GDF15 linked to maternal risk of nausea and vomiting during pregnancy.

GDF15, a hormone acting on the brainstem, has been implicated in the nausea and vomiting of pregnancy, including its most severe form, hyperemesis gravidarum (HG), but a full mechanistic understanding is lacking1-4. Here we report that fetal production of GDF15 and maternal sensitivity to it both contribute substantially to the risk of HG. We confirmed that higher GDF15 levels in maternal blood are associated with vomiting in pregnancy and HG. Using mass spectrometry to detect a naturally labelled GDF15 variant, we demonstrate that the vast majority of GDF15 in the maternal plasma is derived from the feto-placental unit. By studying carriers of rare and common genetic variants, we found that low levels of GDF15 in the non-pregnant state increase the risk of developing HG. Conversely, women with ß-thalassaemia, a condition in which GDF15 levels are chronically high5, report very low levels of nausea and vomiting of pregnancy. In mice, the acute food intake response to a bolus of GDF15 is influenced bi-directionally by prior levels of circulating GDF15 in a manner suggesting that this system is susceptible to desensitization. Our findings support a putative causal role for fetally derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by prepregnancy exposure to the hormone, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG.

The potential benefit of statin prescription based on prediction of treatment responsiveness in older individuals: An application to the PROSPER randomised controlled trial.

BACKGROUND & AIMS: Clinical guidelines often recommend to treat individuals based on their cardiovascular risk. We revisit this paradigm and quantify the efficacy of three treatment strategies: (i) overall prescription, i.e. treatment to all individuals sharing the eligibility criteria of a trial; (ii) risk-stratified prescription, i.e. treatment only to those at an elevated outcome risk; and (iii) prescription based on predicted treatment responsiveness. METHODS: We reanalysed the PROSPER randomised controlled trial, which included individuals aged 70-82 years with a history of, or risk factors for, vascular diseases. We conducted the derivation and internal-external validation of a model predicting treatment responsiveness. We compared to placebo (n= 2913): (i) pravastatin (n= 2891); (ii) pravastatin in the presence of previous vascular diseases and placebo in the absence thereof (n= 2925); and (iii) pravastatin in the presence of a favourable prediction of treatment response and placebo in the absence thereof (n= 2890). RESULTS: We found an absolute difference in primary outcome events composed of coronary death, non-fatal myocardial infarction, fatal or non-fatal stroke, per 10 000 person-years equal to: -78 events (95% CI, -144 to -12) when prescribing pravastatin to all participants; -66 events (95% CI, -114 to -18) when treating only individuals with an elevated vascular risk; and -103 events (95% CI, -162 to -44) when restricting pravastatin to individuals with a favourable prediction of treatment response. CONCLUSIONS: Pravastatin prescription based on predicted responsiveness may have an encouraging potential for cardiovascular prevention. Further external validation of our results and clinical experiments are needed.

This study invistigates whether an algorithm to predict how much old age individuals would benefit from a statin treatment could be useful to guide clinicians in their prescription decision-making; the key findings are: About one out of seven individuals included in the study has no predicted benefit of pravastatin; Compared to prescribing pravastatin to all old age individuals at risk of cardiovascular diseases, withholding pravastatin in those with no predicted benefit seems to lead to a better prevention of cardiovascular events.

Fetally-encoded GDF15 and maternal GDF15 sensitivity are major determinants of nausea and vomiting in human pregnancy.

