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Abstract 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.

Abstract 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.

Abstract 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

Abstract Aims Patients with a reduced left ventricular ejection fraction (LVEF) following an acute myocardial infarction (MI) are at risk of progressive adverse cardiac remodelling that can lead to the development of heart failure and death. The early addition of a sodium‐glucose cotransporter 2 (SGLT2) inhibitor to standard treatment may delay or prevent progressive adverse remodelling in these patients. Methods and results EMpagliflozin to PREvent worSening of left ventricular volumes and Systolic function after Myocardial Infarction (EMPRESS‐MI) is a randomized, double‐blind, placebo‐controlled, multi‐centre trial designed to assess the effect of empagliflozin on cardiac remodelling evaluated using cardiovascular magnetic resonance (CMR) in 100 patients with left ventricular systolic dysfunction following MI. Eligible patients were those ≥12 h and ≤14 days following acute MI, with an LVEF

Healthcare commissioners and those making reimbursement decisions require data on the “natural history” of diseases to estimate quantities such as life expectancy and quality of life. However, such data are commonly acquired from unrepresentative sources like trial placebo arms or case series. We used Scottish Diabetes Research Network-National Diabetes Dataset to characterise life expectancy for people with type 2 diabetes mellitus (T2DM). Data from >99% of people with diabetes in Scotland are available from primary and secondary care (including from clinical investigations) and can be linked to hospital admission and death records for research purposes. As part of an MRC-funded (MR/T017112/1) systematic review and modelling study (PROSPERO registration CRD42020184174) building on work funded by the Chief Scientific Office for Scotland (CSO HIPS_17_26), we used these linked data to define a treatment-eligible population for three drug classes — SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors. Fitting a Gompertz model, we estimated life expectancy for this ‘treatment-eligible’ group. The treatment-eligible population, compared to the entire Scottish T2DM population, was younger (63.8 (12.1) vs. 66.7 (12.7) year-old), with larger proportions of men (60.6% vs. 56.2%), higher HbA1c levels (67.4 (13.1) vs. 60.2 (15.1) mmol/L), larger proportions prescribed metformin (69.2% vs 55.2%) and higher life expectancy at age 65 (in women 21 vs 19 years and in men 20 vs 18 years). Using linked data to define and characterise treatment-eligible populations is feasible and may impact decision models. These findings will be useful to those making resourcing decisions and future economic analyses.

Associations between obesity and health are unequivocal and coupled with a substantial body of evidence suggesting that associations are likely causal. These associations and the supporting causal evidence are useful, but hide both the inadequacies of the measures used to qualify obesity and the mechanisms that are responsible for the observable relationships. A challenge therefore remains to determine both the intermediate factors associated with obesity and the mechanisms responsible for connecting excess adiposity (the defining feature of obesity) and health. A growing collection of detailed measures including examples in genomics, proteomics, metabolomics, and the microbiome are now available, allowing a broad approach to characterising obesity and analysing the associations between excess adiposity and health—but to what extent do these associations also provide insight into mechanism? In this specialist review, the problems facing the analysis of obesity (and related measures) both as a disease and as a risk factor for many downstream health outcomes are explored. This review looks to shift focus away from mechanisms of obesity and towards a useful interpretation of mechanisms associated with obesity in the context of promising developments in causal epidemiology.

Abstract Background The associations between deprivation and illness trajectory after hospitalisation for coronavirus disease-19 (COVID-19) are uncertain. Methods A prospective, multicentre cohort study was conducted on post-COVID-19 patients, enrolled either in-hospital or shortly post-discharge. Two evaluations were carried out: an initial assessment and a follow-up at 28–60 days post-discharge. The study encompassed research blood tests, patient-reported outcome measures, and multisystem imaging (including chest computed tomography (CT) with pulmonary and coronary angiography, cardiovascular and renal magnetic resonance imaging). Primary and secondary outcomes were analysed in relation to socioeconomic status, using the Scottish Index of Multiple Deprivation (SIMD). The EQ-5D-5L, Brief Illness Perception Questionnaire (BIPQ), Patient Health Questionnaire-4 (PHQ-4) for Anxiety and Depression, and the Duke Activity Status Index (DASI) were used to assess health status. Results Of the 252 enrolled patients (mean age 55.0 ± 12.0 years; 40% female; 23% with diabetes), deprivation status was linked with increased BMI and diabetes prevalence. 186 (74%) returned for the follow-up. Within this group, findings indicated associations between deprivation and lung abnormalities (p = 0.0085), coronary artery disease (p = 0.0128), and renal inflammation (p = 0.0421). Furthermore, patients with higher deprivation exhibited worse scores in health-related quality of life (EQ-5D-5L, p = 0.0084), illness perception (BIPQ, p = 0.0004), anxiety and depression levels (PHQ-4, p = 0.0038), and diminished physical activity (DASI, p = 0.002). At the 3-month mark, those with greater deprivation showed a higher frequency of referrals to secondary care due to ongoing COVID-19 symptoms (p = 0.0438). However, clinical outcomes were not influenced by deprivation. Conclusions In a post-hospital COVID-19 population, socioeconomic deprivation was associated with impaired health status and secondary care episodes. Deprivation influences illness trajectory after COVID-19.

