Birth weight and cardiac function assessed by echocardiography in adolescence: Avon Longitudinal Study of Parents and Children.

OBJECTIVE: Maternal hemodynamics in pregnancy is associated with fetal growth and birth weight, which in turn are associated with offspring cardiovascular disease later in life. The aim of this study was to quantify the extent to which birth weight is associated with cardiac structure and function in adolescence. METHODS: A subset of offspring (n = 1964; 55% female) of the Avon Longitudinal Study of Parents and Children were examined with echocardiography at a mean age of 17.7 (SD, 0.3) years. The associations of birth-weight Z-score for sex and gestational age with cardiac structure (assessed by relative wall thickness, left ventricular mass index (LVMI) and left atrial diameter index), systolic function (assessed by ejection fraction and left ventricular wall velocity) and diastolic function (assessed by early/late mitral inflow velocity (E/A) and early mitral inflow velocity/mitral annular early diastolic velocity (E/e')) were evaluated. Linear regression models were adjusted for several potential confounders, including maternal prepregnancy body mass index, age, level of education and smoking during pregnancy. RESULTS: Higher birth-weight Z-score was associated with lower E/A (mean difference, -0.024; 95% CI, -0.043 to -0.005) and E/e' (mean difference, -0.05; 95% CI, -0.10 to -0.001) and higher LVMI (mean difference, 0.38 g/m2.7 ; 95% CI, 0.09 to 0.67). There was no or inconsistent evidence of associations of birth-weight Z-score with relative wall thickness, left atrial diameter and measurements of systolic function. Further analyses suggested that the association between birth-weight Z-score and LVMI was driven mainly by an association observed in participants born small-for-gestational age and it did not persist when risk factors in adolescence were accounted for. CONCLUSIONS: Higher birth weight adjusted for sex and gestational age was associated with differences in measures of diastolic function in adolescence, but the observed associations were small. It remains to be determined the extent to which these associations translate into increased susceptibility to cardiovascular disease later in life. © 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Performance Analysis of GaN Capping Layer Thickness on GaN/AlGaN/GaN High Electron Mobility Transistors.

In this paper, we present an investigation of the impact of GaN capping layer and AlGaN layer thickness on the two-dimensional (2D)-electron mobility and the carrier concentration which was formed close to the AlGaN/GaN buffer layer for Al0.25Ga0.75N/GaN and GaN/Al0.25Ga0.75N/GaN heterostructures deposited on sapphire substrates. The results of our analysis clearly indicate that expanding the GaN capping layer thickness from 1 nm to 100 nm prompts an increment in the electron concentration at hetero interface. As consequence of which drain current was additionally increments with GaN cap layer thicknesses, and eventually saturates at approximately 1.85 A/mm for capping layer thickness greater than 40 nm. Interestingly, for the same structure, the 2D-electron mobility, decrease monotonically with GaN capping layer thickness, and saturate at approximately 830 cm2/Vs for capping layer thickness greater than 50 nm. A device with a GaN cap layer didn't exhibit gate leakage current. Furthermore, it was observed that the carrier concentration was first decrease 1.03 × 1019/cm3 to 6.65 × 1018/cm3 with AlGaN Layer thickness from 5 to 10 nm and after that it increases with the AlGaN layer thickness from 10 to 30 nm. The same trend was followed for electric field distributions. Electron mobility decreases monotonically with AlGaN layer thickness. Highest electron mobility 1354 cm2/Vs were recorded for the AlGaN layer thickness of 5 nm. Results obtained are in good agreement with published experimental data.

Bullseye's representation of cerebral white matter hyperintensities.

BACKGROUND AND PURPOSE: Visual rating scales have limited capacities to depict the regional distribution of cerebral white matter hyperintensities (WMH). We present a regional-zonal volumetric analysis alongside a visualization tool to compare and deconstruct visual rating scales. MATERIALS AND METHODS: 3D T1-weighted, T2-weighted spin-echo and FLAIR images were acquired on a 3T system, from 82 elderly participants in a population-based study. Images were automatically segmented for WMH. Lobar boundaries and distance to ventricular surface were used to define white matter regions. Regional-zonal WMH loads were displayed using bullseye plots. Four raters assessed all images applying three scales. Correlations between visual scales and regional WMH as well as inter and intra-rater variability were assessed. A multinomial ordinal regression model was used to predict scores based on regional volumes and global WMH burdens. RESULTS: On average, the bullseye plot depicted a right-left symmetry in the distribution and concentration of damage in the periventricular zone, especially in frontal regions. WMH loads correlated well with the average visual rating scores (e.g. Kendall's tau [Volume, Scheltens]=0.59 CI=[0.53 0.62]). Local correlations allowed comparison of loading patterns between scales and between raters. Regional measurements had more predictive power than global WMH burden (e.g. frontal caps prediction with local features: ICC=0.67 CI=[0.53 0.77], global volume=0.50 CI=[0.32 0.65], intra-rater=0.44 CI=[0.23 0.60]). CONCLUSION: Regional-zonal representation of WMH burden highlights similarities and differences between visual rating scales and raters. The bullseye infographic tool provides a simple visual representation of regional lesion load that can be used for rater calibration and training.

