Adiposity and metabolic health in Asian populations: an epidemiological study using dual-energy x-ray absorptiometry in Singapore.

BACKGROUND: Type 2 diabetes, cardiovascular disease, and related cardiometabolic disturbances are increasing rapidly in the Asia-Pacific region. We investigated the contribution of excess adiposity, a key determinant of type 2 diabetes and cardiovascular risk, to unfavourable cardiometabolic profiles among Asian ethnic subgroups. METHODS: The Health for Life in Singapore (HELIOS) Study is a population-based cohort comprising multiethnic Asian men and women living in Singapore, aged 30-84 years. We performed a cross-sectional analysis of data from individuals who had assessment of body composition by dual-energy x-ray absorptiometry and metabolic characterisation. In a subset of participants on no medication for type 2 diabetes, hypertension, and hypercholesterolaemia, we tested the relationship of BMI and visceral fat mass index (vFMI) with cardiometabolic phenotypes (glycaemic indices, lipid levels, and blood pressure), disease outcomes (type 2 diabetes, hypercholesterolaemia, and hypertension), and metabolic syndrome score with multivariable regression analyses. FINDINGS: Between April 2, 2018, and Jan 28, 2022, 10 004 individuals consented to be part of the HELIOS cohort, of whom 9067 were included in the study (5404 [59·6%] female, 3663 [40·4%] male; 6224 [68·6%] Chinese, 1169 [12·9%] Malay, 1674 [18·5%] Indian; mean age 52·8 years [SD 11·8]). The prevalence of type 2 diabetes, hypercholesterolaemia, and hypertension was 8·2% (n=744), 27·2% (n=2469), and 18·0% (n=1630), respectively. Malay and Indian participants had 3-4-times higher odds of obesity and type 2 diabetes, and showed adverse metabolic and adiposity profiles, compared with Chinese participants. Excess adiposity was associated with adverse cardiometabolic health indices including type 2 diabetes (p<0·0001). However, while vFMI explained the differences in triglycerides and blood pressure between the Asian ethnic groups, increased vFMI did not explain higher glucose levels, reduced insulin sensitivity, and increased risk of type 2 diabetes among Indian participants. INTERPRETATION: Visceral adiposity is an independent risk factor for metabolic disease in Asian populations, and accounts for a large fraction of type 2 diabetes cases in each of the ethnic groups studied. However, the variation in insulin resistance and type 2 diabetes risk between Asian subgroups is not consistently explained by adiposity, indicating an important role for additional mechanisms underlying the susceptibility to cardiometabolic disease in Asian populations. FUNDING: Nanyang Technological University-the Lee Kong Chian School of Medicine, National Healthcare Group, and National Medical Research Council, Singapore.

Community Control of Hypertension and Diabetes (CoCo-HD) program in the Indian states of Kerala and Tamil Nadu: a study protocol for a type 3 hybrid trial.

INTRODUCTION: India grapples with a formidable health challenge, with an estimated 315 million adults afflicted with hypertension and 100 million living with diabetes mellitus. Alarming statistics reveal rates for poor treatment and control of hypertension and diabetes. In response to these pressing needs, the Community Control of Hypertension and Diabetes (CoCo-HD) program aims to implement structured lifestyle interventions at scale in the southern Indian states of Kerala and Tamil Nadu. AIMS: This research is designed to evaluate the implementation outcomes of peer support programs and community mobilisation strategies in overcoming barriers and maximising enablers for effective diabetes and hypertension prevention and control. Furthermore, it will identify contextual factors that influence intervention scalability and it will also evaluate the program's value and return on investment through economic evaluation. METHODS: The CoCo-HD program is underpinned by a longstanding collaborative effort, engaging stakeholders to co-design comprehensive solutions that will be scalable in the two states. This entails equipping community health workers with tailored training and fostering community engagement, with a primary focus on leveraging peer supportat scale in these communities. The evaluation will undertake a hybrid type III trial in, Kerala and Tamil Nadu states, guided by the Institute for Health Improvement framework. The evaluation framework is underpinned by the application of three frameworks, RE-AIM, Normalisation Process Theory, and the Consolidated Framework for Implementation Research. Evaluation metrics include clinical outcomes: diabetes and hypertension control rates, as well as behavioural, physical, and biochemical measurements and treatment adherence. DISCUSSION: The anticipated outcomes of this study hold immense promise, offering important learnings into effective scaling up of lifestyle interventions for hypertension and diabetes control in low- and middle-income countries (LMICs). By identifying effective implementation strategies and contextual determinants, this research has the potential to lead to important changes in healthcare delivery systems. CONCLUSIONS: The project will provide valuable evidence for the scaling-up of structured lifestyle interventions within the healthcare systems of Kerala and Tamil Nadu, thus facilitating their future adaptation to diverse settings in India and other LMICs.