Human pregnancy is frequently accompanied by nausea and vomiting that may become severe and life-threatening, as in hyperemesis gravidarum (HG), the cause of which is unknown. Growth Differentiation Factor-15 (GDF15), a hormone known to act on the hindbrain to cause emesis, is highly expressed in the placenta and its levels in maternal blood rise rapidly in pregnancy. Variants in the maternal GDF15 gene are associated with HG. Here we report that fetal production of GDF15, and maternal sensitivity to it, both contribute substantially to the risk of HG. We found that the great majority of GDF15 in maternal circulation is derived from the feto-placental unit and that higher GDF15 levels in maternal blood are associated with vomiting and are further elevated in patients with HG. Conversely, we found that lower levels of GDF15 in the non-pregnant state predispose women to HG. A rare C211G variant in GDF15 which strongly predisposes mothers to HG, particularly when the fetus is wild-type, was found to markedly impair cellular secretion of GDF15 and associate with low circulating levels of GDF15 in the non-pregnant state. Consistent with this, two common GDF15 haplotypes which predispose to HG were associated with lower circulating levels outside pregnancy. The administration of a long-acting form of GDF15 to wild-type mice markedly reduced subsequent responses to an acute dose, establishing that desensitisation is a feature of this system. GDF15 levels are known to be highly and chronically elevated in patients with beta thalassemia. In women with this disorder, reports of symptoms of nausea or vomiting in pregnancy were strikingly diminished. Our findings support a causal role for fetal derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by pre-pregnancy exposure to GDF15, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG.

Promising Nitrogen-Doped Graphene Derivatives; A Case Study for Preparations, Fabrication Mechanisms, and Applications in Perovskite Solar Cells.

Graphene (G) has been a game-changer for conductive optical devices and has shown promising aspects for its implementation in the power industry due to its diverse structures. Graphene has played an essential role as electrodes, hole transport layers (HTLs), electron transport layers (ETLs), and a chemical modulator for perovskite layers in perovskite solar cells (PSCs) over the past decade. Nitrogen-doped graphene (N-DG) derivatives are frequently evaluated among the existing derivatives of graphene because of their versatility of design, easy synthesis process, and high throughput. This review presents a state-of-the-art overview of N-DG preparation methods, including wet chemical process, bombardment, and high thermal treatment methods. Furthermore, it focuses on different structures of N-DG derivatives and their various applications in PSC applications. Finally, the challenges and opportunities for N-DG derivatives for the continuous performance improvement of PSCs have been highlighted.

Prevention and early treatment of the long-term physical effects of COVID-19 in adults: design of a randomised controlled trial of resistance exercise-CISCO-21.

BACKGROUND: Coronavirus disease-19 (COVID-19) infection causes persistent health problems such as breathlessness, chest pain and fatigue, and therapies for the prevention and early treatment of post-COVID-19 syndromes are needed. Accordingly, we are investigating the effect of a resistance exercise intervention on exercise capacity and health status following COVID-19 infection. METHODS: A two-arm randomised, controlled clinical trial including 220 adults with a diagnosis of COVID-19 in the preceding 6 months. Participants will be classified according to clinical presentation: Group A, not hospitalised due to COVID but persisting symptoms for at least 4 weeks leading to medical review; Group B, discharged after an admission for COVID and with persistent symptoms for at least 4 weeks; or Group C, convalescing in hospital after an admission for COVID. Participants will be randomised to usual care or usual care plus a personalised and pragmatic resistance exercise intervention for 12 weeks. The primary outcome is the incremental shuttle walks test (ISWT) 3 months after randomisation with secondary outcomes including spirometry, grip strength, short performance physical battery (SPPB), frailty status, contacts with healthcare professionals, hospitalisation and questionnaires assessing health-related quality of life, physical activity, fatigue and dyspnoea. DISCUSSION: Ethical approval has been granted by the National Health Service (NHS) West of Scotland Research Ethics Committee (REC) (reference: GN20CA537) and recruitment is ongoing. Trial findings will be disseminated through patient and public forums, scientific conferences and journals. TRIAL REGISTRATION: ClinicialTrials.gov NCT04900961 . Prospectively registered on 25 May 2021.

MDP Salts: A New Bonding Strategy for Zirconia.

