DNAm scores for serum GDF15 and NT-proBNP levels associate with a range of traits affecting the body and brain.

BACKGROUND: Plasma growth differentiation factor 15 (GDF15) and N-terminal proB-type natriuretic peptide (NT-proBNP) are cardiovascular biomarkers that associate with a range of diseases. Epigenetic scores (EpiScores) for GDF15 and NT-proBNP may provide new routes for risk stratification. RESULTS: In the Generation Scotland cohort (N ≥ 16,963), GDF15 levels were associated with incident dementia, ischaemic stroke and type 2 diabetes, whereas NT-proBNP levels were associated with incident ischaemic heart disease, ischaemic stroke and type 2 diabetes (all PFDR < 0.05). Bayesian epigenome-wide association studies (EWAS) identified 12 and 4 DNA methylation (DNAm) CpG sites associated (Posterior Inclusion Probability [PIP] > 95%) with levels of GDF15 and NT-proBNP, respectively. EpiScores for GDF15 and NT-proBNP were trained in a subset of the population. The GDF15 EpiScore replicated protein associations with incident dementia, type 2 diabetes and ischaemic stroke in the Generation Scotland test set (hazard ratios (HR) range 1.36-1.41, PFDR < 0.05). The EpiScore for NT-proBNP replicated the protein association with type 2 diabetes, but failed to replicate an association with ischaemic stroke. EpiScores explained comparable variance in protein levels across both the Generation Scotland test set and the external LBC1936 test cohort (R2 range of 5.7-12.2%). In LBC1936, both EpiScores were associated with indicators of poorer brain health. Neither EpiScore was associated with incident dementia in the LBC1936 population. CONCLUSIONS: EpiScores for serum levels of GDF15 and Nt-proBNP associate with body and brain health traits. These EpiScores are provided as potential tools for disease risk stratification.

Social and Environmental Determinants of Health and Cardio-Kidney-Metabolic Syndrome-Related Mortality.

Importance: It is not well understood if and how various social and environmental determinants of health (SEDoH) are associated with mortality rates related to cardio-kidney-metabolic syndrome (CKM) across the US. Objective: To study the magnitude of the association strength of SEDoH with CKM-related mortality at the county level across the US. Design, Setting, and Participants: This cross-sectional, retrospective, population-based study used aggregate county-level data from the US Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research (WONDER) data portal from 2010-2019. Data analysis occurred from September 2023 to January 2024. Exposures: A total of 7 diverse SEDoH were chosen, including median annual household income, percentage of racial and ethnic minority residents per county, fine particulate air pollution (PM2.5) concentrations, high-school completion rate, primary health care access, food insecurity, and rurality rate. Main Outcomes and Measures: The primary outcome was county-level age-adjusted mortality rate (aaMR) attributable to CKM. The association of county-level CKM-related aaMR with the 7 SEDoH was analyzed using geographically weighted models and the model median coefficients for each covariate studied. Results: Data from 3101 of 3243 counties (95.6%) were analyzed. There was substantial variation in SEDoH between states and counties. The overall pooled median (IQR) aaMR (2010-2019) in the US was 505.5 (441.3-578.9) per 100 000 residents. Most counties in the lower half of the US had rates much higher than the pooled median (eg, Southern US median [IQR] aaMR, 537.3 [466.0-615.9] per 100 000 residents). CKM-related mortality was positively associated with the food insecurity rate (median [IQR] ß = 6.78 [2.78-11.56]) and PM2.5 concentrations (median [IQR] ß = 5.52 [-11.06 to 19.70]), while it was negatively associated with median annual household income (median [IQR] ß = -0.002 [-0.003 to -0.001]), rurality (median [IQR] ß = -0.32 [-0.67 to 0.02]), high school completion rate (median [IQR] ß = -1.89 [-4.54 to 0.10]), racial and ethnic minority rate (median [IQR] ß = -0.66 [-1.85 to 0.89]), and primary health care access rate (median [IQR] ß = -0.18 [-0.35 to 0.07]). Conclusions and Relevance: In this cross-sectional study of county-level data across the US, there were substantial geographical differences in the magnitude of the association of SEDoH with CKM-related aaMR. These findings may provide guidance for deciding local health care policy.

In which common chronic conditions can (or cannot) obesity and lifestyle factors explain higher concentrations of C-reactive protein?