Background Pre-existing cardiovascular disease (CVD) or cardiovascular risk factors have been associated with an increased risk of complications following hospitalisation with COVID-19, but their impact on the rate of recovery following discharge is not known.Objectives To determine whether the rate of patient-perceived recovery following hospitalisation with COVID-19 was affected by the presence of CVD or cardiovascular risk factors.Methods In a multicentre prospective cohort study, patients were recruited following discharge from the hospital with COVID-19 undertaking two comprehensive assessments at 5 months and 12 months. Patients were stratified by the presence of either CVD or cardiovascular risk factors prior to hospitalisation with COVID-19 and compared with controls with neither. Full recovery was determined by the response to a patient-perceived evaluation of full recovery from COVID-19 in the context of physical, physiological and cognitive determinants of health.Results From a total population of 2545 patients (38.8% women), 472 (18.5%) and 1355 (53.2%) had CVD or cardiovascular risk factors, respectively. Compared with controls (n=718), patients with CVD and cardiovascular risk factors were older and more likely to have had severe COVID-19. Full recovery was significantly lower at 12 months in patients with CVD (adjusted OR (aOR) 0.62, 95% CI 0.43 to 0.89) and cardiovascular risk factors (aOR 0.66, 95% CI 0.50 to 0.86).Conclusion Patients with CVD or cardiovascular risk factors had a delayed recovery at 12 months following hospitalisation with COVID-19. Targeted interventions to reduce the impact of COVID-19 in patients with cardiovascular disease remain an unmet need.Trail registration number ISRCTN10980107.

Abstract Background An obesity paradox has been described in relation to adverse clinical outcomes (e.g., mortality) with lower body mass index (BMI). Aims We sought to evaluate the association between BMI and weight loss with long-term all-cause mortality in adult populations under the care of family physicians. Methods LIPIDOGRAM studies were conducted in primary care in Poland in 2004, 2006, and 2015 and enrolled a total of 45,615 patients. The LIPIDOGRAM Plus study included 1627 patients recruited in the LIPIDOGRAM 2004 and repeated measurements in 2006 edition. Patients were classified by BMI categories as underweight, normal weight, overweight and class I, II, or III (obesity). Follow-up data up to December 2021 were obtained from the Central Statistical Office. Differences in all-cause mortality were analyzed using Kaplan‒Meier and Cox regression analyses. Results Of 45,615 patients, 10,987 (24.1%) were normal weight, 320 (0.7%) were underweight, 19,134 (41.9%) were overweight, and 15,174 (33.2%) lived with obesity. Follow-up was available for 44,620 patients (97.8%, median duration 15.3 years, 61.7% females). In the crude analysis, long-term all-cause mortality was lowest for the normal-weight group (14%) compared with other categories. After adjusting for comorbidities, the highest risk of death was observed for the class III obesity and underweight categories (hazard ratio, HR 1.79, 95% CI [1.55–2.05] and HR 1.57, 95% CI [1.22–2.04]), respectively. The LIPIDOGRAM Plus analysis revealed that a decrease in body weight (by 5 and 10%) over 2 years was associated with a significantly increased risk of death during long-term follow-up—HR 1.45 (95% CI 1.05–2.02, p = 0.03) and HR 1.67 (95% CI 1.02–2.74, p

Abstract Thousands of proteins circulate in the bloodstream; identifying those which associate with weight and intervention-induced weight loss may help explain mechanisms of diseases associated with adiposity. We aimed to identify consistent protein signatures of weight loss across independent studies capturing changes in body mass index (BMI). We analysed proteomic data from studies implementing caloric restriction (Diabetes Remission Clinical trial) and bariatric surgery (By-Band-Sleeve), using SomaLogic and Olink Explore1536 technologies, respectively. Linear mixed models were used to estimate the effect of the interventions on circulating proteins. Twenty-three proteins were altered in a consistent direction after both bariatric surgery and caloric restriction, suggesting that these proteins are modulated by weight change, independent of intervention type. We also integrated Mendelian randomisation (MR) estimates of the effect of BMI on proteins measured by SomaLogic from a UK blood donor cohort as a third line of causal evidence. These MR estimates provided further corroborative evidence for a role of BMI in regulating the levels of six proteins including alcohol dehydrogenase-4, nogo receptor and interleukin-1 receptor antagonist protein. These results indicate the importance of triangulation in interrogating causal relationships; further study into the role of proteins modulated by weight in disease is now warranted.

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/m2. 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/m2 (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).