Durable resin-ceramic adhesion may influence the clinical success of ceramic restorations, which has been one of the challenging issues in dentistry. The present study assessed the bond strength and chemical interaction of 10-methacryloxydecyl dihydrogen phosphate (MDP), MDP+silane, and MDP-salt primers to alumina-blasted zirconia ceramic by tensile bond strength test, surface elemental composition with x-ray photoelectron spectroscopy analysis, contact angle measurement, surface morphology with scanning electron microscopy, and surface topography with 3-dimensional confocal laser scanning microscope analyses. MDP-salt showed the highest tensile bond strength before and after thermocycling when compared with MDP and MDP+silane (P < 0.05). The measured contact angle values differed significantly (P < 0.001) in the order of MDP-salt > control (no chemical pretreatment) > MDP+silane > MDP. There was no difference in surface roughness (P = 0.317) and surface topography among all tested groups. Zirconia treated with MDP-salt showed phosphorus peaks in addition to zirconia and alumina peaks. MDP-salt has zirconia priming properties, which improves bonding performance to resin cement.

Diverging trends for onset of acute myocardial infarction, heart failure, stroke and mortality in young males: role of changes in obesity and fitness.

BACKGROUND: As opposed to the decreasing overall rates of coronary heart disease (CHD) incidence and overall cardiovascular disease (CVD) mortality, heart failure (HF) and stroke incidence are increasing in young people, potentially due to rising rates of obesity and reduced cardiorespiratory fitness (CRF). OBJECTIVES: We investigated trends in early major CVD outcomes in a large cohort of young men. METHODS: Successive cohorts of Swedish military conscripts from 1971 to 1995 (N = 1,258,432; mean age, 18.3 years) were followed, using data from the National Inpatient and Cause of Death registries. Cox proportional hazard models were used to analyse changes in 21-year CVD event rates. RESULTS: 21-year CVD and all-cause mortality and incidence of acute myocardial infarction (AMI) decreased progressively. Compared with the cohort conscripted in 1971-1975 (reference), the hazard ratios (HRs) for the last 1991-1995 cohort were 0.50 [95% confidence interval (CI) 0.42-0.59] for CVD mortality; 0.57 (95% CI 0.54-0.60) for all-cause mortality; and 0.63 (95% CI 0.53-0.75) for AMI. In contrast, the incidence of ischaemic stroke, intracerebral haemorrhage and HF increased with HRs of 1.43 (95% CI 1.17-1.75), 1.30 (95% CI 1.01-1.68) and 1.84 (95% CI 1.47-2.30), respectively. During the period, rates of obesity increased from 1.04% to 2.61%, whilst CRF scores decreased slightly. Adjustment for these factors influenced these secular trends only moderately. CONCLUSION: Secular trends of young-onset CVD events demonstrated a marked shift from AMI and CVD mortality to HF and stroke incidence. Trends were significantly, though moderately, influenced by changing baseline BMI and CRF.

Predictors of type 2 diabetes remission in the Diabetes Remission Clinical Trial (DiRECT).

AIM: To identify predictors of type 2 diabetes remission in the intervention arm of DiRECT (Diabetes Remission Clinical Trial). METHODS: Participants were aged 20-65 years, with type 2 diabetes duration of <6 years and BMI 27-45 kg/m2 , and were not receiving insulin. Weight loss was initiated by total diet replacement (825-853 kcal/day, 3-5 months, shakes/soups), and weight loss maintenance support was provided for 2 years. Remissions (HbA1c <48 mmol/mol [<6.5%], without antidiabetes medications) in the intervention group (n = 149, mean age 53 years, BMI 35 kg/m2 ) were achieved by 68/149 participants (46%) at 12 months and by 53/149 participants (36%) at 24 months. Potential predictors were examined by logistic regression analyses, with adjustments for weight loss and effects independent of weight loss. RESULTS: Baseline predictors of remission at 12 and 24 months included being prescribed fewer antidiabetes medications, having lower triglyceride and gamma-glutamyl transferase levels, and reporting better quality of life with less anxiety/depression. Lower baseline HbA1c was a predictor at 12 months, and older age and male sex were predictors at 24 months. Being prescribed antidepressants predicted non-remission. Some, but not all effects were explained by weight loss. Weight loss was the strongest predictor of remission at 12 months (adjusted odds ratio per kg weight loss 1.24, 95% CI 1.14, 1.34; P < 0.0001) and 24 months (adjusted odds ratio 1.23, 95% CI 1.13, 1.35; P <0.0001). Weight loss in kilograms and percentage weight loss were equally good predictors. Early weight loss and higher programme attendance predicted more remissions. Baseline BMI, fasting insulin, fasting C-peptide and diabetes duration did not predict remission. CONCLUSIONS: Other than weight loss, most predictors were modest, and not sufficient to identify subgroups for which remission was not a worthwhile target.