Methylome-wide studies of six metabolic traits.

Exploring the molecular correlates of metabolic health measures may identify the shared and unique biological processes and pathways that they track. Here, we performed epigenome-wide association studies (EWASs) of six metabolic traits: body mass index (BMI), body fat percentage, waist-hip ratio (WHR), and blood-based measures of glucose, high-density lipoprotein (HDL) cholesterol, and total cholesterol. We considered blood-based DNA methylation (DNAm) from >750,000 CpG sites in over 17,000 volunteers from the Generation Scotland (GS) cohort. Linear regression analyses identified between 304 and 11,815 significant CpGs per trait at P<3.6×10-8, with 37 significant CpG sites across all six traits. Further, we performed a Bayesian EWAS that jointly models all CpGs simultaneously and conditionally on each other, as opposed to the marginal linear regression analyses. This identified between 3 and 27 CpGs with a posterior inclusion probability ≥ 0.95 across the six traits. Next, we used elastic net penalised regression to train epigenetic scores (EpiScores) of each trait in GS, which were then tested in the Lothian Birth Cohort 1936 (LBC1936; European ancestry) and Health for Life in Singapore (HELIOS; Indian-, Malay- and Chinese-ancestries). A maximum of 27.1% of the variance in BMI was explained by the BMI EpiScore in the subset of Malay-ancestry Singaporeans. Four metabolic EpiScores were associated with general cognitive function in LBC1936 in models adjusted for vascular risk factors (Standardised ßrange: 0.08 - 0.12, PFDR < 0.05). EpiScores of metabolic health are applicable across ancestries and can reflect differences in brain health.

Antithrombotic therapy after heart valve surgery: contemporary practice in the UK.

OBJECTIVES: There is a lack of high-quality data informing the optimal antithrombotic drug strategy following bioprosthetic heart valve replacement or valve repair. Disparity in recommendations from international guidelines reflects this. This study aimed to document current patterns of antithrombotic prescribing after heart valve surgery in the UK. METHODS: All UK consultant cardiac surgeons were e-mailed a custom-designed survey. The use of oral anticoagulant (OAC) and/or antiplatelet drugs following bioprosthetic aortic valve replacement or mitral valve replacement, or mitral valve repair (MVrep), for patients in sinus rhythm, without additional indications for antithrombotic medication, was assessed. Additionally, we evaluated anticoagulant choice following MVrep in patients with atrial fibrillation. RESULTS: We identified 260 UK consultant cardiac surgeons from 36 units, of whom 103 (40%) responded, with 33 units (92%) having at least 1 respondent. The greatest consensus was for patients undergoing bioprosthetic aortic valve replacement, in which 76% of surgeons favour initial antiplatelet therapy and 53% prescribe lifelong treatment. Only 8% recommend initial OAC. After bioprosthetic mitral valve replacement, 48% of surgeons use an initial OAC strategy (versus 42% antiplatelet), with 66% subsequently prescribing lifelong antiplatelet therapy. After MVrep, recommendations were lifelong antiplatelet agent alone (34%) or following 3 months OAC (20%), no antithrombotic agent (20%), or 3 months OAC (16%). After MVrep for patients with established atrial fibrillation, surgeons recommend warfarin (38%), a direct oral anticoagulant (37%) or have no preference between the 2 (25%). CONCLUSIONS: There is considerable variation in the use of antithrombotic drugs after heart valve surgery in the UK and a lack of high-quality evidence to guide practice, underscoring the need for randomized studies.

Blood-based epigenome-wide analyses of chronic low-grade inflammation across diverse population cohorts.