Ethnic differences in cross-sectional associations between impaired glucose regulation, identified by oral glucose tolerance test or HbA1c values, and cardiovascular disease in a cohort of European and South Asian origin.

AIMS: We contrasted impaired glucose regulation (prediabetes) prevalence, defined according to oral glucose tolerance test or HbA1c values, and studied cross-sectional associations between prediabetes and subclinical/clinical cardiovascular disease (CVD) in a cohort of European and South Asian origin. METHODS: For 682 European and 520 South Asian men and women, aged 58-85 years, glycaemic status was determined by oral glucose tolerance test or HbA1c thresholds. Questionnaires, record review, coronary artery calcification scores and cerebral magnetic resonance imaging established clinical plus subclinical coronary heart and cerebrovascular disease. RESULTS: Prediabetes was more prevalent in South Asian participants when defined by HbA1c rather than by oral glucose tolerance test criteria. Accounting for age, sex, smoking, systolic blood pressure, triglycerides and waist-hip ratio, prediabetes was associated with coronary heart disease and cerebrovascular disease in European participants, most obviously when defined by HbA1c rather than by oral glucose tolerance test [odds ratios for HbA1c -defined prediabetes 1.60 (95% CI 1.07, 2.39) for coronary heart disease and 1.57 (95% CI 1.00, 2.51) for cerebrovascular disease]. By contrast, non-significant associations were present between oral glucose tolerance test-defined prediabetes only and coronary heart disease [odds ratio 1.41 (95% CI 0.84, 2.36)] and HbA1c -defined prediabetes only and cerebrovascular disease [odds ratio 1.39 (95% CI 0.69, 2.78)] in South Asian participants. Prediabetes defined by HbA1c or oral glucose tolerance test criteria was associated with cardiovascular disease (defined as coronary heart and/or cerebrovascular disease) in Europeans [odds ratio 1.95 (95% CI 1.31, 2.91) for HbA1c prediabetes criteria] but not in South Asian participants [odds ratio 1.00 (95% CI 0.62, 2.66); ethnicity interaction P = 0.04]. CONCLUSIONS: Prediabetes appeared to be less associated with cardiovascular disease in the South Asian than in the European group. These findings have implications for screening, and early cardiovascular prevention strategies in South Asian populations.

Is a reduction in albuminuria associated with renal and cardiovascular protection? A post hoc analysis of the ALTITUDE trial.

AIMS: To investigate whether the degree of albuminuria reduction observed in the ALTITUDE trial is associated with renal and cardiovascular protection, and secondly, whether the reduction in albuminuria was too small to afford clinical benefit. METHODS: In a post hoc analysis of the ALTITUDE trial in 8561 patients with type 2 diabetes and chronic kidney disease or cardiovascular disease we examined the effect of albuminuria changes at 6 months on renal and cardiovascular outcomes using Cox proportional hazard regression. RESULTS: The median change in albuminuria in the first 6 months in the aliskiren arm of the trial was -12% (25th to 75th percentile: -48.7_to_ +41.9%) and 0.0% (25th to 75th percentile: -40.2_to_55%) in the placebo arm. Changes in albuminuria in the first 6 months were linearly associated with renal and cardiovascular endpoints: a >30% reduction in albuminuria in the first 6 months was associated with a 62% reduction in renal risk and a 25% reduction in cardiovascular risk compared with an increase in albuminuria. The association between changes at 6 months in albuminuria and renal or cardiovascular endpoints was similar in the two treatment groups (p for interaction >0.1 for both endpoints). CONCLUSIONS: The addition of aliskiren to angiotensin-converting enzyme inhibitor/angiotensin receptor blocker therapy resulted in albuminuria changes that were associated with renal and cardiovascular risk changes. This did not translate into renal or cardiovascular protection because the overall reduction in albuminuria in the aliskiren arm was too small and nearly similar to that in the placebo arm.