Summary: Background: Type 2 diabetes is associated with higher risk of several cancer types. However, the biological intermediates driving this relationship are not fully understood. As novel interventions for treating and managing type 2 diabetes become increasingly available, whether they also disrupt the pathways leading to increased cancer risk is currently unknown. We investigated the effect of a type 2 diabetes intervention, in the form of intentional weight loss, on circulating proteins associated with cancer risk to gain insight into potential mechanisms linking type 2 diabetes and adiposity with cancer development. Methods: Fasting serum samples from participants with diabetes enrolled in the Diabetes Remission Clinical Trial (DiRECT) receiving the Counterweight-Plus weight-loss programme (intervention, N = 117, mean weight-loss 10 kg, 46% diabetes remission) or best-practice care by guidelines (control, N = 143, mean weight-loss 1 kg, 4% diabetes remission) were subject to proteomic analysis using the Olink Oncology-II platform (48% of participants were female; 52% male). To identify proteins which may be altered by the weight-loss intervention, the difference in protein levels between groups at baseline and 1 year was examined using linear regression. Mendelian randomization (MR) was performed to extend these results to evaluate cancer risk and elucidate possible biological mechanisms linking type 2 diabetes and cancer development. MR analyses were conducted using independent datasets, including large cancer meta-analyses, UK Biobank, and FinnGen, to estimate potential causal relationships between proteins modified during intentional weight loss and the risk of colorectal, breast, endometrial, gallbladder, liver, and pancreatic cancers. Findings: Nine proteins were modified by the intervention: glycoprotein Nmb; furin; Wnt inhibitory factor 1; toll-like receptor 3; pancreatic prohormone; erb-b2 receptor tyrosine kinase 2; hepatocyte growth factor; endothelial cell specific molecule 1 and Ret proto-oncogene (Holm corrected P-value

Background Bariatric surgery is a common procedure worldwide for the treatment of severe obesity and associated comorbid conditions but there is a lack of evidence as to medium-term safety and effectiveness outcomes in a United Kingdom setting. Objective To establish the clinical outcomes and adverse events of different bariatric surgical procedures, their impact on quality of life and the effect on comorbidities. Design Prospective observational cohort study. Setting National Health Service secondary care and private practice in Scotland, United Kingdom. Participants Adults (age >16 years) undergoing their first bariatric surgery procedure. Main outcome measures Change in weight, hospital length of stay, readmission and reoperation rate, mortality, diabetes outcomes (HbA1c, medications), quality of life, anxiety, depression. Data sources Patient-reported outcome measures, hospital records, national electronic health records (Scottish Morbidity Record 01, Scottish Care Information Diabetes, National Records Scotland, Prescription Information System). Results Between December 2013 and February 2017, 548 eligible patients were approached and 445 participants were enrolled in the study. Of those, 335 had bariatric surgery and 1 withdrew from the study. Mean age was 46.0 (9.2) years, 74.7% were female and the median body mass index was 46.4 (42.4; 52.0) kg/m2. Weight was available for 128 participants at 3 years: mean change was −19.0% (±14.1) from the operation and −24.2% (±12.8) from the start of the preoperative weight-management programme. One hundred and thirty-nine (41.4%) participants were readmitted to hospital in the same or subsequent 35 months post surgery, 18 (5.4% of the operated cohort) had a reoperation or procedure considered to be related to bariatric surgery gastrointestinal complications or revisions. Fewer than five participants (

Abstract Background Post-COVID-19 syndromes have associated with female sex, but the pathophysiological basis is uncertain. Aim There are sex differences in myocardial inflammation identified using cardiac magnetic resonance (CMR) in post-COVID-19 patients, and in patient reported health outcomes following COVID-19 infection. Design This prospective study investigated the time-course of multiorgan injury in survivors of COVID-19 during convalescence. Methods Clinical information, blood biomarkers, and patient reported outcome measures were prospectively acquired at enrolment (visit 1) and 28–60 days post-discharge (visit 2). Chest computed tomography (CT) and CMR were performed at visit 2. Follow-up was carried out for serious adverse events, including death and rehospitalization. Results Sixty-nine (43%) of 159 patients recruited were female. During the index admission, females had a lower peak C-reactive protein (74 mg/l (21,163) versus 123 mg/l (70, 192) p = 0.008) and peak ferritin (229 μg/l (103, 551) versus 514 μg/l (228, 1122) p