Chronic inflammation is a hallmark of age-related disease states. The effectiveness of inflammatory proteins including C-reactive protein (CRP) in assessing long-term inflammation is hindered by their phasic nature. DNA methylation (DNAm) signatures of CRP may act as more reliable markers of chronic inflammation. We show that inter-individual differences in DNAm capture 50% of the variance in circulating CRP (N = 17,936, Generation Scotland). We develop a series of DNAm predictors of CRP using state-of-the-art algorithms. An elastic-net-regression-based predictor outperformed competing methods and explained 18% of phenotypic variance in the Lothian Birth Cohort of 1936 (LBC1936) cohort, doubling that of existing DNAm predictors. DNAm predictors performed comparably in four additional test cohorts (Avon Longitudinal Study of Parents and Children, Health for Life in Singapore, Southall and Brent Revisited, and LBC1921), including for individuals of diverse genetic ancestry and different age groups. The best-performing predictor surpassed assay-measured CRP and a genetic score in its associations with 26 health outcomes. Our findings forge new avenues for assessing chronic low-grade inflammation in diverse populations.

Chimeric Antigen Receptor T-Cell Access in Patients with Relapsed/Refractory Large B-Cell Lymphoma: Association of Access with Social Determinants of Health and Travel Time to Treatment Centers.

Large B-cell lymphoma (LBCL) is the most common type of non-Hodgkin lymphoma. Chimeric antigen receptor T-cell (CAR T) therapy represents a novel treatment with curative potential for relapsed or refractory (R/R) LBCL, but there are access barriers to this innovative therapy that are not well-studied. Study objectives were: (1) Assess the impact of geographic factors and social determinants of health (SDOH) on access to treatment with CAR T in a sample of patients with R/R LBCL and ≥2 prior lines of therapy (LOT). (2) Compare and contrast patient characteristics, SDOH, and travel time between patients with R/R LBCL who received CAR T and those who did not. An observational, nested case-control study of patients with R/R LBCL, ≥2 prior LOT, not in a clinical trial, identified using 100% Medicare Fee-For-Service and national multi-payer claims databases. Patients were linked to near-neighborhood SDOH using 9-digit ZIP-code address. Driving distance and time between residence and nearest CAR T treatment center (TC) was calculated. Patients were stratified based on treatments received upon third LOT initiation (Index Date) or later: (1) received CAR T and (2) did not receive CAR T. Multivariable logistic regression was used to evaluate factors associated with CAR T. 5011 patients met inclusion criteria, with 628 (12.5%) in the CAR T group. Regression models found the likelihood of receiving CAR T decreased with patient age (odds ratio [OR] = .96, P < .001), and males were 29% more likely to receive CAR T (OR = 1.29, P = .02). Likelihood of CAR T increased with Charlson Comorbidity Index (CCI; OR = 1.07, P < .001) indicating patients with more comorbidities were more likely to receive CAR T. Black patients were less than half as likely to receive CAR T than White patients (OR = .44, P = .01). Asian patients did not significantly differ from White patients (OR = 1.43, P = .24), and there was a trend for Hispanic patients to have a slightly lower likelihood of CAR T (OR = .50, P = .07). Higher household income was associated with receipt of CAR T, with the lowest income group more than 50% less likely to receive CAR T than the highest (OR = .44, P = .002), and the second lowest income group more than 30% less likely (OR = .68, P = .02). Finally, likelihood of CAR T therapy was reduced when the driving time to the nearest TC was 121 to 240 minutes (reference group: ≤30 minutes; OR = .64, P = .04). Travel times between 31 and 121 or greater than 240 minutes were not significantly different from ≤30 minutes. Payer type was collinear with age and could not be included in the regression analysis, but patients with commercial insurance were 1.5 to 3 times more likely to receive CAR T than other payers on an unadjusted basis. We identified significant disparities in access to CAR T related to demographics and SDOH. Patients who were older, female, low income, or Black were less likely to receive CAR T. The positive association of CCI with CAR T requires further research. Given the promising outcomes of CAR T, there is urgent need to address identified disparities and increase efforts to overcome access barriers.

Recent Insights Into Native Valve Infective Endocarditis: JACC Focus Seminar 4/4.