AIM: Elevated C-reactive protein (CRP), a marker of inflammation, is common in many chronic conditions. We aimed to examine to what extent elevated CRP in chronic conditions could be explained by concurrent adiposity. MATERIALS AND METHODS: This cross-sectional study analysed UK Biobank data on 10 chronic conditions reported at baseline. Linear regression models explored the extent to which CRP concentrations were elevated in each condition, unadjusted; adjusted for sociodemographic confounders and lifestyle and body mass index (BMI) in a series of models; or adjusted for BMI and waist circumference together or for adiposity alone. RESULTS: After exclusion of participants with a potential acute infection at baseline, we tested the association in 292 772 UK Biobank participants. Linear regression showed that elevated CRP concentration was associated with all included conditions. After adjustment for sociodemographic confounders, lifestyle and BMI, chronic kidney disease, heart failure, liver disease, psoriasis, rheumatoid arthritis and chronic obstructive pulmonary disease were still associated with elevated CRP. In contrast, the association between prevalent diabetes, prior myocardial infarction (MI), hypertension and sleep apnoea and CRP could be mostly explained by adiposity alone. For example, the 42% higher CRP concentrations in diabetes compared to those without diabetes in the unadjusted model (lnCRP ß: 0.35; 95% confidence interval [CI]: 0.32-0.37, p < 0.001) were completely attenuated after adjustment for BMI (lnCRP ß: -0.07; 95% CI: -0.09-0.05, p < 0.001). CONCLUSIONS/INTERPRETATION: In diabetes, MI, hypertension and sleep apnoea and elevated CRP appears to be accounted for by the greater adiposity typically evident in these conditions. However, for the other conditions, systemic inflammation cannot be explained by excess adiposity alone.

Zibotentan in Microvascular Angina: A Randomized, Placebo-Controlled, Crossover Trial.

Background: Microvascular angina is associated with dysregulation of the endothelin system and impairments in myocardial blood flow, exercise capacity, and health-related quality of life. The G allele of the noncoding single nucleotide polymorphism RS9349379 enhances expression of the endothelin-1 gene (EDN1) in human vascular cells, potentially increasing circulating concentrations of Endothelin-1 (ET-1). Whether zibotentan, an oral ET-A receptor selective antagonist, is efficacious and safe for the treatment of microvascular angina is unknown. Methods: Patients with microvascular angina were enrolled in this double-blind, placebo-controlled, sequential crossover trial of zibotentan (10 mg daily for 12 weeks). The trial population was enriched to ensure a G allele frequency of 50% for the RS9349379 single nucleotide polymorphism. Participants and investigators were blinded to genotype. The primary outcome was treadmill exercise duration (seconds) using the Bruce protocol. The primary analysis estimated the mean within-participant difference in exercise duration after treatment with zibotentan versus placebo. Results: A total of 118 participants (mean ±SD; years of age 63.5 [9.2 ]; 71 [60.2% ] females; 25 [21.2% ] with diabetes) were randomized. Among 103 participants with complete data, the mean exercise duration with zibotentan treatment compared with placebo was not different (between-treatment difference, -4.26 seconds [95 ] CI, -19.60 to 11.06] P=0.5871). Secondary outcomes showed no improvement with zibotentan. Zibotentan reduced blood pressure and increased plasma concentrations of ET-1. Adverse events were more common with zibotentan (60.2%) compared with placebo (14.4%; P<0.001). Conclusions: Among patients with microvascular angina, short-term treatment with a relatively high dose (10 mg daily) of zibotentan was not beneficial. Target-related adverse effects were common.