Depressive symptoms are doubled in older British South Asian and Black Caribbean people compared with Europeans: associations with excess co-morbidity and socioeconomic disadvantage.

BACKGROUND: Despite elevated risk profiles for depression among South Asian and Black Caribbean people in the UK, prevalences of late-life depressive symptoms across the UK's three major ethnic groups have not been well characterized. METHOD: Data were collected at baseline and 20-year follow-up from 632 European, 476 South Asian and 181 Black Caribbean men and women (aged 58-88 years), of a community-based cohort study from north-west London. The 10-item Geriatric Depression Scale was interviewer-administered during a clinic visit (depressive symptoms defined as a score of ⩾4 out of 10), with clinical data (adiposity, diabetes, cardiovascular disease, cognitive function) also collected. Sociodemographic, psychosocial, behavioural, disability, and medical history information was obtained by questionnaire. RESULTS: Prevalence of depressive symptoms varied by ethnic group, affecting 9.7% of White European, 15.5% of South Asian, and 17.7% of Black Caribbean participants. Compared with White Europeans, South Asian and Black Caribbean participants were significantly more likely to have depressive symptoms (odds ratio 1.79, 95% confidence interval 1.24-2.58 and 1.80, 1.11-2.92, respectively). Adjustment for co-morbidities had most effect on the excess South Asian odds, and adjustment for socioeconomic position had most effect on the elevated Black Caribbean odds. CONCLUSIONS: Higher prevalence of depressive symptoms observed among South Asian people were attenuated after adjustment for physical health, whereas the Black Caribbean increased prevalence was most explained by socioeconomic disadvantage. It is important to understand the reasons for these ethnic differences to identify opportunities for interventions to address inequalities.

Ethnicity-specific obesity cut-points in the development of Type 2 diabetes - a prospective study including three ethnic groups in the United Kingdom.

AIMS: Conventional definitions of obesity, e.g. body mass index (BMI) ≥ 30 kg/m² or waist circumference cut-points of 102 cm (men) and 88 cm (women), may underestimate metabolic risk in non-Europeans. We prospectively identified equivalent ethnicity-specific obesity cut-points for the estimation of diabetes risk in British South Asians, African-Caribbeans and Europeans. METHODS: We studied a population-based cohort from London, UK (1356 Europeans, 842 South Asians, 335 African-Caribbeans) who were aged 40-69 years at baseline (1988-1991), when they underwent anthropometry, fasting and post-load (75 g oral glucose tolerance test) blood tests. Incident Type 2 diabetes was identified from primary care records, participant recall and/or follow-up biochemistry. Ethnicity-specific obesity cut-points in association with diabetes incidence were estimated using negative binomial regression. RESULTS: Diabetes incidence rates (per 1000 person years) at a median follow-up of 19 years were 20.8 (95% CI: 18.4, 23.6) and 12.0 (8.3, 17.2) in South Asian men and women, 16.5 (12.7, 21.4) and 17.5 (13.0, 23.7) in African-Caribbean men and women, and 7.4 (6.3, 8.7), and 7.2 (5.3, 9.8) in European men and women. For incidence rates equivalent to those at a BMI of 30 kg/m² in European men and women, age- and sex-adjusted cut-points were: South Asians, 25.2 (23.4, 26.6) kg/m²; and African-Caribbeans, 27.2 (25.2, 28.6) kg/m². For South Asian and African-Caribbean men, respectively, waist circumference cut-points of 90.4 (85.0, 94.5) and 90.6 (85.0, 94.5) cm were equivalent to a value of 102 cm in European men. Waist circumference cut-points of 84.0 (74.0, 90.0) cm in South Asian women and 81.2 (71.4, 87.4) cm in African-Caribbean women were equivalent to a value of 88 cm in European women. CONCLUSIONS: In prospective analyses, British South Asians and African-Caribbeans had equivalent diabetes incidence rates at substantially lower obesity levels than the conventional European cut-points.

Association of physical activity with all-cause mortality and incident and prevalent cardiovascular disease among patients with type 1 diabetes: the EURODIAB Prospective Complications Study.