This focused review highlights the latest issues in native valve infective endocarditis. Native valve disease moderately increases the risk of developing infective endocarditis. In 2023, new diagnostic criteria were published by the Duke-International Society of Cardiovascular Infectious Diseases group. New pathogens were designated as typical, and findings on computed tomography imaging were included as diagnostic criteria. It is now recognized that a multidisciplinary approach to care is vital, and the role of an "endocarditis team" is highlighted. Recent studies have suggested that a transition from intravenous to oral antibiotics in selected patients may be reasonable, and the role of long-acting antibiotics is discussed. It is also now clear that an aggressive surgical approach can be life-saving in some patients. Finally, results of several recent studies have suggested there is an association between dental and other invasive procedures and an increased risk of developing infective endocarditis. Moreover, data indicate that antibiotic prophylaxis may be effective in some scenarios.

Mechanistic basis for potassium efflux-driven activation of the human NLRP1 inflammasome.

Nigericin, an ionophore derived from Streptomyces hygroscopicus, is arguably the most commonly used tool compound to study the NLRP3 inflammasome. Recent findings, however, showed that nigericin also activates the NLRP1 inflammasome in human keratinocytes. In this study, we resolve the mechanistic basis of nigericin-driven NLRP1 inflammasome activation. In multiple nonhematopoietic cell types, nigericin rapidly and specifically inhibits the elongation stage of the ribosome cycle by depleting cytosolic potassium ions. This activates the ribotoxic stress response (RSR) sensor kinase ZAKα, p38, and JNK, as well as the hyperphosphorylation of the NLRP1 linker domain. As a result, nigericin-induced pyroptosis in human keratinocytes is blocked by extracellular potassium supplementation, ZAKα knockout, or pharmacologic inhibitors of ZAKα and p38 kinase activities. By surveying a panel of ionophores, we show that electroneutrality of ion movement is essential to activate ZAKα-driven RSR and a greater extent of K+ depletion is necessary to activate ZAKα-NLRP1 than NLRP3. These findings resolve the mechanism by which nigericin activates NLRP1 in nonhematopoietic cell types and demonstrate an unexpected connection between RSR, perturbations of potassium ion flux, and innate immunity.

Smokeless and combustible tobacco use among 148,944 South Asian adults: a cross-sectional study of South Asia Biobank.

INTRODUCTION: Tobacco use, in both smoking and smokeless forms, is highly prevalent among South Asian adults. The aims of the study were twofold: (1) describe patterns of SLT and combustible tobacco product use in four South Asian countries stratified by country and sex, and (2) assess the relationships between SLT and smoking intensity, smoking quit attempts, and smoking cessation among South Asian men. METHODS: Data were obtained from South Asia Biobank Study, collected between 2018 and 2022 from 148,944 men and women aged 18 years and above, living in Bangladesh, India, Pakistan, or Sri Lanka. Mixed effects multivariable logistic and linear regression were used to quantify the associations of SLT use with quit attempt, cessation, and intensity. RESULTS: Among the four South Asian countries, Bangladesh has the highest rates of current smoking (39.9% for male, 0.4% for female) and current SLT use (24.7% for male and 23.4% for female). Among male adults, ever SLT use was associated with a higher odds of smoking cessation in Bangladesh (OR, 2.88; 95% CI, 2.65, 3.13), India (OR, 2.02; 95% CI, 1.63, 2.50), and Sri Lanka (OR, 1.36; 95% CI, 1.14, 1.62). Ever SLT use and current SLT use was associated with lower smoking intensity in all countries. CONCLUSIONS: In this large population-based study of South Asian adults, rates of smoking and SLT use vary widely by country and gender. Men who use SLT products are more likely to abstain from smoking compared with those who do not.

Pain Assessment in Goat Kids: Focus on Disbudding.

Farm animals are routinely subjected to painful husbandry procedures for various purposes. Goat kids are disbudded to improve goat welfare and to ensure safety of other livestock, farm personnel, attending veterinarians and for various other production and managemental procedures. Disbudding is commonly performed on dairy goat farms, in kids under 3 weeks of age. Many scientific studies reported physiological and behavioural changes indicating pain and distress following disbudding, and this can be a significant cause of welfare compromise in goat kids. Recognition and measurement of pain is important to treat and/or manage pain and distress following painful procedures. This review focuses on pain assessment in goat kids following disbudding, using both physiological and behavioural measures. As only a limited information is available on the topic of interest, relevant studies in other young farm animals have also been discussed to compare the status quo in goat kids.