Reaffirmation of Mechanistic Proteomic Signatures Accompanying SGLT2 Inhibition in Patients With Heart Failure: A Validation Cohort of the EMPEROR Program.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors exert a distinctive pattern of direct biological effects on the heart and kidney under experimental conditions, but the meaningfulness of these signatures for patients with heart failure has not been fully defined. OBJECTIVES: We performed the first mechanistic validation study of large-scale proteomics in a double-blind randomized trial of any treatment in patients with heart failure. METHODS: In a discovery cohort from the EMPEROR (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure and Reduced Ejection Fraction) program, we studied the effect of randomized treatment with placebo or empagliflozin on 1,283 circulating proteins in 1,134 patients with heart failure with a reduced or preserved ejection fraction. In a validation cohort, we expanded the number to 2,155 assessed proteins, which were measured in 1,120 EMPEROR participants who had not been studied previously. RESULTS: In the validation cohort, 25 proteins were the most differentially enriched by empagliflozin (ie, ≥15% between-group difference and false discovery rate <1% at 12 weeks with known effects on the heart or kidney): 1) 13 proteins promote autophagy and other cellular quality-control functions (IGFBP1, OTUB1, DNAJB1, DNAJC9, RBP2, IST1, HSPA8, H-FABP, FABP6, ATPIFI, TfR1, EPO, IGBP1); 2) 12 proteins enhance mitochondrial health and ATP production (UMtCK, TBCA, L-FABP, H-FABP, FABP5, FABP6, RBP2, IST1, HSPA8, ATPIFI, TfR1, EPO); 3) 7 proteins augment cellular iron mobilization or erythropoiesis (TfR1, EPO, IGBP1, ERMAP, UROD, ATPIF1, SNCA); 4) 3 proteins influence renal tubular sodium handling; and 5) 9 proteins have restorative effects in the heart or kidneys, with many proteins exerting effects in >1 domain. These biological signatures replicated those observed in our discovery cohort. When the threshold for a meaningful between-group difference was lowered to ≥10%, there were 58 additional differentially enriched proteins with actions on the heart and kidney, but the biological signatures remained the same. CONCLUSIONS: The replication of mechanistic signatures across discovery and validation cohorts closely aligns with the experimental effects of SGLT2 inhibitors. Thus, the actions of SGLT2 inhibitors-to promote autophagy, restore mitochondrial health and production of ATP, promote iron mobilization and erythropoiesis, influence renal tubular ion reabsorption, and normalize cardiac and renal structure and function-are likely to be relevant to patients with heart failure. (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction [EMPEROR-Preserved], NCT03057951; EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction [EMPEROR-Reduced], NCT03057977).

Preclinical modeling of metabolic syndrome to study the pleiotropic effects of novel antidiabetic therapy independent of obesity.

Cardiovascular-kidney-metabolic health reflects the interactions between metabolic risk factors, chronic kidney disease, and the cardiovascular system. A growing body of literature suggests that metabolic syndrome (MetS) in individuals of normal weight is associated with a high prevalence of cardiovascular diseases and an increased mortality. The aim of this study was to establish a non-invasive preclinical model of MetS in support of future research focusing on the effects of novel antidiabetic therapies beyond glucose reduction, independent of obesity. Eighteen healthy adult Beagle dogs were fed an isocaloric Western diet (WD) for ten weeks. Biospecimens were collected at baseline (BAS1) and after ten weeks of WD feeding (BAS2) for measurement of blood pressure (BP), serum chemistry, lipoprotein profiling, blood glucose, glucagon, insulin secretion, NT-proBNP, angiotensins, oxidative stress biomarkers, serum, urine, and fecal metabolomics. Differences between BAS1 and BAS2 were analyzed using non-parametric Wilcoxon signed-rank testing. The isocaloric WD model induced significant variations in several markers of MetS, including elevated BP, increased glucose concentrations, and reduced HDL-cholesterol. It also caused an increase in circulating NT-proBNP levels, a decrease in serum bicarbonate, and significant changes in general metabolism, lipids, and biogenic amines. Short-term, isocaloric feeding with a WD in dogs replicated key biological features of MetS while also causing low-grade metabolic acidosis and elevating natriuretic peptides. These findings support the use of the WD canine model for studying the metabolic effects of new antidiabetic therapies independent of obesity.

Rising to the challenge of cardio-renal-metabolic disease in the 21st century: Translating evidence into best clinical practice to prevent and manage atherosclerosis.

Rising rates of obesity-associated cardiometabolic disorders allied to ageing populations are driving increases in cardiovascular morbidity and mortality. These adverse trends present challenges for healthcare systems that are struggling to prevent and manage the burgeoning cardiometabolic nexus of multiple long-term conditions. While potent new medications and non-pharmacological interventions have ushered in a promising new therapeutic era, translating clinical trial data to real-world clinical practice is often suboptimal. Postgraduate training and narrowly focused clinical specialisations reflect the traditional siloed approach to managing cardiovascular-metabolic disease that appears increasingly outmoded in the 21st century. It is our contention that greater inter-disciplinary collaboration allied to increased awareness of the continuum of cardiometabolic disease should enable clinicians to address this global public health threat more effectively. With this aim in mind, we have established an International Cardiometabolic Working Group. It is our hope to stimulate the interest of clinicians and clinical researchers across a range of medical specialties who share the vision of better care for people living with cardiometabolic diseases.