Socio-economic differences in cardiovascular disease risk factor prevalence in people with type 2 diabetes in Scotland: a cross-sectional study.

AIM: To describe the association between socio-economic status and prevalence of key cardiovascular risk factors in people with type 2 diabetes in Scotland. METHODS: A cross-sectional study of 264 011 people with type 2 diabetes in Scotland in 2016 identified from the population-based diabetes register. Socio-economic status was defined using quintiles of the area-based Scottish Index of Multiple Deprivation (SIMD) with quintile (Q)1 and Q5 used to identify the most- and least-deprived fifths of the population, respectively. Logistic regression models adjusted for age, sex, health board, history of cardiovascular disease and duration of diabetes were used to estimate odds ratios (ORs) for Q1 compared with Q5 for each risk factor. RESULTS: The mean (sd) age of the study population was 66.7 (12.8) years, 56% were men, 24% were in Q1 and 15% were in Q5. Crude prevalence in Q1/Q5 was 24%/8.8% for smoking, 62%/49% for BMI ≥ 30 kg/m2 , 44%/40% for HbA1c ≥ 58 mmol/mol (7.5%), 31%/31% for systolic blood pressure (SBP) ≥ 140 mmHg, and 24%/25% for total cholesterol ≥ 5 mmol/l, respectively. ORs [95% confidence intervals (CI)] were 3.08 (2.95-3.21) for current smoking, 1.48 (1.44-1.52) for BMI ≥ 30 kg/m2 , 1.11 (1.08-1.15) for HbA1c ≥ 58 mmol/mol (7.5%), 1.03 (1.00-1.06) for SBP ≥ 140 mmHg and 0.87 (0.84-0.90) for total cholesterol ≥ 5 mmol/l. CONCLUSIONS: Socio-economic deprivation is associated with higher prevalence of smoking, BMI ≥ 30 kg/m2 and HbA1c ≥ 58 mmol/mol (7.5%), and lower prevalence of total cholesterol ≥ 5 mmol/l among people with type 2 diabetes in Scotland. Effective approaches to reducing inequalities are required as well as reducing risk factor prevalence across the whole population.

Socio-economic status and mortality in people with type 1 diabetes in Scotland 2006-2015: a retrospective cohort study.

AIMS: To describe the association between socio-economic status and mortality in a nation-wide cohort of people with type 1 diabetes in Scotland and to compare patterns over time and with the general population. METHODS: A retrospective cohort study was performed using data for people with type 1 diabetes from a population-based register linked to mortality records. Socio-economic status was derived from quintiles of an area-based measure: the Scottish Index of Multiple Deprivation. Sex-specific directly age-standardized mortality rates for each Scottish Index of Multiple Deprivation quintile and rate ratios comparing the most vs least deprived quintile were calculated for two time periods: 2006-2010 and 2011-2015. Data for the population without type 1 diabetes between 2011 and 2015 were available for comparison. RESULTS: Data for 3802 deaths among 33 547 people with type 1 diabetes were available. The age-standardized mortality rate per 1000 person-years decreased over time (from 2006-2010 to 2011-2015) for men and women with type 1 diabetes: 24.8 to 20.2 and 22.5 to 17.6, respectively. Mortality in populations with and without type 1 diabetes was generally higher for men than women and was inversely associated with socio-economic status. Rate ratios for the most vs least deprived groups increased over time among people with type 1 diabetes (men: 2.49 to 2.81; women: 1.92 to 2.86) and were higher than among populations without type 1 diabetes in 2011-2015 (men: 2.06; women: 1.66). CONCLUSIONS: Socio-economic deprivation was associated with a steeper mortality gradient in people with type 1 diabetes than in the population without type 1 diabetes in Scotland. Age-standardized mortality has decreased over time but socio-economic inequalities may be increasing.