Enhancing care quality and accessibility through digital technology-supported decentralisation of hypertension and diabetes management: a proof-of-concept study in rural Bangladesh.

OBJECTIVE: The critical shortage of healthcare workers, particularly in rural areas, is a major barrier to quality care for non-communicable diseases (NCD) in low-income and middle-income countries. In this proof-of-concept study, we aimed to test a decentralised model for integrated diabetes and hypertension management in rural Bangladesh to improve accessibility and quality of care. DESIGN AND SETTING: The study is a single-cohort proof-of-concept study. The key interventions comprised shifting screening, routine monitoring and dispensing of medication refills from a doctor-managed subdistrict NCD clinic to non-physician health worker-managed village-level community clinics; a digital care coordination platform was developed for electronic health records, point-of-care support, referral and routine patient follow-up. The study was conducted in the Parbatipur subdistrict, Rangpur Division, Bangladesh. PARTICIPANTS: A total of 624 participants were enrolled in the study (mean (SD) age, 59.5 (12.0); 65.1% female). OUTCOMES: Changes in blood pressure and blood glucose control, patient retention and patient-visit volume at the NCD clinic and community clinics. RESULTS: The proportion of patients with uncontrolled blood pressure reduced from 60% at baseline to 26% at the third month of follow-up, a 56% (incidence rate ratio 0.44; 95% CI 0.33 to 0.57) reduction after adjustment for covariates. The proportion of patients with uncontrolled blood glucose decreased from 74% to 43% at the third month of follow-up. Attrition rates immediately after baseline and during the entire study period were 29.1% and 36.2%, respectively. CONCLUSION: The proof-of-concept study highlights the potential for involving lower-level primary care facilities and non-physician health workers to rapidly expand much-needed services to patients with hypertension and diabetes in Bangladesh and in similar global settings. Further investigations are needed to evaluate the effectiveness of decentralised hypertension and diabetes care.

Impact of gender, ethnicity and social deprivation on access to surgical or transcatheter aortic valve replacement in aortic stenosis: a retrospective database study in England.

OBJECTIVE: To assess gender, ethnicity, and deprivation-based differences in provision of aortic valve replacement (AVR) in England for adults with aortic stenosis (AS). METHODS: We retrospectively identified adults with AS from the English Hospital Episode Statistics (HES) between April 2016 and March 2019 and those who subsequently had an AVR. We separately used HES-linked Clinical Practice Research Datalink (CPRD) to identify people with AVR and evaluate the timeliness of their procedure (CPRD-AVR cohort). ORs for AVR in people with an AS diagnosis were estimated using multivariable logistic regression adjusted for age, region and comorbidity. AVR was considered timely if performed electively and without evidence of cardiac decompensation before AVR. RESULTS: 183 591 adults with AS were identified in HES; of these, 31 436 underwent AVR. The CPRD-AVR cohort comprised 10 069 adults. Women had lower odds of receiving AVR compared with men (OR 0.65; 95% CI 0.63 to 0.66); as did people of black (OR 0.70; 95% CI 0.60 to 0.82) or South Asian (OR 0.75; 95% CI 0.69 to 0.82) compared with people of white ethnicities. People in the most deprived areas were less likely to receive AVR than the least deprived areas (OR 0.8; 95% CI 0.75 to 0.86). Timely AVR occurred in 65% of those of white ethnicities compared with 55% of both those of black and South Asian ethnicities. 77% of the least deprived had a timely procedure compared with 58% of the most deprived; there was no gender difference. CONCLUSIONS: In this large, national dataset, female gender, black or South Asian ethnicities and high deprivation were associated with significantly reduced odds of receiving AVR in England. A lower proportion of people of minority ethnicities or high deprivation had a timely procedure. Public health initiatives may be required to increase clinician and public awareness of unconscious biases towards minority and vulnerable populations to ensure timely AVR for everyone.

Risk prediction models for type 2 diabetes using either fasting plasma glucose or HbA1c in Chinese, Malay, and Indians: Results from three multi-ethnic Singapore cohorts.