N-terminal pro-B-type natriuretic peptide levels vary by ethnicity and are associated with insulin sensitivity after gestational diabetes mellitus.

BACKGROUND: Individuals of South Asian origin have a greater risk of cardiovascular disease after gestational diabetes mellitus (GDM) than European individuals. B-type natriuretic peptide (BNP) and the amino-terminal fragment of its prohormone (NT-proBNP) are commonly used for heart failure screening and diagnosis, but biologically BNP exerts several beneficial cardiovascular effects primarily by counteracting the renin-angiotensin-aldosterone-system. We asked whether ethnic differences in circulating NT-proBNP levels could be explained by the differences in cardiometabolic and inflammatory risk markers? METHODS: We examined 162 South Asian and 107 Nordic women in Norway 1-3 years after GDM with a clinical examination, fasting blood samples and an oral glucose tolerance test. We measured the levels of NT-proBNP, high-sensitivity cardiac troponin T, high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), leptin, adiponectin and markers of insulin sensitivity, such as the Matsuda insulin sensitivity index (ISI). Finally, we tried to identify which independent covariate best mediated the ethnic differences in NT-proBNP. RESULTS: The mean (SD) age was 35.3 (4.5) years, BMI 29.1 (6.0) kg/m2, waist-height ratio 0.60 (0.08) and 164 women (61%) had prediabetes/diabetes. Notably, South Asian women had lower levels of NT-proBNP than Nordic women in both the normoglycemic and prediabetes/diabetes groups (median (IQR) 26  (15-38)  vs. 42 (22-66) ng/L, p < 0.001). Higher NT-proBNP levels were associated with greater insulin sensitivity in both South Asian and Nordic women (p = 0.005 and p < 0.001). South Asian women had higher levels of hsCRP (median (IQR) 2.2 (1.1-4.4) vs. 1.2 (0.3-4.2) mg/L), IL-6 (2.3 (1.5-3.2) vs. 1.5 (1.5-2.5) pg/mL), leptin (1647 (1176-2480) vs. 1223 (876-2313) pmol/L), and lower adiponectin levels (7.2 (5.3-9.3) vs. 10.0 (7.2-13.5) mg/L) and Matsuda ISI (2.4 (1.7-3.7) vs. 4.2 (2.9-6.1), pall<0.01) than Nordic women. Even after adjusting for these differences, higher NT-proBNP levels remained associated with insulin sensitivity (22% higher NT-proBNP per SD Matsuda ISI, p = 0.015). Insulin sensitivity and adiponectin mediated 53% and 41% of the ethnic difference in NT-proBNP. CONCLUSIONS: NT-proBNP levels are lower in South Asian than in Nordic women after GDM. Lower NT-proBNP levels correlate with impaired insulin sensitivity. Lower NT-proBNP levels in South Asian women could, therefore, be attributed to impaired insulin sensitivity rather than total body fat.

Weight gain leads to greater adverse metabolic responses in South Asian compared with white European men: the GlasVEGAS study.

South Asians (SAs) develop type 2 diabetes at lower body mass index values than white Europeans (WEs). This basic human experimental study aimed to compare the metabolic consequences of weight gain in SA and WE men without overweight or obesity. Fourteen SAs and 21 WEs had assessments of body composition, metabolic responses to mixed-meal ingestion, cardiorespiratory fitness and physical activity, and a subcutaneous abdominal adipose tissue biopsy, before and after 4-6 weeks of overfeeding to induce 5-7% weight gain. Here we show that body mass index and whole-body adipose tissue volume increases similarly between ethnic groups, but SAs gain less lean tissue. SAs experience a substantially greater decrease in insulin sensitivity compared with WEs (38% versus 7% decrease, P = 0.009), have fewer small (37.1% versus 60.0%, P = 0.003) and more large (26.2% versus 9.1%, P = 0.005) adipocytes at baseline and have a smaller decrease in very small adipocytes with weight gain (-0.1% versus -1.9%, P < 0.0001). Ethnic differences in adipocyte morphology are associated with SA's greater adverse metabolic changes with weight gain. ClinicalTrials.gov registration: NCT02399423 .

