and it was 1.88, 2.16, and 2.83 for the second, third, and fourth quartiles of CRP, respectively, compared with the first quartile. The risk estimates attenuated but remained statistically significant after additional adjustment for obesity indexes, which agreed with the results of the meta-analysis. The most common genetic haplotype was associated with a significantly lower CRP level compared with the three other haplotypes. The risk of diabetes was significantly higher in the haplotype with the highest serum CRP level compared with the most common haplotype (OR 1.45, 95% CI 1.08–1.96). These findings support the hypothesis that serum CRP enhances the development of diabetes. CRP, C-reactive protein MONICA, Monitoring of Trends and Determinants in Cardiovascular Diseases Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted December 12, 2006. Received July 5, 2006. DIABETES

Objective To evaluate differences in first manifestations of cardiovascular disease between men and women in a competing risks framework.Design Prospective population based cohort study.Setting People living in the community in Rotterdam, the Netherlands.Participants 8419 participants (60.9% women) aged ≥55 and free from cardiovascular disease at baseline.Main outcome measures First diagnosis of coronary heart disease (myocardial infarction, revascularisation, and coronary death), cerebrovascular disease (stroke, transient ischaemic attack, and carotid revascularisation), heart failure, or other cardiovascular death; or death from non-cardiovascular causes. Data were used to calculate lifetime risks of cardiovascular disease and its first incident manifestations adjusted for competing non-cardiovascular death.Results During follow-up of up to 20.1 years, 2888 participants developed cardiovascular disease (826 coronary heart disease, 1198 cerebrovascular disease, 762 heart failure, and 102 other cardiovascular death). At age 55, overall lifetime risks of cardiovascular disease were 67.1% (95% confidence interval 64.7% to 69.5%) for men and 66.4% (64.2% to 68.7%) for women. Lifetime risks of first incident manifestations of cardiovascular disease in men were 27.2% (24.1% to 30.3%) for coronary heart disease, 22.8% (20.4% to 25.1%) for cerebrovascular disease, 14.9% (13.3% to 16.6%) for heart failure, and 2.3% (1.6% to 2.9%) for other deaths from cardiovascular disease. For women the figures were 16.9% (13.5% to 20.4%), 29.8% (27.7% to 31.9%), 17.5% (15.9% to 19.2%), and 2.1% (1.6% to 2.7%), respectively. Differences in the number of events that developed over the lifespan in women compared with men (per 1000) were −7 for any cardiovascular disease, −102 for coronary heart disease, 70 for cerebrovascular disease, 26 for heart failure, and −1 for other cardiovascular death; all outcomes manifested at a higher age in women. Patterns were similar when analyses were restricted to hard atherosclerotic cardiovascular disease outcomes, but absolute risk differences between men and women were attenuated for both coronary heart disease and stroke.Conclusions At age 55, though men and women have similar lifetime risks of cardiovascular disease, there are considerable differences in the first manifestation. Men are more likely to develop coronary heart disease as a first event, while women are more likely to have cerebrovascular disease or heart failure as their first event, although these manifestations appear most often at older ages.

Background Dietary electrolytes influence blood pressure, but their effect on clinical outcomes remains to be established. We examined sodium and potassium intake in relation to cardiovascular disease (CVD) and mortality in an unselected older population. Methods A case–cohort analysis was performed in the Rotterdam Study among subjects aged 55 years and over, who were followed for 5 years. Baseline urinary samples were analyzed for sodium and potassium in 795 subjects who died, 206 with an incident myocardial infarction and 181 subjects with an incident stroke, and in 1,448 randomly selected subjects. For potassium, dietary data were additionally obtained by food-frequency questionnaire for 78% of the cohort. Results There was no consistent association of urinary sodium, potassium, or sodium/potassium ratio with CVD and all-cause mortality over the range of intakes observed in this population. Dietary potassium estimated by food frequency questionnaire, however, was associated with a lower risk of all-cause mortality in subjects initially free of CVD and hypertension (RR = 0.71 per standard deviation increase; 95% confidence interval: 0.51–1.00). We observed a significant positive association between urinary sodium/potassium ratio and all-cause mortality, but only in overweight subjects who were initially free of CVD and hypertension (RR = 1.19 (1.02–1.39) per unit). Conclusion The effect of sodium and potassium intake on CVD morbidity and mortality in Western societies remains to be established.