AIMS: To assess three well-established type 2 diabetes (T2D) risk prediction models based on fasting plasma glucose (FPG) in Chinese, Malays, and Indians, and to develop simplified risk models based on either FPG or HbA1c. METHODS: We used a prospective multiethnic Singapore cohort to evaluate the established models and develop simplified models. 6,217 participants without T2D at baseline were included, with an average follow-up duration of 8.3 years. The simplified risk models were validated in two independent multiethnic Singapore cohorts (N = 12,720). RESULTS: The established risk models had moderate-to-good discrimination (area under the receiver operating characteristic curves, AUCs 0.762 - 0.828) but a lack of fit (P-values < 0.05). Simplified risk models that included fewer predictors (age, BMI, systolic blood pressure, triglycerides, and HbA1c or FPG) showed good discrimination in all cohorts (AUCs ≥ 0.810), and sufficiently captured differences between the ethnic groups. While recalibration improved fit the simplified models in validation cohorts, there remained evidence of miscalibration in Chinese (p ≤ 0.012). CONCLUSIONS: Simplified risk models including HbA1c or FPG had good discrimination in predicting incidence of T2D in three major Asian ethnic groups. Risk functions with HbA1c performed as well as those with FPG.

Investigating causal relationships between obesity and skin barrier function in a multi-ethnic Asian general population cohort.

BACKGROUND: Skin diseases impact significantly on the quality of life and psychology of patients. Obesity has been observed as a risk factor for skin diseases. Skin epidermal barrier dysfunctions are typical manifestations across several dermatological disturbances. OBJECTIVES: We aim to establish the association between obesity and skin physiology measurements and investigate whether obesity may play a possible causal role on skin barrier dysfunction. METHODS: We investigated the relationship of obesity with skin physiology measurements, namely transepidermal water loss (TEWL), skin surface moisture and skin pH in an Asian population cohort (n = 9990). To assess for a possible causal association between body mass index (BMI) and skin physiology measurements, we performed Mendelian Randomization (MR), along with subsequent additional analyses to assess the potential causal impact of known socioeconomic and comorbidities of obesity on TEWL. RESULTS: Every 1 kg/m2 increase in BMI was associated with a 0.221% (95%CI: 0.144-0.298) increase in TEWL (P = 2.82E-08), a 0.336% (95%CI: 0.148-0.524) decrease in skin moisture (P = 4.66E-04) and a 0.184% (95%CI: 0.144-0.224) decrease in pH (P = 1.36E-19), adjusting for age, gender, and ethnicity. Relationships for both TEWL and pH with BMI remained strong (Beta 0.354; 95%CI: 0.189-0.520 and Beta -0.170; 95%CI: -0.253 to -0.087, respectively) even after adjusting for known confounders, with MR experiments further supporting BMI's possible causal relationship with TEWL. Based on additional MR performed, none of the socioeconomic and comorbidities of obesity investigated are likely to have possible causal relationships with TEWL. CONCLUSION: We establish strong association of BMI with TEWL and skin pH, with MR results suggestive of a possible causal relationship of obesity with TEWL. It emphasizes the potential impact of obesity on skin barrier function and therefore opportunity for primary prevention.

A five-safes approach to a secure and scalable genomics data repository.

Genomic researchers increasingly utilize commercial cloud service providers (CSPs) to manage data and analytics needs. CSPs allow researchers to grow Information Technology (IT) infrastructure on demand to overcome bottlenecks when combining large datasets. However, without adequate security controls, the risk of unauthorized access may be higher for data stored on the cloud. Additionally, regulators are mandating data access patterns and specific security protocols for the storage and use of genomic data. While CSP provides tools for security and regulatory compliance, building the necessary controls required for cloud solutions is not trivial. Research Assets Provisioning and Tracking Online Repository (RAPTOR) by the Genome Institute of Singapore is a cloud-native genomics data repository and analytics platform that implements a "five-safes" framework to provide security and governance controls to data contributors and users, leveraging CSP for sharing and analysis of genomic datasets without the risk of security breaches or running afoul of regulations.

Integrative genomic analyses in adipocytes implicate DNA methylation in human obesity and diabetes.