Diet modifies the association between alcohol consumption and severe alcohol-related liver disease incidence.

It is elusive why some heavy drinkers progress to severe alcohol-related liver disease (ALD) while others do not. This study aimed to investigate if the association between alcohol consumption and severe ALD is modified by diet. This prospective study included 303,269 UK Biobank participants. Alcohol consumption and diet were self-reported. The diet score was created from 4 items selected using LASSO. Cox proportional hazard model showed that the diet score was monotonically associated with severe ALD risk, adjusted for sociodemographics, lifestyle factors, and alcohol consumption. Relative excess risk due to interaction analysis indicated that having a higher ALD diet score and a higher alcohol consumption simultaneously confers to 2.44 times (95% CI: 1.06-3.83) higher risk than the sum of excess risk of each factor. In this work, we show that people who have a poor diet might be more susceptible to severe ALD due to alcohol consumption.

Baseline Characteristics in the Remote Diet Intervention to REduce long-COVID Symptoms Trial (ReDIRECT).

Background: The persistence of symptoms for ≥12 weeks after a COVID-19 infection is known as Long COVID (LC), a condition with unclear pathophysiology and no proven treatments to date. Living with obesity is a risk factor for LC and has symptoms which may overlap with and aggravate LC. Methods: ReDIRECT is a remotely delivered trial assessing whether weight management can reduce LC symptoms. We recruited people with LC and BMI >27kg/m 2. The intervention was delivered remotely by dietitians, with online data collection (medical and dietary history, COVID-19 infection and vaccination, body composition, LC history/symptoms, blood pressure, quality of life, sociodemographic data). Participants self-selected the dominant LC symptoms they most wanted to improve from the intervention. Results: Participants (n=234) in England (64%) and Scotland (30%) were mainly women (85%) of white ethnicity (90%), with 13% living in the 20% most deprived areas, a mean age of 46 (SD10) years, and median BMI of 35kg/m 2 (IQR 32-40). Before starting the study, 30% reported more than one COVID-19 infection (82% confirmed with one or more positive tests). LC Diagnosis was mainly by GPs (71%), other healthcare professionals (9%), or self-diagnosed (21%). The median total number of symptoms was 6 (IQR 4-8). Self-selected dominant LC symptoms included fatigue (54%), breathlessness (16%), pain (12%), anxiety/depression (1%) and "other" (17%). At baseline, 82% were taking medication, 57% reported 1+ other medical conditions. Quality of life was poor; 20% were on long-term sick leave or reduced working hours. Most (92%) reported having gained weight since contracting COVID-19 (median weight change +11.5 kg, range -11.5 to +45.3 kg). Conclusions: Symptoms linked to LC and overweight are diverse and complex. Remote trial delivery enabled rapid recruitment across the UK yet certain groups (e.g. men and those from ethnic minority groups) were under-represented. Trial registration: ISRCTN registry ( ISRCTN12595520, 25/11/2021).

Long COVID (LC, symptoms lasting 12 weeks or more after a COVID-19 infection) is a poorly understood condition, with no proven treatments. Living with obesity increases the risk of developing LC; symptoms of obesity overlap and aggravate those of LC. The ReDIRECT study tests, in people living with both LC and overweight, whether weight management can reduce LC symptoms. The study involves total diet replacement (with porridge, soups and shakes) for 12 weeks and is delivered remotely, with dietitian support via internet and/or phone. Researchers collected all data via online forms (medical and diet history, COVID-19 infection and vaccination, weight, height, LC history and symptoms, blood pressure, quality of life, and other demographic data). Each participant selected the LC symptom they most wanted to see improve. Participants (n=234) lived across the UK, were mainly women (85%) of white ethnicity (90%), with 13% living in the 20% most deprived areas. Their average age was 46 years old with an average body mass index (BMI) of 35kg/m ². Diagnosis of LC was mainly by GPs (71%), other healthcare professionals (9%), or self-diagnosed (21%). Participants reported on average 6 symptoms each, identifying fatigue (54%), breathlessness (16%), pain (12%), anxiety/depression (1%) and "other" (17%) as the symptom they would most like to see improve. At the start of the study, most (82%) were taking medication, half (57%) reported 1+ other medical conditions. Quality of life was poor, and 20% were on long-term sick leave or reduced working hours. Most (92%) reported gaining weight since contracting COVID-19, on average +11.5 kg. The baseline characteristics of ReDIRECT study participants show that symptoms linked to LC and overweight are diverse and complex. The study being "remote" means that recruitment was rapid and across the UK, yet certain groups (e.g. men and those from ethnic minority groups) were under-represented.