Abstract Background The insulin-like growth factors (IGF) play a crucial role in regulating cellular proliferation, apoptosis, and key metabolic pathways. The ratio of IGF-1 to IGF binding protein-3 (IGFBP-3) is an important factor in determining IGF-1 bioactivity. We sought to investigate the association of IGF-1 and IGFBP-3 with cardio-renal outcomes among persons with type 2 diabetes. Methods Samples were available from 2627 individuals with type 2 diabetes and chronic kidney disease that were randomized to receive canagliflozin or placebo and were followed up for incident cardio-renal events. Primary outcome was defined as a composite of end-stage kidney disease, doubling of the serum creatinine level, or renal/cardiovascular death. IGF-1 and IGFBP-3 were measured at baseline, Year-1 and Year-3. Elevated IGF-1 level was defined according to age-specific cutoffs. Cox proportional hazard regression was used to investigate the association between IGF-1 level, IGFBP-3, and the ratio of IGF-1/IGFBP-3 with clinical outcomes. Results Elevated IGF-1 was associated with lower glomerular filtration rate at baseline. Treatment with canagliflozin did not significantly change IGF-1 and IGFBP-3 concentrations by 3 years (p-value > 0.05). In multivariable models, elevated IGF-1 (above vs below age-specific cutoffs) was associated with the primary composite outcome (incidence rate:17.8% vs. 12.7% with a hazard ratio [HR]: 1.52; 95% confidence interval CI 1.09–2.13;P: 0.01), renal composite outcome (HR: 1.65; 95% CI 1.14–2.41; P: 0.01), and all-cause mortality (HR: 1.52; 95% CI 1.00–2.32; P; 0.05). Elevations in log IGFBP-3 did not associate with any clinical outcomes. Increase in log IGF-1/IGFBP-3 ratio was also associated with a higher risk of the primary composite outcome (HR per unit increase: 1.57; 95% CI 1.09–2.26; P; 0.01). Conclusions These results further suggest potential importance of IGF biology in the risk for cardio-renal outcomes in type 2 diabetes. SGLT2 inhibition has no impact on the biology of IGF despite its significant influence on outcomes. Trial registration: CREDENCE; ClinicalTrials.gov Identifier: NCT02065791.

South Asians (SAs) have a higher risk of developing type 2 diabetes (T2D) than white Europeans, especially following gestational diabetes mellitus (GDM). Despite similar blood glucose levels post-GDM, SAs exhibit more insulin resistance (IR) than Nordics, though the underlying mechanisms are unclear. This study aimed to assess markers of adipose tissue (AT) IR and liver fat in SA and Nordic women post-GDM. A total of 179 SA and 108 Nordic women in Norway underwent oral glucose tolerance tests 1–3 years post-GDM. We measured metabolic markers and calculated the AT IR index and non-alcoholic fatty liver disease liver fat (NAFLD-LFS) scores. Results showed that normoglycaemic SAs had less non-esterified fatty acid (NEFA) suppression during the test, resembling prediabetes/T2D responses, and higher levels of plasma fetuin-A, CRP, and IL-6 but lower adiponectin, indicating AT inflammation. Furthermore, normoglycaemic SAs had higher NAFLD-LFS scores, lower insulin clearance, and higher peripheral insulin than Nordics, indicating increased AT IR, inflammation, and liver fat in SAs. Higher liver fat markers significantly contributed to the ethnic disparities in glucose metabolism, suggesting a key area for intervention to reduce T2D risk post-GDM in SAs.

Abstract Background Most studies investigating the association between physical activity (PA) and the risk of type 2 diabetes are derived from self-reported questionnaires, with limited evidence using device-based measurements. Therefore, this study aimed to investigate the dose–response relationship between device-measured PA and incident type 2 diabetes. Methods This prospective cohort study included 40,431 participants of the UK Biobank. Wrist-worn accelerometers were used to estimate total, light, moderate, vigorous and moderate-to-vigorous PA. The associations between PA and incident type 2 diabetes were analysed using Cox-proportional hazard models. The mediating role of body mass index (BMI) was tested under a causal counterfactual framework. Results The median follow-up period was 6.3 years (IQR: 5.7–6.8), with 591 participants developing type 2 diabetes. Compared to those achieving 600 min/week were at 49% (95% CI 62–32%), 62% (95% CI 71–50%) and 71% (95% CI 80–59%) lower risk of type 2 diabetes, respectively. For vigorous PA, compared to those achieving 75 min/week were at 38% (95% CI 48–33%), 48% (95% CI 64–23%) and 64% (95% CI 78–42%) lower type 2 diabetes risk, respectively. Twelve per cent and 20% of the associations between vigorous and moderate PA and type 2 diabetes were mediated by lower BMI, respectively. Conclusions PA has clear dose-response relationship with a lower risk of type 2 diabetes. Our findings support the current aerobic PA recommendations but suggest that additional PA beyond the recommendations is associated with even greater risk reduction. Trial registration The UK Biobank study was approved by the North West Multi-Centre Research Ethics Committee (Ref 11/NW/0382 on June 17, 2011).