The association between driving time and unhealthy lifestyles: a cross-sectional, general population study of 386 493 UK Biobank participants.

BACKGROUND: Driving is a common type of sedentary behaviour; an independent risk factor for poor health. The study explores whether driving is also associated with other unhealthy lifestyle factors. METHODS: In a cross-sectional study of UK Biobank participants, driving time was treated as an ordinal variable and other lifestyle factors dichotomized into low/high risk based on guidelines. The associations were explored using chi-square tests for trend and binary logistic regression. RESULTS: Of the 386 493 participants who drove, 153 717 (39.8%) drove <1 h/day; 140 140 (36.3%) 1 h/day; 60 973 (15.8%) 2 h/day; and 31 663 (8.2%) ≥3 h/day. Following adjustment for potential confounders, driving ≥3 h/day was associated with being overweight/obese (OR = 1.74, 95% CI: 1.64-1.85), smoking (OR = 1.48, 95% CI: 1.37-1.63), insufficient sleep (1.70, 95% CI: 1.61-1.80), low fruit/vegetable intake (OR = 1.26, 95% CI: 1.18-1.35) and low physical activity (OR = 1.05, 95% CI: 1.00-1.11), with dose relationships for the first three, but was not associated with higher alcohol consumption (OR = 0.94, 95% CI: 0.87-1.02). CONCLUSIONS: Sedentary behaviour, such as driving, is known to have an independent association with adverse health outcomes. It may have additional impact mediated through its effect on other aspects of lifestyle. People with long driving times are at higher risk and might benefit from targeted interventions.

Associations of dietary protein intake with bone mineral density: An observational study in 70,215 UK Biobank participants.

PURPOSE: Adequate dietary protein intake is important for the maintenance of bone health; however, data in this area is ambiguous with some suggestion that high protein intake can have deleterious effects on bone health. The aim of the current study was to explore the associations of protein intake with bone mineral density (BMD). METHODS: We used baseline data from the UK Biobank (participants aged 40-69 years) to examine the association of protein intake with BMD (measured by ultrasound). These associations were examined, in women (n = 39,066) and men (n = 31,149), after adjustment for socio-demographic and lifestyle confounders and co-morbidities. RESULTS: Protein intake was positively and linearly associated with BMD in women (ß-coefficient 0.010 [95% CI 0.005; 0.015, p < 0.0001]) and men (ß-coefficient 0.008 [95% CI 0.000; 0.015, p = 0.044]); per 1.0 g/kg/day increment in protein intake, independently of socio-demographics, dietary factors and physical activity. CONCLUSIONS: The current data have demonstrated that higher protein intakes are positively associated with BMD in both men and women. This indicates that higher protein intakes may be beneficial for both men and women.

Cardiovascular disease prevalence and risk factor prevalence in Type 2 diabetes: a contemporary analysis.