Change in physical activity and its association with decline in kidney function: A UK Biobank-based cohort study.

BACKGROUND: Previous research on the association between physical activity (PA) and kidney function is inconsistent. The association between muscle mass and serum creatinine (SCr) may have implications for interpreting the effect of PA on estimated glomerular filtration rate (eGFR). Few studies have reported changes in physical activity and changes in kidney function. METHODS: A cohort study was constructed using the UK Biobank. Changes in physical activity were self-reported as metabolic equivalent task (MET) minutes/week. eGFR was calculated using SCr and cystatin C (CysC). Cox and nonlinear regressions with restricted cubic splines were applied to explore the association between changes in physical activity and rapid decline of kidney function (RDKF, eGFR annual decrease ≥3 mL/min/1.73 m2), and the annual change of eGFR. An exploratory analysis of cardiorespiratory fitness as the exposure was conducted. RESULTS: Among 11 757 participants, the median follow-up time was 4.4 years. Participants whose PA decreased by 1000 MET minutes/week at the follow-up assessment had a 2% reduction in risk of developing RDKFSCr (HR = 0.98, 95% CI: 0.96, 1.00). In contrast, a 1000 MET minutes/week increase in PA was associated with a 4% reduction in risk of developing RDKFCysC (HR = 0.96, 95% CI: 0.93, 0.99). A PA increase of 1000 MET minutes/week was associated with eGFRCysC annual increase of 0.04 mL/min/1.73 m2 (95% CI: 0.03, 0.06) but no significant changes in eGFRSCr. CONCLUSIONS: In this general population study, there are differing associations between changes in PA and changes in kidney function depending on the kidney biomarker used. Increasing PA is modestly associated with improving annual eGFRCysC and reduced risk of RDKF.

Association of glycaemic control with intraocular pressure in a large general population: Results from the UK Biobank.

AIM: To evaluate the association of glycated haemoglobin (HbA1c) and serum glucose with intraocular pressure (IOP) in a large UK general population. MATERIALS AND METHODS: Participants were selected from the UK Biobank, excluding those with eye conditions that may affect IOP. IOP was measured using an ocular response analyser. Goldmann-correlated IOP (IOPg) and corneal-compensated IOP (IOPcc) were outcomes of interest, and ocular hypertension was defined as left-eye IOPg or IOPcc > 21 mmHg. HbA1c and random (non-fasting) serum glucose were the exposures of interest. Multivariate restricted cubic spline models, as well as linear regression, were applied to explore the associations of interest. RESULTS: Among 68 806 participants (46.5% male), the mean age was 56.7 years. The mean (standard deviation) for IOPg was 15.7 (3.6) mmHg and 15.9 (3.6) mmHg for IOPcc. Occular hypertension was prevalent in 8055 participants (11.7%) and 4178 participants (6.1%) had diabetes. Those with diabetes had higher IOP and a higher prevalence of ocular hypertension. After adjustment for demographic and clinical variables, HbA1c was positively associated with IOP in participants with diabetes, but not in those without diabetes. For every 10-mmol/mol increase in HbA1c, IOPg increased by 0.20 mmHg (95% confidence interval [CI] 0.12, 0.28) and IOPcc by 0.15 mmHg (95% CI 0.07, 0.23); the odds of ocular hypertension was increased by 6% (95% CI 1.00, 1.13) in participants with diabetes. A borderline positive association between serum glucose and IOP was found only in participants without diabetes. CONCLUSIONS: Impaired glycaemic control was associated with elevated IOP and a possible risk of ocular hypertension among participants with diabetes but of normal ocular health.

The association between excess weight and COVID-19 outcomes: An umbrella review.