Background We tested the potential of the Secondary Manifestations of Arterial Disease (SMART2) risk score for use in patients undergoing coronary artery bypass grafting. Methods and Results We conducted an external validation of the SMART2 score in a racially diverse high‐risk national cohort (2010–2019) that underwent isolated coronary artery bypass grafting. We calculated the preoperative SMART2 score and modeled the 5‐year major adverse cardiovascular event (cardiovascular mortality+myocardial infarction+stroke) incidence. We evaluated SMART2 score discrimination at 5 years using c‐statistic and calibration with observed/expected ratio and calibration plots. We analyzed the potential clinical benefit using decision curves. We repeated these analyses in clinical subgroups, diabetes, chronic kidney disease, and polyvascular disease, and separately in White and Black patients. In 27 443 (mean age, 65 years; 10% Black individuals) US veterans undergoing coronary artery bypass grafting (2010–2019) nationwide, the 5‐year major adverse cardiovascular event rate was 25%; 27% patients were in high predicted risk (>30% 5‐year major adverse cardiovascular events). SMART2 score discrimination (c‐statistic: 64) was comparable to the original study (c‐statistic: 67) and was best in patients with chronic kidney disease (c‐statistic: 66). However, it underpredicted major adverse cardiovascular event rates in the whole cohort (observed/expected ratio, 1.45) as well as in all studied subgroups. The SMART2 score performed better in White than Black patients. On decision curve analysis, the SMART2 score provides a net benefit over a wide range of risk thresholds. Conclusions The SMART2 model performs well in a racially diverse coronary artery bypass grafting cohort, with better predictive capabilities at the upper range of baseline risk, and can therefore be used to guide secondary preventive pharmacotherapy.

Background: The multisystem associations between baseline mental health status and coronavirus disease-19 (COVID)-19 illness trajectory are uncertain. Objectives: This article will investigate the associations between baseline mental health status and disease trajectory following COVID-19 hospitalization, which may have implications for practice and future research. Methods: The Chief Scientist Office Cardiovascular and Pulmonary Imaging in severe acute respiratory syndrome (SARS) COVID-19 study is a prospective, observational, multicenter, longitudinal, secondary care cohort study that assessed the time-course of multi-organ injury in posthospital survivors of COVID-19. Patients were assessed in-hospital, at 28–60 days after discharge and in the longer term using electronic health record linkage. Results: One hundred and fifty-two patients (mean ± standard deviation [SD] age 54.3 ± 11.8 years, 43% female, 40% most socio-economically deprived quintile, 33% history of mental health history) were enrolled and had mental health serially assessed using the Patient Health Questionnaire-4 (PHQ-4) questionnaire. Fifty-three (35%) had PHQ-4 score of 6–12 consistent with moderate-severe symptoms of anxiety or depression and this was associated with diagnostic criteria for myocarditis (P = 0.0498). Moderate-severe symptoms of anxiety or depression were positively associated with higher perception of illness, lower health-related quality of life (HRQoL), and poorer physical function. The mean (SD) duration of follow-up after hospital discharge was 428 (86) days (range, 290–627 days). PHQ-4 score was not associated with clinical outcomes at follow-up. Conclusions: In patients who have been hospitalized with COVID-19, moderate-severe symptoms of anxiety or depression were associated with myocarditis, worse HRQoL, higher perception of illness, and lower levels of physical function. Public Registration: ClinicalTrials.gov identifier is NCT04403607.

Abstract The association between type 2 diabetes (T2D) and the development of cardiac arrhythmias and conduction disturbances has not been extensively studied. Arrhythmia was defined as atrial fibrillation and flutter (AF/AFl), ventricular tachycardia (VT) and ventricular fibrillation (VF), and conduction abnormality as sinus node disease (SND), atrioventricular (AV) block or pacemaker implantation, and intraventricular conduction blocks (IVCB). Incidence rates and Cox regression were used to compare outcomes, and to assess optimal levels for cardiometabolic risk factors and risk associated with multifactorial risk factor control (i.e., HbA1c, LDL-C, systolic blood pressure (SBP), BMI and eGFR), between patients with versus without T2D. The analyses included data from 617,000 patients with T2D and 2,303,391 matched controls. Patients with diabetes and the general population demonstrated a gradual increase in rates for cardiac conduction abnormalities and virtually all age-groups for AF/AFI showed increased incidence during follow-up. For patients with versus without T2D, risks for cardiac arrhythmias were higher, including for AF/AFl (HR 1.17, 95% CI 1.16–1.18), the composite of SND, AV-block or pacemaker implantation (HR 1.40, 95% CI 1.37–1.43), IVCB (HR 1.23, 95% CI 1.18–1.28) and VT/VF (HR 1.08, 95% CI 1.04–1.13). For patients with T2D who had selected cardiometabolic risk factors within target ranges, compared with controls, risk of arrythmia and conduction abnormalities for T2D vs not were: AF/AFl (HR 1.09, 95% CI 1.05–1.14), the composite of SND, AV-block or pacemaker implantation (HR 1.06, 95% CI 0.94–1.18), IVCB (HR 0.80, 95% CI 0.60–0.98), and for VT/VF (HR 0.97, 95% CI 0.80–1.17). Cox models showed a linear risk increase for SBP and BMI, while eGFR showed a U-shaped association. Individuals with T2D had a higher risk of arrhythmias and conduction abnormalities than controls, but excess risk associated with T2D was virtually not evident among patients with T2D with all risk factors within target range. BMI, SBP and eGFR displayed significant associations with outcomes among patients with T2D.

