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.

Gnomonious projections for bend-free textures: thoughts on the splay-twist phase.

The Hopf fibration has inspired any number of geometric structures in physical systems, in particular, in chiral liquid crystalline materials. Because the Hopf fibration lives on the three sphere, S 3 , some method of projection or distortion must be employed to realize textures in flat space. Here, we explore the geodesic-preserving gnomonic projection of the Hopf fibration, and show that this could be the basis for a new liquid crystalline texture with only splay and twist. We outline the structure and show that it is defined by the tangent vectors along the straight line rulings on a series of hyperboloids. The phase is defined by a lack of bend deformations in the texture, and is reminiscent of the splay-bend and twist-bend nematic phases. We show that domains of this phase may be stabilized through anchoring and saddle-splay.

Ethnic differences in the severity and clinical management of type 2 diabetes at time of diagnosis: A cohort study in the UK Clinical Practice Research Datalink.

AIMS: To characterize ethnic differences in the severity and clinical management of type 2 diabetes at initial diagnosis. METHODS: An observational cohort study of 179,886 people with incident type 2 diabetes between 2004 and 2017 in the Clinical Practice Research Datalink was undertaken; 63.4% of the cohort were of white ethnicity, 3.9% south Asian, and 1.6% black. Ethnic differences in clinical profile at diagnosis, consultation rates, and risk factor recording were derived from linear and logistic regression. Cox-proportional hazards regression was used to determine ethnic differences in time to initiation of therapeutic and non-therapeutic management following diagnosis. All analyses adjusted for age, sex, deprivation, and clustering by practice. RESULTS: In the 12 months prior to diagnosis, non-white groups had fewer consultations compared to white groups, but risk factor recording was better than or equivalent to white groups for 9/10 risk factors for south Asian groups and 8/10 risk factors for black groups (p < 0.002). Blood pressure, BMI, cholesterol, eGFR, and CVD risk levels were more favourable in non-white groups, and prevalence of macrovascular disease was significantly lower (p < 0.003). Time to initiation of antidiabetic treatment and first risk assessment was faster in non-white groups relative to white groups, while time to risk factor measurement and diabetes review was slower. CONCLUSIONS: We find limited evidence of systematic ethnic inequalities around the time of type 2 diabetes diagnosis. Ethnic disparities in downstream consequences may relate to genetic risk factors, or manifest later in the care pathway, potentially in relation to long-term risk factor control.

Mechanisms to splay-bend nematic phases.

While twist-bend nematic phases have been extensively studied, the experimental observation of two dimensional, oscillating splay-bend phases is recent. We consider two theoretical models that have been used to explain the formation of twist-bend phases-flexoelectricity and bond orientational order-as mechanisms to induce splay-bend phases. Flexoelectricity is a viable mechanism, and splay and bend flexoelectric couplings can lead to splay-bend phases with different modulations. We show that while bond orientational order circumvents the need for higher order terms in the free energy, the important role of nematic symmetry and phase chirality rules it out as a basic mechanism.

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.

The risk of cardiac failure following metal-on-metal hip arthroplasty.

AIMS: The aim of this study was to determine whether patients with metal-on-metal (MoM) arthroplasties of the hip have an increased risk of cardiac failure compared with those with alternative types of arthroplasties (non-MoM). PATIENTS AND METHODS: A linkage study between the National Joint Registry, Hospital Episodes Statistics and records of the Office for National Statistics on deaths was undertaken. Patients who underwent elective total hip arthroplasty between January 2003 and December 2014 with no past history of cardiac failure were included and stratified as having either a MoM (n = 53 529) or a non-MoM (n = 482 247) arthroplasty. The primary outcome measure was the time to an admission to hospital for cardiac failure or death. Analysis was carried out using data from all patients and from those matched by propensity score. RESULTS: The risk of cardiac failure was lower in the MoM cohort compared with the non-MoM cohort (adjusted hazard ratio (aHR) 0.901; 95% confidence interval (CI) 0.853 to 0.953). The risk of cardiac failure was similar following matching (aHR 0.909; 95% CI 0.838 to 0.987) and the findings were consistent in subgroup analysis. CONCLUSION: The risk of cardiac failure following total hip arthroplasty was not increased in those in whom MoM implants were used, compared with those in whom other types of prostheses were used, in the first seven years after surgery. Cite this article: Bone Joint J 2018;100-B:20-7.