AIMS/HYPOTHESIS: The aim of this study was to examine the association of physical activity (PA) with all-cause mortality and incident and prevalent cardiovascular disease (CVD) among patients with type 1 diabetes. METHODS: The EURODIAB Prospective Complications Study is a cohort including 3,250 male and female patients with type 1 diabetes (mean age 32.7 ± 10.2 years) from 16 European countries, of whom 1,880 participated in follow-up examinations. In analysis 1 (longitudinal), the association of baseline PA (based on the reported number of hours per week spent in mild, moderate and vigorous PA) with all-cause mortality and incident CVD was examined by performing survival analysis. In analysis 2 (cross-sectional), we focused on the association between PA at follow-up (data on sports, walking distance and regular bicycling) and prevalent CVD by performing logistic regression analysis. Adjustments were made for age, sex, BMI, smoking, consumption of alcohol, consumption of certain nutrients and diabetic complications. RESULTS: Analysis 1 (longitudinal): participation in moderate or vigorous PA once a week or more was borderline inversely associated with all-cause mortality (men and women combined) (HR 0.66, 95% CI 0.42, 1.03) and incident CVD (women only) (HR 0.66, 95% CI 0.40, 1.08). No association was found in men. Analysis 2 (cross-sectional): total PA (indexed by sports, walking, bicycling) and distance walked were inversely associated with prevalent CVD (OR(totalPA) 0.66, 95% CI 0.45, 0.97; and OR(walking) 0.61, 95% CI 0.42, 0.89). CONCLUSIONS/INTERPRETATION: PA showed a borderline inverse association with both all-cause mortality (both sexes) and incident CVD (women only) in patients with type 1 diabetes. Since this is an under-researched clinical population, future longitudinal studies with objective PA measurements are needed to expand on these results.

Unhealthy dietary patterns associated with inflammation and endothelial dysfunction in type 1 diabetes: the EURODIAB study.

BACKGROUND AND AIMS: A healthy diet has been inversely associated with endothelial dysfunction (ED) and low-grade inflammation (LGI). We investigated the association between nutrient consumption and biomarkers of ED and LGI in type 1 diabetes. METHODS AND RESULTS: We investigated 491 individuals. Nutrient consumption and lifestyle risk factors were measured in 1989 and 1997. Biomarkers of ED (von Willebrand factor, soluble vascular cell adhesion molecule-1 and soluble endothelial selectin) and LGI (C-reactive protein, interleukin 6 and tumour necrosis factor α) were measured in 1997 and averaged into Z-scores. The nutrient residual method was used to adjust individual nutrient intake for energy intake. Data were analysed with generalised estimation equations. We report increments/decrements in nutrient consumption, averaged over time, per +1 standard deviation (SD) of 1997 ED or LGI Z-scores, after adjustment for sex, age, duration of diabetes, investigation centre, body mass index, energy intake, smoking behaviour, alcohol consumption, and each of the other nutrients. One SD elevation in ED Z-score was associated with a diet lower in fibre [ß(95%CI);-0.09(-0.18;-0.004)], polyunsaturated fat [-0.18(-0.31;-0.05)] and vegetable protein [-0.10(-0.20;-0.001)]. For the LGI Z-score results showed associations with fibre [-0.09(-0.17;-0.01)], polyunsaturated fat [-0.14(-0.24;-0.03)] and cholesterol [0.10(0.01; 0.18)]. CONCLUSION: In type 1 diabetes, consumption of less fibre, polyunsaturated fat and vegetable protein, and more cholesterol over the study period was associated with more ED and LGI. Following dietary guidelines in type 1 diabetes may reduce cardiovascular disease risk by favourably affecting ED and LGI.

Identifying and ranking novel independent features for cardiovascular disease prediction in people with type 2 diabetes.