Metabolic mechanisms underlying the heterogeneity of major adverse cardiovascular (CV) event (MACE) risk in individuals with type 2 diabetes mellitus (T2D) remain unclear. We hypothesized that circulating metabolites reflecting mitochondrial dysfunction predict incident MACE in T2D. Targeted mass-spectrometry profiling of 60 metabolites was performed on baseline plasma samples from the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS; discovery cohort) and Exenatide Study of Cardiovascular Event Lowering (EXSCEL; validation cohort) biomarker substudy cohorts. A principal components analysis metabolite factor comprising medium-chain acylcarnitines (MCACs) was associated with MACE in TECOS and validated in EXSCEL, with higher levels associated with higher MACE risk. Meta-analysis showed that long-chain acylcarnitines (LCACs) and dicarboxylacylcarnitines were also associated with MACE. Metabolites remained associated with MACE in multivariate models and favorably changed with exenatide therapy. A third cohort (Cardiac Catheterization Genetics [CATHGEN]) with T2D was assessed to determine whether these metabolites improved discriminative capability of multivariate models for MACE. Nine metabolites (MCACs and LCACs and 1 dicarboxylacylcarnitine) were associated with time to MACE in the CATHGEN cohort. Addition of these metabolites to clinical models minimally improved the discriminative capability for MACE but did significantly down reclassify risk. Thus, metabolites reporting on dysregulated mitochondrial fatty acid oxidation are present in higher levels in individuals with T2D who experience subsequent MACE. These biomarkers may improve CV risk prediction models, be therapy responsive, and highlight emerging risk mechanisms.

Objectives: The Remote Diet Intervention to Reduce Long COVID Symptoms Trial (ReDIRECT) evaluates whether the digitally delivered, evidence-based, cost-effective Counterweight-Plus weight management programme improves symptoms of Long COVID in people with overweight/obesity. Methods: Baseline randomised, non-blinded design with 240 participants allocated in a 1:1 ratio either to continue usual care or to add the remotely delivered Counterweight-Plus weight management programme, which includes a Counterweight dietitian supported delivery of 12 weeks total diet replacement, food reintroduction, and long-term weight loss maintenance. Randomisation is achieved by accessing a web-based randomisation system incorporated into the study web portal developed by a registered Clinical Trials Unit. We are using an innovative approach to outcome personalisation, with each participant selecting their most dominant Long COVID symptom as their primary outcome assessed at six months. Participants in the control arm enter the weight management programme after six months. We are recruiting participants from social media and existing networks (e.g., Long COVID Scotland groups), through newspaper advertisements and from primary care. Main inclusion criteria: people with Long COVID symptoms persisting > three months, aged 18 years or above, body mass index (BMI) above 27kg/m2 (>25kg/m2 for South Asians). The trial includes a process evaluation (involving qualitative interviews with participants and analysis of data on dose, fidelity and reach of the intervention) and economic evaluation (within-trial and long-term cost-utility analyses). Anticipated results: The recruitment for this study started in December 2021 and ended in July 2022. Project results are not yet available and will be shared via peer-reviewed publication once the six-months outcomes have been analysed. Trial registration: Current Controlled Trials ISRCTN12595520

Abstract Background Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.

Abstract Background Whether women’s physical function in mid-life is related to their reproductive age is not known. The objectives of this study were to examine and compare changes in physical function in women by reproductive age, measured as time since final menstrual period (FMP), and chronological age, and to explore associations with repeatedly assessed levels of reproductive hormones. Methods We used data from 2319 UK women with up to three repeated measurements of physical function (median length of follow up: 2 years), focusing on changes occurring in women experiencing a natural menopausal transition. The main outcome was a composite physical function score that incorporated assessments of strength (grip strength), balance (one-leg stand) and cardiorespiratory fitness (timed chair rises). Associations with time since FMP, age, and time-updated measures of anti-Müllerian hormone, follicle-stimulating hormone and luteinizing hormone were assessed by multilevel models and generalised estimating equations models adjusted for the underlying effects of chronological age and confounding by education, age at first birth and smoking. Results The results showed that, adjusted for these confounders, time since FMP (− 0.21 SD per 10 years, 95% CI − 0.37, − 0.06) and chronological age (− 0.31 SD per 10 years, 95% CI − 0.46, − 0.15) were inversely associated with the physical function composite score. Grip strength seemed to be the main contributor to the decline in the composite score by time since FMP. There was no strong evidence of associations between any of the three reproductive hormones and the composite score. Conclusions Physical function in women in mid-life declined with both chronological and reproductive age. The decline with reproductive age was independent of chronological age but did not seem to be driven by changes in reproductive hormones.