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.

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.

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.

Association of diet and lifestyle with glycated haemoglobin in type 1 diabetes participants in the EURODIAB prospective complications study.

BACKGROUND/OBJECTIVES: Diet and lifestyle advice for type 1 diabetes (T1DM) patients is based on little evidence and putative effects on glycaemic control. Therefore, we investigated the longitudinal relation between dietary and lifestyle variables and HbA1c levels in patients with type 1 diabetes. SUBJECTS/METHODS: A 7-year prospective cohort analysis was performed in 1659 T1DM patients (52% males, mean age 32.5 years) participating in the EURODIAB Prospective Complications Study. Baseline dietary intake was assessed by 3- day records and physical activity, smoking status and alcohol intake by questionnaires. HbA1c during follow-up was centrally assessed by immunoassay. Analysis of variance (ANOVA) and restricted cubic spline regression analyses were performed to assess dose-response associations between diet and lifestyle variables and HbA1c levels, adjusted for age, sex, lifestyle and body composition measures, baseline HbA1c, medication use and severe hypoglycaemic attacks. RESULTS: Mean follow-up of our study population was 6.8 (s.d. 0.6) years. Mean HbA1c level was 8.25% (s.d. 1.85) (or 66.6 mmol/mol) at baseline and 8.27% (s.d. 1.44) at follow-up. Physical activity, smoking status and alcohol intake were not associated with HbA1c at follow-up in multivariable ANOVA models. Baseline intake below the median of vegetable protein (<29 g/day) and dietary fibre (<18 g/day) was associated with higher HbA1c levels. Restricted cubic splines showed nonlinear associations with HbA1c levels for vegetable protein (P (nonlinear)=0.008) and total dietary fibre (P (nonlinear)=0.0009). CONCLUSIONS: This study suggests that low intake of vegetable protein and dietary fibre are associated with worse glycaemic control in type 1 diabetes.

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.

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.

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.

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.

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.

Impaired post-ischaemic microvascular hyperaemia in Indian Asians is unexplained by diabetes or other cardiovascular risk factors.

OBJECTIVE: People of Indian Asian descent have an increased risk of cardiovascular disease (CVD) that cannot be explained by diabetes and other established CVD risk factors. We investigated if microcirculatory function was impaired in a population-based sample of people of Indian Asian descent compared with Europeans in the UK and whether any differences could be accounted for by diabetes or other CVD risk factors. RESEARCH DESIGN AND METHODS: Cutaneous microvascular function was assessed using laser Doppler fluximetry in response to heating to 42 °C (maximum hyperaemia) and 3 min arterial occlusion (post occlusive reactive hyperaemia: PORH) in 148 Indian Asians and 147 Europeans. Blood pressure, anthropometry and fasting bloods were also measured. RESULTS: Maximum hyperaemia and minimum resistance did not differ significantly by ethnicity. Resting flux and PORH were lower in Indian Asians and time to peak of PORH was prolonged. Diabetes was associated with reduced maximum hyperaemia and PORH. Adjustment for diabetes accounted for differences in resting flux and time to peak but not differences in PORH (Europeans = 45.0 (40.3, 50.1)au, Indian Asians = 35.6 (31.9, 39.7)au, mean (95% confidence interval); p = 0.008 after adjustment). Differences in conventional CVD risk factors did not account for interethnic differences in microvascular responses. CONCLUSIONS: People of Indian Asian descent have impaired post-occlusive reactive hyperaemia unexplained by diabetes, dysglycaemia or other CVD risk factors. Abnormal microvascular function in response to ischaemia could represent a novel mechanism contributing to the elevated risk of CVD in Indian Asians.

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.