AIMS: To describe the prevalence of major cardiovascular disease (CVD) and risk factor control in a contemporary population with Type 2 diabetes. METHODS: We used data from the national registry in Scotland, Scottish Care Information-Diabetes, linked to hospital admissions. Using descriptive statistics and logistic regression we described associations of risk factors with CVD. CVD was defined based on diagnostic codes in primary or secondary care data for ischaemic heart disease, cerebrovascular disease peripheral arterial disease, heart failure, cardiac arrhythmia, hypertensive heart disease and revascularization procedures. RESULTS: Among 248 400 people with Type 2 diabetes with a median age of 67.5 years (IQR 58.2, 76.1) and median diabetes duration of 7.8 years (3.8, 13.0), 32% had prior CVD (35% of men, 29% of women). Median HbA1c overall was 55 mmol/mol (7.2%), median SBP was 132 mmHg, median total cholesterol was 4.1 mmol/l and mean BMI was 32 kg/m2 . Overall two-thirds (65% of men, 68% of women) have two or more of the following CVD risk factor thresholds: HbA1c ≥ 53 mmol/mol (7%), SBP > 130 mmHg or DBP > 80 mmHg, total cholesterol ≥ 5 mmol/l or BMI ≥ 30 kg/m2 , or were currently smoking. Overall 84% were taking anti-hypertensives and 75% a statin. Use of metformin was common at 58%, but other diabetes drugs that reduce CVD were rarely used. CONCLUSIONS: There continues to be a high prevalence of CVD among people with Type 2 diabetes and a high level of unmet need for risk factor control. This implies substantial scope for reducing the excess risk of CVD in diabetes through improved management of known risk factors.

Dulaglutide decreases plasma aminotransferases in people with Type 2 diabetes in a pattern consistent with liver fat reduction: a post hoc analysis of the AWARD programme.

AIMS: To evaluate the effects of dulaglutide vs placebo on liver and glycaemic/metabolic measurements in a population with Type 2 diabetes and in a subgroup with non-alcoholic fatty liver/non-alcoholic steatohepatitis. METHODS: A total of 1499 participants from AWARD-1, AWARD-5, AWARD-8 and AWARD-9 clinical trials were included in this analysis (dulaglutide 1.5 mg, n=971 and placebo, n=528). Thresholds of alanine aminotransferase levels ≥30 IU/l in men and ≥19 IU/l in women were used to determine the subgroup who had non-alcoholic fatty liver/non-alcoholic steatohepatitis. Objectives included changes from baseline to 6 months in: (1) alanine aminotransferase, aspartate transaminase and gamma-glutamyl transpeptidase levels in the overall population and (2) alanine aminotransferase, aspartate transaminase, gamma-glutamyl transpeptidase and glycaemic/metabolic measurements (e.g. HbA1c , fasting serum glucose, body weight, lipids and homeostatic model assessment) in the non-alcoholic fatty liver/non-alcoholic steatohepatitis subgroup. RESULTS: In the overall population at 6 months, dulaglutide significantly reduced alanine aminotransferase, aspartate transaminase and gamma-glutamyl transpeptidase levels vs placebo [least squares mean treatment differences: -1.7 IU/l (95% CI -2.8, -0.6), P=0.003; -1.1 IU/l (95% CI -2.1, -0.1), P=0.037; -6.6 IU/l (95% CI -12.4, -0.8), P=0.025, respectively]. In the subgroup with non-alcoholic fatty liver/non-alcoholic steatohepatitis (alanine aminotransferase levels greater than or equal to the upper limit of normal), mean baseline liver enzyme values were 38.0 IU/l, 27.8 IU/l and 43.9 IU/l for alanine aminotransferase, aspartate transaminase and gamma-glutamyl transpeptidase, respectively. In this population, more pronounced reductions from baseline in alanine aminotransferase were observed with dulaglutide vs placebo (-8.8 IU/l vs -6.7 IU/l). In the subgroup of people with alanine aminotransferase levels less than the upper limit of normal, changes from baseline in alanine aminotransferase did not significantly differ between treatment groups (0.0 IU/l vs 0.7 IU/l). CONCLUSIONS: Once-weekly dulaglutide improved alanine aminotransferase, aspartate transaminase and gamma-glutamyl transpeptidase levels compared with placebo in a pattern consistent with liver fat reductions. Our results add further weight to the notion that glucagon-like peptide-1 receptor agonists may provide benefit in lowering liver fat in addition to their other metabolic actions.