Abstract Background The type 2 diabetes risk after gestational diabetes mellitus (GDM) is twice as high in South Asian compared to European women. Current guidelines differ regarding which test to use as a screening-tool post-GDM. We aimed to identify ethnic differences in the prevalence rates and early predictors for actionable HbA1c (defined as prediabetes and diabetes) short time after GDM. Methods This cross-sectional study, enrolling South Asian and Nordic women 1–3 years after a diagnosis of GDM, was undertaken at three hospitals in Norway. We performed a clinical and laboratory evaluation including an oral glucose tolerance test (OGTT). Medical records were used to retrieve data during pregnancy. Prediabetes was classified with HbA1c alone or combined with OGTT glucose measurements according to the WHO, WHO-IEC, and ADA criteria (fasting plasma glucose (FPG) 6.1–6.9 mmol/L, FPG 6.1–6.9 mmol/L and/or HbA1c 42-47 mmol/mol (6.0-6.4%), and FPG 5.6–6.9 mmol/L and/or HbA1c 39-47 mmol/mol (5.7-6.4%)). Ethnic differences in prevalence and predictors of glucose deterioration were assed by χ 2 (Pearson) tests and logistic regression models. Results We included 163 South Asian and 108 Nordic women. Actionable HbA1c levels were highly prevalent and more so among South Asian than Nordic women (WHO-IEC-HbA1c: 25.8% vs. 6.5% (p ≤ 0.001), ADA-HbA1c: 58.3% vs. 22.2% (p ≤ 0.001)). Although adding OGTT-data gave higher combined prevalence rates of prediabetes and diabetes (WHO: 65.6% vs. 47.2% (p ≤ 0.05), WHO-IEC: 70.6% vs. 47.2% (p ≤ 0.001), ADA: 87.8% vs. 65.7% (p ≤ 0.001)), the excess risk in the South Asian women was best captured by the HbA1c. Important predictors for glucose deterioration after GDM were: South Asian ethnicity, GDM before the index pregnancy, use of glucose-lowering drugs in pregnancy, higher age, and higher in-pregnancy fasting glucose levels. Conclusions In women with GDM 1–3 year previously, we found high prevalence and significant ethnic differences in actionable ADA-HbA1c levels, with South Asian ethnicity, GDM before the index pregnancy, and the use of glucose-lowering drugs in pregnancy as the most important risk factors. This study reinforces the importance of annual screening—preferably with HbA1c measurements—to facilitate early intervention after GDM.

Abstract Background Women experience adverse changes in cardiovascular health in mid-life; whether the menopausal transition influences these remains strongly debated. The aim of this study was to examine associations of reproductive age (time since final menstrual period (FMP)) with change in carotid intima media thickness (CIMT) and cardiovascular risk factors and determine the role of chronological and reproductive age. Methods We used data from 1702 women from a pregnancy-based UK cohort who had up to four repeat cardiovascular health measures between mean age 51 (SD = 4.0) and 56 (SD = 3.6) years and experienced a natural menopause. Multilevel models were used to assess the relationship between cardiovascular measures and time since FMP (reproductive age), whilst adjusting for the underlying effects of chronological age and confounders (socioeconomic factors, body mass index, smoking, alcohol, parity, age at menarche). In addition, we looked at the relationship between cardiovascular measures by chronological age according to menopausal stages (pre-menopause, peri-menopause and post-menopause) using information from women who had and had not experienced menopause (N = 3892). Results There was no strong evidence that reproductive age was associated with CIMT (difference in mean 0.8 μm/year, 95% CI − 0.4, 2.1), whereas there was a strong positive association of chronological age (7.6 μm/year, 95% CI 6.3, 8.9). Consistent with this, we found weaker linear associations of reproductive compared with chronological age for atherosclerotic risk factors, such as with systolic blood pressure (− 0.1 mmHg/year, 95% CI − 0.3, 0.1, and 0.4 mmHg/year, 95% CI 0.2, 0.5, respectively) and non-HDL-cholesterol (0.02 mmol/l/year, 95% CI 0.005, 0.03, and 0.06, 95% CI 0.04, 0.07, respectively). In contrast, associations with fat mass (0.06 kg/m2/year, 95% CI 0.03, 0.10, and 0 kg/m2/year, 95% CI − 0.04, 0.04, respectively) and C-reactive protein (0.01, 95% CI 0.001, 0.02, and 0.01, 95% CI − 0.001, 0.02 natural logged mg/l/year, respectively) were stronger for reproductive compared with chronological age. Both reproductive and chronological age were (weakly) positively associated with glucose (0.002, 95% CI 0.0001, 0.003, and 0.002, 95% CI 0.0001, 0.003 natural logged mmol/l/year, respectively). Conclusions Our results suggest that going through the menopausal transition does not further increase women’s risk of atherosclerosis (measured by CIMT) beyond effects of ageing. Menopausal transition may, in additional to ageing, modestly increase adiposity and glucose levels and therefore a possible associated diabetes risk.