Background: CVD prediction models do not perform well in people with diabetes. We therefore aimed to identify novel predictors for six facets of CVD, (including coronary heart disease (CHD), Ischemic stroke, heart failure (HF), and atrial fibrillation (AF)) in people with T2DM. Methods: Analyses were conducted using the UK biobank and were stratified on history of CVD and of T2DM: 459,142 participants without diabetes or a history of CVD, 14,610 with diabetes but without CVD, and 4,432 with diabetes and a history of CVD. Replication was performed using a 20% hold-out set, ranking features on their permuted c-statistic. Results: Out of the 600+ candidate features, we identified a subset of replicated features, ranging between 32 for CHD in people with diabetes to 184 for CVD+HF+AF in people without diabetes. Classical CVD risk factors (e.g. parental or maternal history of heart disease, or blood pressure) were relatively highly ranked for people without diabetes. The top predictors in the people with diabetes without a CVD history included: cystatin C, self-reported health satisfaction, biochemical measures of ill health (e.g. plasma albumin). For people with diabetes and a history of CVD top features were: self-reported ill health, and blood cell counts measurements (e.g. red cell distribution width). We additionally identified risk factors unique to people with diabetes, consisting of information on dietary patterns, mental health and biochemistry measures. Consideration of these novel features improved risk classification, for example per 1000 people with diabetes 133 CVD and 165 HF cases appropriately received a higher risk. Conclusion: Through data-driven feature selection we identified a substantial number of features relevant for prediction of cardiovascular risk in people with diabetes, the majority of which related to non-classical risk factors such as mental health, general illness markers, and kidney disease.

Dietary saturated fat and fibre and risk of cardiovascular disease and all-cause mortality among type 1 diabetic patients: the EURODIAB Prospective Complications Study.

AIMS/HYPOTHESIS: Low adherence to recommendations for dietary saturated fatty acid (SFA) and fibre intake in patients with type 1 diabetes mellitus may heighten their increased risk of cardiovascular disease (CVD) and mortality. We examined the relationship of SFA and total, soluble and insoluble fibre with incident CVD and all-cause mortality in type 1 diabetic patients. METHODS: A prospective cohort analysis was performed in 2,108 European type 1 diabetic patients aged 15-60 years who were free of CVD at baseline and enrolled in the EURODIAB Prospective Complications Study (51% male). Diet was assessed from a standardised 3 day dietary record. HR were calculated using Cox proportional hazards models. RESULTS: During a mean follow-up of 7.3 years, 148 incident cases of fatal and non-fatal CVD and 46 all-cause deaths were documented. No statistically significant association was found between SFA and CVD and all-cause mortality. Total dietary fibre, per 5 g/day, was associated with lower all-cause mortality risk (HR 0.72; 95% CI 0.55, 0.95). This association was stronger for soluble fibre (per 5 g/day, HR 0.34; 95% CI 0.14, 0.80) compared with insoluble fibre (per 5 g/day; HR 0.66; 95% CI 0.45, 0.97). Similar results were found for the association with CVD. CONCLUSIONS/INTERPRETATION: This study suggests that reported dietary SFA is not significantly associated with CVD and all-cause mortality in type 1 diabetic patients. On the contrary, higher dietary fibre consumption, especially soluble fibre, within the range commonly consumed by type 1 diabetic patients, may contribute to the prevention of CVD and all-cause mortality in type 1 diabetic patients.

Multiple genetic variants explain measurable variance in type 2 diabetes-related traits in Pakistanis.

AIMS/HYPOTHESIS: Multiple genetic variants are associated with type 2 diabetes-related traits in Europeans, but their role in South Asian populations needs further study. We hypothesised that genetic variants associated with diabetes-related traits in Europeans would explain a similar proportion of phenotypic variance in a Pakistani population and could be used in Mendelian randomisation analyses. METHODS: We used data from 2,131 individuals from the Control of Blood Pressure and Risk Attenuation Trial (COBRA) in Karachi, Pakistan. Individuals were aged 40 years or older. RESULTS: Combining information from multiple genetic variants showed that fasting glucose, BMI, triacylglycerol, and systolic and diastolic blood pressure variants explained 2.9%, 0.7%, 5.5%, 1.2% and 1.8% of the variance in those traits respectively. Genetic risk scores of fasting glucose, triacylglycerol, BMI, systolic blood pressure and diastolic blood pressure variants were associated with these traits, with per allele SD effects of 0.057 (95% CI 0.041, 0.074), p=3.44 × 10(-12), 0.130 (95% CI 0.105, 0.155), p=2.9 × 10(-21), 0.04 (95% CI 0.014, 0.072), p=0.004, 0.031 (95% CI 0.016, 0.047), p=7.9 × 10(-5), 0.028 (95% CI 0.015, 0.042), p = 5.5 × 10(-5), respectively. These effects are consistent with those observed in Europeans, except that the effect of triacylglycerol variants in South Asians was slightly lower. Mendelian randomisation provided evidence that genetically influenced, raised triacylglycerol levels do not causally affect type 2 diabetes risk to the extent predicted from observational data (p=0.0003 for difference between observed and instrumental variables correlations). CONCLUSIONS/INTERPRETATION: Genetic variants identified in Europeans are associated with type 2 diabetes-related traits in Pakistanis, with comparable effect sizes. Larger studies are needed to perform adequately powered Mendelian randomisation and help dissect the relationships between type 2 diabetes-related traits in diverse South Asian subgroups.