Cannabis use and risk of schizophrenia: a Mendelian randomization study.

Cannabis use is observationally associated with an increased risk of schizophrenia, but whether the relationship is causal is not known. Using a genetic approach, we took 10 independent genetic variants previously identified to associate with cannabis use in 32 330 individuals to determine the nature of the association between cannabis use and risk of schizophrenia. Genetic variants were employed as instruments to recapitulate a randomized controlled trial involving two groups (cannabis users vs nonusers) to estimate the causal effect of cannabis use on risk of schizophrenia in 34 241 cases and 45 604 controls from predominantly European descent. Genetically-derived estimates were compared with a meta-analysis of observational studies reporting ever use of cannabis and risk of schizophrenia or related disorders. Based on the genetic approach, use of cannabis was associated with increased risk of schizophrenia (odds ratio (OR) of schizophrenia for users vs nonusers of cannabis: 1.37; 95% confidence interval (CI), 1.09-1.67; P-value=0.007). The corresponding estimate from observational analysis was 1.43 (95% CI, 1.19-1.67; P-value for heterogeneity =0.76). The genetic markers did not show evidence of pleiotropic effects and accounting for tobacco exposure did not alter the association (OR of schizophrenia for users vs nonusers of cannabis, adjusted for ever vs never smoker: 1.41; 95% CI, 1.09-1.83). This adds to the substantial evidence base that has previously identified cannabis use to associate with increased risk of schizophrenia, by suggesting that the relationship is causal. Such robust evidence may inform public health messages about cannabis use, especially regarding its potential mental health consequences.

Large-scale pharmacogenomic study of sulfonylureas and the QT, JT and QRS intervals: CHARGE Pharmacogenomics Working Group.

Sulfonylureas, a commonly used class of medication used to treat type 2 diabetes, have been associated with an increased risk of cardiovascular disease. Their effects on QT interval duration and related electrocardiographic phenotypes are potential mechanisms for this adverse effect. In 11 ethnically diverse cohorts that included 71 857 European, African-American and Hispanic/Latino ancestry individuals with repeated measures of medication use and electrocardiogram (ECG) measurements, we conducted a pharmacogenomic genome-wide association study of sulfonylurea use and three ECG phenotypes: QT, JT and QRS intervals. In ancestry-specific meta-analyses, eight novel pharmacogenomic loci met the threshold for genome-wide significance (P<5 × 10-8), and a pharmacokinetic variant in CYP2C9 (rs1057910) that has been associated with sulfonylurea-related treatment effects and other adverse drug reactions in previous studies was replicated. Additional research is needed to replicate the novel findings and to understand their biological basis.

Incident ischaemic stroke and Type 2 diabetes: trends in incidence and case fatality in Scotland 2004-2013.

AIM: To describe trends in first ischaemic stroke incidence and case fatality in adults with and without a diagnosis of Type 2 diabetes prior to their ischaemic stroke event in Scotland between 2004 and 2013. METHODS: Using population-wide hospital admission, death and diabetes datasets, we conducted a retrospective cohort study. Negative binomial and logistic regression models were used to calculate year-specific incidence and case-fatality rates for people with Type 2 diabetes and for people without diabetes. RESULTS: During 41.0 million person-years of follow-up there were 69 757 ischaemic stroke events. Type 2 diabetes prevalence among patients who experienced ischaemic stroke increased from 13.5% to 20.3% between 2004 and 2013. Stroke incidence rates declined by 2.7% (95% CI 2.4, 3.0) annually for people with and without diabetes [diabetes/year interaction: rate ratio 0.99 (95% CI 0.98, 1.01)]. Type 2 diabetes was associated with an increased risk of ischaemic stroke in men [rate ratio 1.23 (95% CI 1.17, 1.30)] and women [rate ratio 1.41 (95% CI 1.35, 1.48)]. Case-fatality rates were 14.2% and 12.7% in people with Type 2 diabetes and without diabetes, respectively. Case fatality declined by 3.5% (95% CI 2.7, 4.5) annually [diabetes/year interaction: odds ratio 1.01 (95% CI 0.98, 1.02)]. CONCLUSIONS: Ischaemic stroke incidence declined no faster in people with a diagnosis of Type 2 diabetes than in people without diabetes. Increasing prevalence of Type 2 diabetes among stroke patients may mean that declines in case fatality over time will be less marked in the future.