DNA methylation variations are prevalent in human obesity but evidence of a causative role in disease pathogenesis is limited. Here, we combine epigenome-wide association and integrative genomics to investigate the impact of adipocyte DNA methylation variations in human obesity. We discover extensive DNA methylation changes that are robustly associated with obesity (N = 190 samples, 691 loci in subcutaneous and 173 loci in visceral adipocytes, P < 1 × 10-7). We connect obesity-associated methylation variations to transcriptomic changes at >500 target genes, and identify putative methylation-transcription factor interactions. Through Mendelian Randomisation, we infer causal effects of methylation on obesity and obesity-induced metabolic disturbances at 59 independent loci. Targeted methylation sequencing, CRISPR-activation and gene silencing in adipocytes, further identifies regional methylation variations, underlying regulatory elements and novel cellular metabolic effects. Our results indicate DNA methylation is an important determinant of human obesity and its metabolic complications, and reveal mechanisms through which altered methylation may impact adipocyte functions.

Expert consensus recommendations for the provision of infective endocarditis services: updated guidance from the Joint British Societies.

Infective endocarditis (IE) remains a difficult condition to diagnose and treat and is an infection of high consequence for patients, causing long hospital stays, life-changing complications and high mortality. A new multidisciplinary, multiprofessional, British Society for Antimicrobial Chemotherapy (BSAC)-ledWorking Party was convened to undertake a focused systematical review of the literature and to update the previous BSAC guidelines relating delivery of services for patients with IE. A scoping exercise identified new questions concerning optimal delivery of care, and the systematic review identified 16 231 papers of which 20 met the inclusion criteria. Recommendations relating to endocarditis teams, infrastructure and support, endocarditis referral processes, patient follow-up and patient information, and governance are made as well as research recommendations. This is a report of a joint Working Party of the BSAC, British Cardiovascular Society, British Heart Valve Society, British Society of Echocardiography, Society of Cardiothoracic Surgeons of Great Britain and Ireland, British Congenital Cardiac Association and British Infection Association.

Adiposity impacts cognitive function in Asian populations: an epidemiological and Mendelian Randomization study.

Background: Obesity and related metabolic disturbances including diabetes, hypertension and hyperlipidemia predict future cognitive decline. Asia has a high prevalence of both obesity and metabolic disease, potentially amplifying the future burden of dementia in the region. We aimed to investigate the impact of adiposity and metabolic risk on cognitive function in Asian populations, using an epidemiological analysis and a two-sample Mendelian Randomization (MR) study. Methods: The Health for Life in Singapore (HELIOS) Study is a population-based cohort of South-East-Asian men and women in Singapore, aged 30-84 years. We analyzed 8769 participants with metabolic and cognitive data collected between 2018 and 2021. Whole-body fat mass was quantified with Dual X-Ray Absorptiometry (DEXA). Cognition was assessed using a computerized cognitive battery. An index of general cognition ' g ' was derived through factor analysis. We tested the relationship of fat mass indices and metabolic measures with ' g ' using regression approaches. We then performed inverse-variance-weighted MR of adiposity and metabolic risk factors on ' g ', using summary statistics for genome-wide association studies of BMI, visceral adipose tissue (VAT), waist-hip-ratio (WHR), blood pressure, HDL cholesterol, triglycerides, fasting glucose, HbA1c, and general cognition. Findings: Participants were 58.9% female, and aged 51.4 (11.3) years. In univariate analysis, all 29 adiposity and metabolic measures assessed were associated with ' g ' at P < 0.05. In multivariable analyses, reduced ' g ' was consistently associated with increased visceral fat mass index and lower HDL cholesterol (P < 0.001), but not with blood pressure, triglycerides, or glycemic indices. The reduction in ' g ' associated with 1SD higher visceral fat, or 1SD lower HDL cholesterol, was equivalent to a 0.7 and 0.9-year increase in chronological age respectively (P < 0.001). Inverse variance MR analyses showed that reduced ' g ' is associated with genetically determined elevation of VAT, BMI and WHR (all P < 0.001). In contrast, MR did not support a causal role for blood pressure, lipid, or glycemic indices on cognition. Interpretation: We show an independent relationship between adiposity and cognition in a multi-ethnic Asian population. MR analyses suggest that both visceral adiposity and raised BMI are likely to be causally linked to cognition. Our findings have important implications for preservation of cognitive health, including further motivation for action to reverse the rising burden of obesity in the Asia-Pacific region. Funding: The Nanyang Technological University-the Lee Kong Chian School of Medicine, National Healthcare Group, National Medical Research Council, Ministry of Education, Singapore.