Exposure to candesartan during the first trimester of pregnancy in type 1 diabetes: experience from the placebo-controlled DIabetic REtinopathy Candesartan Trials.

AIMS/HYPOTHESIS: The teratogenic consequences of angiotensin-converting enzyme inhibitors angiotensin receptor blockers (ARBs) during the second and third trimesters of pregnancy are well described. However, the consequences of exposure during the first trimester are unclear, especially in diabetes. We report the experience from DIRECT (DIabetic REtinopathy and Candesartan Trials), three placebo-controlled studies designed to examine the effects of an ARB, candesartan, on diabetic retinopathy. METHODS: Over 4 years or longer, 178 normotensive women with type 1 diabetes (86 randomised to candesartan, 32 mg once daily, and 92 assigned to placebo) became pregnant (total of 208 pregnancies). RESULTS: More than half of patients were exposed to candesartan or placebo prior to or in early pregnancy, but all discontinued it at an estimated 8 weeks from the last menstrual period. Full-term pregnancies (51 vs 50), premature deliveries (21 vs 27), spontaneous miscarriages (12 vs 15), elective terminations (15 vs 14) and other outcomes (1 vs 2) were similar in the candesartan and placebo groups. There were two stillbirths and two 'sick babies' in the candesartan group, and one stillbirth, eight 'sick babies' and one cardiac malformation in the placebo group. CONCLUSIONS/INTERPRETATION: The risk for fetal consequences of ARBs in type 1 diabetes may not be high if exposure is clearly limited to the first trimester. Long-term studies in fertile women can be conducted with ARBs during pregnancy, provided investigators diligently stop their administration upon planning or detection of pregnancy. TRIAL REGISTRATION: ClinicalTrials.gov DIRECT-Prevent 1 NCT00252733; DIRECT-Protect 1 NCT00252720; DIRECT-Protect 2 NCT00252694. FUNDING: The study was funded jointly by AstraZeneca and Takeda.

Extending the clinical research network approach to all of healthcare.

The development of Clinical Research Networks (CRN) has been central to the work conducted by Health Departments and research funders to promote and support clinical research within the NHS in the UK. In England, the National Institute for Health Research has supported the delivery of clinical research within the NHS primarily through CRN. CRN provide the essential infrastructure within the NHS for the set up and delivery of clinical research within a high-quality peer-reviewed portfolio of studies. The success of the National Cancer Research Network is summarized in Chapter 5. In this chapter progress in five other topics, and more recently in primary care and comprehensively across the NHS, is summarized. In each of the 'topic-specific' networks (Dementias and Neurodegenerative Diseases, Diabetes, Medicines for Children, Mental Health, Stroke) there has been a rapid and substantial increase in portfolios and in the recruitment of patients into studies in these portfolios. The processes and the key success factors are described. The CRN have worked to support research supported by pharmaceutical, biotechnology and medical device companies and there has been substantial progress in improving the speed, cost and delivery of these 'industry' studies. In particular, work to support the increased speed of set up and delivery of industry studies, and to embed this firmly in the NHS, was explored in the North West of England in an Exemplar Programme which showed substantial reductions in study set-up times and improved recruitment into studies and showed how healthcare (NHS) organizations can overcome delays in set up times when they actively manage the process. Seven out of 20 international studies reported that the first patient to be entered anywhere in the world was from the UK. In addition, the CRN have supported research management and governance, workforce development and clinical trials unit collaboration and coordination. International peer reviews of all of the CRN have been positive and resulted in the continuation of the system for a further 5 years in all cases.

Self management and patient understanding of diabetes in the older person.