Men across a range of ethnicities have a higher prevalence of diabetes: findings from a cross-sectional study of 500 000 UK Biobank participants.

AIMS: Studies show that white men have a higher prevalence of Type 2 diabetes mellitus than women at a given age and BMI, but equivalent standardized data for other ethnic groups in the UK are sparse. METHODS: This cross-sectional study analysed UK Biobank data from 489 079 participants to compare the prevalence of diabetes mellitus across four major ethnic groups including: 471 700 (96.4%) white, 7871 (1.6%) South Asian, 7974 (1.6%) black and 1534 (0.3%) Chinese participants, before and after standardizing for age, socio-economic status (SES), BMI and lifestyle factors including physical activity, TV viewing, fruit and vegetable intake, processed meat, red meat, oily fish, alcohol intake and smoking. A subgroup analysis of South Asians was also undertaken. RESULTS: Crude diabetes prevalence was higher in men across all four ethnicities. After standardizing for age, SES, BMI and lifestyle factors, a significant sex difference in diabetes prevalence persisted in white (men 6.0% vs. women 3.6%), South Asian (21.0% vs. 13.8%) and black individuals (13.3% vs. 9.7%) (P < 0.0001); there was a non-significant difference between Chinese men and women (7.1% vs. 5.5%) (P = 0.211). Sex differences persisted across South Asian subgroups. CONCLUSIONS: Men across a range of major ethnic groups including white, South Asian and black, have a higher prevalence of diabetes compared with women of similar age, BMI, SES and lifestyle in the UK.

The effects of remote ischaemic preconditioning on coronary artery function in patients with stable coronary artery disease.

BACKGROUND: Remote ischaemic preconditioning (RIPC) is a cardioprotective intervention invoking intermittent periods of ischaemia in a tissue or organ remote from the heart. The mechanisms of this effect are incompletely understood. We hypothesised that RIPC might enhance coronary vasodilatation by an endothelium-dependent mechanism. METHODS: We performed a prospective, randomised, sham-controlled, blinded clinical trial. Patients with stable coronary artery disease (CAD) undergoing elective invasive management were prospectively enrolled, and randomised to RIPC or sham (1:1) prior to angiography. Endothelial-dependent vasodilator function was assessed in a non-target coronary artery with intracoronary infusion of incremental acetylcholine doses (10-6, 10-5, 10-4mol/l). Venous blood was sampled pre- and post-RIPC or sham, and analysed for circulating markers of endothelial function. Coronary luminal diameter was assessed by quantitative coronary angiography. The primary outcome was the between-group difference in the mean percentage change in coronary luminal diameter following the maximal acetylcholine dose (Clinicaltrials.gov identifier: NCT02666235). RESULTS: 75 patients were enrolled. Following angiography, 60 patients (mean±SD age 57.5±8.5years; 80% male) were eligible and completed the protocol (n=30 RIPC, n=30 sham). The mean percentage change in coronary luminal diameter was -13.3±22.3% and -2.0±17.2% in the sham and RIPC groups respectively (difference 11.32%, 95%CI: 1.2- 21.4, p=0.032). This remained significant when age and sex were included as covariates (difference 11.01%, 95%CI: 1.01- 21.0, p=0.035). There were no between-group differences in endothelial-independent vasodilation, ECG parameters or circulating markers of endothelial function. CONCLUSIONS: RIPC attenuates the extent of vasoconstriction induced by intracoronary acetylcholine infusion. This endothelium-dependent mechanism may contribute to the cardioprotective effects of RIPC.