This umbrella review assessed the association between excess weight and COVID-19 outcomes. MEDLINE, PsycINFO, and CINAHL were systematically searched for reviews that assessed the association between excess weight and COVID-19 outcomes. A second-order meta-analysis was conducted on the available data for intensive care unit admission, invasive mechanical ventilation administration, disease severity, hospitalization, and mortality. The quality of included reviews was assessed using the AMSTAR-2 appraisal tool. In total, 52 systematic reviews were included, 49 of which included meta-analyses. The risk of severe outcomes (OR = 1.86; 95% CI: 1.70 to 2.05), intensive care unit admission (OR = 1.58; 95% CI: 1.45 to 1.72), invasive mechanical ventilation administration (OR = 1.70; 95% CI: 1.57 to 1.83), hospitalization (OR = 1.82; 95% CI: 1.61 to 2.05), and mortality (OR = 1.35; 95% CI: 1.24 to 1.48) following COVID-19 infection was significantly higher in individuals living with excess weight compared with those with a healthy weight. There was limited evidence available in the included reviews regarding the influence of moderating factors such as ethnicity, and the majority of included reviews were of poor quality. Obesity appears to represent an important modifiable pre-infection risk factor for severe COVID-19 outcomes, including death.

Trends in hospitalization for cardio-renal disease and mortality in people with type 1 diabetes in England, 2009-2019.

AIM: To assess mortality and complication trends in people with type 1 diabetes during the 11 years before the SARS-CoV2 pandemic (2009-2019). MATERIALS AND METHODS: Sequential cohorts of people in England with type 1 diabetes aged ≥20 years from the National Diabetes Audit (2006/2007 to 2016/2017) were analysed. Discretized Poisson regression models, adjusted for age, sex, ethnicity, socioeconomic deprivation and duration of diabetes, were used to calculate mortality and hospitalization rates. RESULTS: Demographic characteristics changed little; average diabetes duration increased. All-cause mortality was unchanged. Cardiovascular and kidney disease mortality declined. Mortality from respiratory disease, diabetes and dementia increased in younger people (aged 20-74 years) as did mortality from liver disease and dementia in the elderly (aged ≥75 years). Younger Asian and Black people had lower all-cause mortality than those of White ethnicity; elderly Mixed, Asian and Black people had lower all-cause mortality. People from more deprived areas had higher all-cause mortality. The deprivation gradient for mortality was steeper at younger ages. In younger people, rates of hospitalization increased for myocardial infarction, stroke, heart failure and kidney disease but only for kidney disease in the elderly. Rates of a composite measure of cardiovascular hospitalizations increased in younger people (rate ratio [RR] 1.07, 95% confidence interval [CI] 1.03-1.11) but declined in the elderly (RR 0.91, 95% CI 0.86-0.95). CONCLUSION: Between 2009 and 2019, hospitalizations for cardiovascular disease increased at younger ages (20-74 years) and hospitalizations for kidney disease increased at all ages, but mortality from cardiovascular and kidney disease declined. All-cause mortality rates were unchanged.

Tirzepatide and blood pressure reduction: stratified analyses of the SURMOUNT-1 randomised controlled trial.

BACKGROUND: Treating obesity may be a pathway to prevent and control hypertension. In the SURMOUNT-1 trial in people with obesity or overweight with weight-related complications, 72-week tirzepatide treatment led to clinically meaningful body weight and blood pressure reduction. Post hoc analyses were conducted to further explore the effects of tirzepatide on the pattern of blood pressure reduction and whether the effects were consistent across various subgroups. METHODS: The mixed effect for repeated measure model was used to compare changes in overall blood pressure, across demographic and clinical subgroups, baseline blood pressure subgroups and hypertension categories between SURMOUNT-1 participants randomised to treatment with tirzepatide and placebo. The association between weight changes and blood pressure and adverse events associated with low blood pressure were also evaluated by mediation analysis. RESULTS: Tirzepatide treatment was associated with a rapid decline in systolic and diastolic blood pressure over the first 24 weeks, followed by blood pressure stabilisation until the end of the observation period, resulting in a significant net reduction by 72 weeks of 6.8 mm Hg systolic and 4.2 mm Hg diastolic blood pressure versus placebo. Participants randomly assigned to any tirzepatide group were more likely than those assigned to placebo to have normal blood pressure at week 72 (58.0% vs 35.2%, respectively). The effects were broadly consistent across baseline blood pressure subgroups, shifting the blood pressure distribution curve to lower blood pressure levels. The mediation analysis indicated that weight loss explained 68% of the systolic and 71% of the diastolic blood pressure reduction. Low blood pressure adverse events were infrequent, but the rate was higher in the tirzepatide group. CONCLUSIONS: In these post hoc analyses, in participants with obesity or overweight, tirzepatide was associated with reduced blood pressure consistently across participant groups primarily via weight loss, with relatively few blood pressure-related adverse events. TRIAL REGISTRATION NUMBER: NCT04184622.