AIM: To examine knowledge and management of diabetes by older people. METHODS: A representative sample of 1047 people with Type 2 diabetes, aged 75 years and over, were asked a series of questions relating to their diabetes management and their understanding of self management. The impact of cognitive impairment and socio-economic status were assessed. RESULTS: The majority of people, 1015 (96.9%), were under the care of a health professional and 1018 (97.2%) were taking insulin, tablets, controlling their diet or a combination. Cognitive impairment (Mini-Mental State Examination ≤ 23) was found in 235 (22.5%) people. Recent eye, foot and dietician assessment was reported by 813 (77.7%), 836 (79.7%) and 326 (31.1%) people, respectively. A quarter overall and 70% of those taking insulin tested their blood glucose. In the insulin group, 78 (54.2%) reported hypoglycaemia and those with cognitive impairment gave more incorrect responses when asked about diabetes management. Socio-economic status made very little difference to any of these outcomes. CONCLUSIONS: Most older people with diabetes, regardless of their socio-economic status, are under the care of a healthcare professional and use medication or diet to manage their disease. Large numbers also attend foot and eye examinations. However, over one fifth of older people with diabetes have cognitive impairment. Older people had a reasonable understanding of their diabetes management but this was worse in those people with cognitive impairment.

Retinal microaneurysm count predicts progression and regression of diabetic retinopathy. Post-hoc results from the DIRECT Programme.

OBJECTIVE: To study the association between baseline retinal microaneurysm score and progression and regression of diabetic retinopathy, and response to treatment with candesartan in people with diabetes. METHODS: This was a multicenter randomized clinical trial. The progression analysis included 893 patients with Type 1 diabetes and 526 patients with Type 2 diabetes with retinal microaneurysms only at baseline. For regression, 438 with Type 1 and 216 with Type 2 diabetes qualified. Microaneurysms were scored from yearly retinal photographs according to the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Retinopathy progression and regression was defined as two or more step change on the ETDRS scale from baseline. Patients were normoalbuminuric, and normotensive with Type 1 and Type 2 diabetes or treated hypertensive with Type 2 diabetes. They were randomized to treatment with candesartan 32 mg daily or placebo and followed for 4.6 years. RESULTS: A higher microaneurysm score at baseline predicted an increased risk of retinopathy progression (HR per microaneurysm score 1.08, P < 0.0001 in Type 1 diabetes; HR 1.07, P = 0.0174 in Type 2 diabetes) and reduced the likelihood of regression (HR 0.79, P < 0.0001 in Type 1 diabetes; HR 0.85, P = 0.0009 in Type 2 diabetes), all adjusted for baseline variables and treatment. Candesartan reduced the risk of microaneurysm score progression. CONCLUSIONS: Microaneurysm counts are important prognostic indicators for worsening of retinopathy, thus microaneurysms are not benign. Treatment with renin-angiotensin system inhibitors is effective in the early stages and may improve mild diabetic retinopathy. Microaneurysm scores may be useful surrogate endpoints in clinical trials.

An FTO variant is associated with Type 2 diabetes in South Asian populations after accounting for body mass index and waist circumference.

AIMS: A common variant, rs9939609, in the FTO (fat mass and obesity) gene is associated with adiposity in Europeans, explaining its relationship with diabetes. However, data are inconsistent in South Asians. Our aim was to investigate the association of the FTO rs9939609 variant with obesity, obesity-related traits and Type 2 diabetes in South Asian individuals, and to use meta-analyses to attempt to clarify to what extent BMI influences the association of FTO variants with diabetes in South Asians. METHODS: We analysed rs9939609 in two studies of Pakistani individuals: 1666 adults aged ≥40 years from the Karachi population-based Control of Blood Pressure and Risk Attenuation (COBRA) study and 2745 individuals of Punjabi ancestry who were part of a Type 2 diabetes case-control study (UK Asian Diabetes Study/Diabetes Genetics in Pakistan; UKADS/DGP). The main outcomes were BMI, waist circumference and diabetes. Regression analyses were performed to determine associations between FTO alleles and outcomes. Summary estimates were combined in a meta-analysis of 8091 South Asian individuals (3919 patients with Type 2 diabetes and 4172 control subjects), including those from two previous studies. RESULTS: In the 4411 Pakistani individuals from this study, the age-, sex- and diabetes-adjusted association of FTO variant rs9939609 with BMI was 0.45 (95%CI 0.24-0.67) kg/m(2) per A-allele (P=3.0 × 10(-5) ) and with waist circumference was 0.88 (95% CI 0.36-1.41) cm per A-allele (P=0.001). The A-allele (30% frequency) was also significantly associated with Type 2 diabetes [per A-allele odds ratio (95%CI) 1.18 (1.07-1.30); P=0.0009]. A meta-analysis of four South Asian studies with 8091 subjects showed that the FTO A-allele predisposes to Type 2 diabetes [1.22 (95%CI 1.14-1.31); P=1.07 × 10(-8) ] even after adjusting for BMI [1.18 (95%CI 1.10-1.27); P=1.02 × 10(-5) ] or waist circumference [1.18 (95%CI 1.10-1.27); P=3.97 × 10(-5) ]. CONCLUSIONS: The strong association between FTO genotype and BMI and waist circumference in South Asians is similar to that observed in Europeans. In contrast, the strong association of FTO genotype with diabetes is only partly accounted for by BMI.