Reporting guidelines for precision medicine research of clinical relevance: the BePRECISE checklist.

Precision medicine should aspire to reduce error and improve accuracy in medical and health recommendations by comparison with contemporary practice, while maintaining safety and cost-effectiveness. The etiology, clinical manifestation and prognosis of diseases such as obesity, diabetes, cardiovascular disease, kidney disease and fatty liver disease are heterogeneous. Without standardized reporting, this heterogeneity, combined with the diversity of research tools used in precision medicine studies, makes comparisons across studies and implementation of the findings challenging. Specific recommendations for reporting precision medicine research do not currently exist. The BePRECISE (Better Precision-data Reporting of Evidence from Clinical Intervention Studies & Epidemiology) consortium, comprising 23 experts in precision medicine, cardiometabolic diseases, statistics, editorial and lived experience, conducted a scoping review and participated in a modified Delphi and nominal group technique process to develop guidelines for reporting precision medicine research. The BePRECISE checklist comprises 23 items organized into 5 sections that align with typical sections of a scientific publication. A specific section about health equity serves to encourage precision medicine research to be inclusive of individuals and communities that are traditionally under-represented in clinical research and/or underserved by health systems. Adoption of BePRECISE by investigators, reviewers and editors will facilitate and accelerate equitable clinical implementation of precision medicine.

Low thiamine status in adults following low-carbohydrate / ketogenic diets: a cross-sectional comparative study of micronutrient intake and status.

BACKGROUND: Low-carbohydrate diets (LCD) are popular for weight loss but lack evidence about micronutrient sufficiency in real-life use. This study assessed the intake and biochemical status of selected micronutrients in people voluntarily following LCDs. METHODS: A cross-sectional study was conducted (2018-20) among 98 adults recruited as self-reporting either LCD (n = 49) or diets not restricting carbohydrates (controls; n = 49). Diets were assessed using the 130-item EPIC-Norfolk food-frequency questionnaire. Red-blood-cell thiamine diphosphate (TDP) was measured for thiamine status using HPLC. Plasma magnesium, zinc, copper, and selenium were measured using inductively coupled plasma mass spectrometry. Between-group biomarker comparisons were conducted using ANCOVA and adjusted for age, sex, body mass index (BMI), and diabetes status. RESULTS: LCD-followers (26% male, median age 36 years, median BMI 24.2 kg/m2) reported adhering to LCDs for a median duration of 9 months (IQR 4-36). The most followed LCD type was 'their own variations of LCD' (30%), followed by ketogenic (23%), 'palaeolithic' (15%), and Atkins diets (8%). Among controls, 41% were male (median age 27 years, median BMI 23 kg/m2). Median macronutrient intakes for LCD vs control groups were carbohydrate 16%Energy (E) vs. 50%E; protein 25%E vs. 19%E; and fat 55%E vs 34%E (saturated fat 18%E vs. 11%E). Two-thirds of LCD followers (32/49) and half of the controls (24/49) reported some use of dietary supplements (p = 0.19). Among LCD-followers, assessing from food data only, 21 (43%) failed to meet the reference nutrient intake (RNI) for thiamine (vs.14% controls, p = 0.002). When thiamine from supplementation (single- or multivitamin) was included, there appeared to be no difference in thiamine intake between groups. Still, red-blood-cell TDP was lower in LCD-followers than controls (407 ± 91 vs. 633 ± 234 ng/gHb, p < 0.001). Three LCD-followers were thiamine-deficient (RBC thiamine < 275 ng/gHb) vs. one control. There were no significant differences in dietary intakes or plasma concentrations of magnesium, zinc, copper, and selenium between groups. CONCLUSIONS: Following LCDs is associated with lower thiamine intake and TDP status than diets without carbohydrate restriction, incompletely corrected by supplement use. These data, coupled with a lack of RCT evidence on body weight control, do not support recommending LCDs for weight management without appropriate guidance and diet supplementation.