Progression to microalbuminuria in type 1 diabetes: development and validation of a prediction rule.

AIMS/HYPOTHESIS: Microalbuminuria is common in type 1 diabetes and is associated with an increased risk of renal and cardiovascular disease. We aimed to develop and validate a clinical prediction rule that estimates the absolute risk of microalbuminuria. METHODS: Data from the European Diabetes Prospective Complications Study (n = 1115) were used to develop the prediction rule (development set). Multivariable logistic regression analysis was used to assess the association between potential predictors and progression to microalbuminuria within 7 years. The performance of the prediction rule was assessed with calibration and discrimination (concordance statistic [c-statistic]) measures. The rule was validated in three other diabetes studies (Pittsburgh Epidemiology of Diabetes Complications [EDC] study, Finnish Diabetic Nephropathy [FinnDiane] study and Coronary Artery Calcification in Type 1 Diabetes [CACTI] study). RESULTS: Of patients in the development set, 13% were microalbuminuric after 7 years. Glycosylated haemoglobin, AER, WHR, BMI and ever smoking were found to be the most important predictors. A high-risk group (n = 87 [8%]) was identified with a risk of progression to microalbuminuria of 32%. Predictions showed reasonable discriminative ability, with c-statistic of 0.71. The rule showed good calibration and discrimination in EDC, FinnDiane and CACTI (c-statistic 0.71, 0.79 and 0.79, respectively). CONCLUSIONS/INTERPRETATION: We developed and validated a clinical prediction rule that uses relatively easily obtainable patient characteristics to predict microalbuminuria in patients with type 1 diabetes. This rule can help clinicians to decide on more frequent check-ups for patients at high risk of microalbuminuria in order to prevent long-term chronic complications.

Indian Asians have poorer cardiovascular autonomic function than Europeans: this is due to greater hyperglycaemia and may contribute to their greater risk of heart disease.

AIMS/HYPOTHESIS: A high prevalence of diabetes contributes to excess CHD in Indian Asians, but the underlying mechanisms are unclear. Heart rate, heart rate variability (HRV) and baroreflex sensitivity (BRS) are measures of cardiac autonomic function that are disturbed by hyperglycaemia and predict CHD. We compared these measures in Indian Asians and Europeans, and sought explanations for the observed differences. METHODS: A representative sample of 149 Europeans and 151 Indian Asians was recruited from primary care, 66% of them men (aged 35-75 years), 34% women (aged 55-75 years). Heart rate, HRV, BRS and cardio-metabolic profiles were measured over four successive 5 min periods with continuous ECG and blood pressure monitoring. RESULTS: Indian Asians were hyperglycaemic compared with Europeans (HbA(1c) (mean +/- SD) 6.5 +/- 1.2% vs 5.9 +/- 1.0%, p = 0.001). They had shorter mean RR intervals ((mean +/- SE) 969 +/- 13 vs 1,022 +/- 12 ms, p = 0.002), lower total RR interval power ((geometric mean, 95% CI) 925 [796-1075] vs 1,224 [1,064-1,422] ms(2), p = 0.008) and lower BRS ((mean +/- SE) 5.7 +/- 1.0 vs 6.6 +/- 1.0 ms/mmHg, p = 0.01). All measures of cardiac autonomic dysfunction were significantly associated with hyperglycaemia (mean RR interval vs HbA(1c) r = -0.22; p < 0.001). Ethnic differences in cardiac autonomic function persisted after adjustment for age, blood pressure and medication (mean RR interval 973 vs 1,021 ms, p = 0.004), but were attenuated or abolished by adjusting for HbA(1c) (979 vs 1,014 ms, p = 0.06) or other markers of hyperglycaemia. CONCLUSIONS/INTERPRETATION: Indian Asians from the general population have impaired cardiovascular autonomic function compared with Europeans. This is due to greater hyperglycaemia in Indian Asians and may determine their increased CHD risk.