Background The association between common carotid artery intima‐media thickness (CCA‐IMT) and incident carotid plaque has not been characterized fully. We therefore aimed to precisely quantify the relationship between CCA‐IMT and carotid plaque development. Methods and Results We undertook an individual participant data meta‐analysis of 20 prospective studies from the Proof‐ATHERO (Prospective Studies of Atherosclerosis) consortium that recorded baseline CCA‐IMT and incident carotid plaque involving 21 494 individuals without a history of cardiovascular disease and without preexisting carotid plaque at baseline. Mean baseline age was 56 years (SD, 9 years), 55% were women, and mean baseline CCA‐IMT was 0.71 mm (SD, 0.17 mm). Over a median follow‐up of 5.9 years (5th–95th percentile, 1.9–19.0 years), 8278 individuals developed first‐ever carotid plaque. We combined study‐specific odds ratios (ORs) for incident carotid plaque using random‐effects meta‐analysis. Baseline CCA‐IMT was approximately log‐linearly associated with the odds of developing carotid plaque. The age‐, sex‐, and trial arm–adjusted OR for carotid plaque per SD higher baseline CCA‐IMT was 1.40 (95% CI, 1.31–1.50; I2=63.9%). The corresponding OR that was further adjusted for ethnicity, smoking, diabetes, body mass index, systolic blood pressure, low‐ and high‐density lipoprotein cholesterol, and lipid‐lowering and antihypertensive medication was 1.34 (95% CI, 1.24–1.45; I2=59.4%; 14 studies; 16 297 participants; 6381 incident plaques). We observed no significant effect modification across clinically relevant subgroups. Sensitivity analysis restricted to studies defining plaque as focal thickening yielded a comparable OR (1.38 [95% CI, 1.29–1.47]; I2=57.1%; 14 studies; 17 352 participants; 6991 incident plaques). Conclusions Our large‐scale individual participant data meta‐analysis demonstrated that CCA‐IMT is associated with the long‐term risk of developing first‐ever carotid plaque, independent of traditional cardiovascular risk factors.

Abstract Background To determine whether there were racial differences in short-term cardiometabolic responses to once-weekly exenatide (EQW) in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL). Methods EXSCEL enrolled 14,752 patients with type 2 diabetes (hemoglobin A1c (HbA1c) 6.5–10.0% [48–86 mmol/mol]) with or without cardiovascular disease who were randomized double-blind to EQW or placebo. Background glucose-lowering/other cardiovascular therapies were unaltered for 6 months post-randomization unless clinically essential, facilitating comparison of EQW-associated effects in 14,665 evaluable participants self-identifying as White (n = 11,113), Asian (n = 1444), Black (n = 870), or Other Race (n = 1,238. Placebo-adjusted 6 month absolute changes in cardiometabolic variables were assessed using generalized linear models. Results Mean 6-month placebo-adjusted HbA1c reductions were similar in the four groups (range 0.54–0.67% [5.9 to 7.3 mmol/mol], P = 0.11 for race×treatment interaction), with no significant difference in Asians (reference) versus other groups after covariate adjustment (all P ≥ 0.10). Six-month placebo-adjusted mean changes in systolic (−1.8 to 0.0 mmHg) and diastolic (0.2 to 1.2 mmHg) blood pressure, serum LDL (− 0.06 to 0.02 mmol/L) and HDL (0.00 to 0.01 mmol/L) cholesterol, and serum triglycerides (−0.1 to 0.0 mmol/L) were similar in the racial groups (P ≥ 0.19 for race×treatment interaction and all P ≥ 0.13 for comparisons of Asians with other races). Resting pulse rate increased more in Asians (4 beats/min) than in other groups (≤ 3 beats/min, P = 0.016 for race×treatment interaction and all P ≤ 0.050 for comparisons of Asians with other races). Conclusions Short-term cardiometabolic responses to EQW were similar in the main racial groups in EXSCEL, apart from a greater pulse rate increase in Asians. Trial registration: https://clinicaltrials.gov NCT01144338.

Abstract Background This study aimed to investigate the associations of grip strength with incidence and mortality from dementia and whether these associations differ by sociodemographic and lifestyle factors. Methods A total of 466 788 participants of the UK Biobank (median age 56.5 years, 54.5% women). The outcome was all‐cause dementia incidence and mortality and the exposure was grip strength. Grip strength was assessed using a Jamar J00105 hydraulic hand dynamometer. Results Excluding the first 2 years of follow‐up (landmark analysis), mean follow‐up was 9.1 years (inter‐quartile range: 8.3; 9.7) for incidence and 9.3 (inter‐quartile range: 8.7; 10.0) for mortality. During this time, 4087 participants developed dementia, and 1309 died from it. Lower grip strength was associated with a higher risk of dementia incidence and mortality independent of major confounding factors (P

Inflammation is associated with a variety of diseases. Here, the authors identify 266 genetic loci associated with C-reactive protein levels, a marker of inflammation, in >500,000 Europeans, along with associated pathways, clinical outcomes and potential causal associations with disease.

Abstract Background Ethnic differences in cardiovascular disease (CVD) risk have been known for decades, but a systematic exploration of how exposure and susceptibility to risk factors may contribute is lacking. This study aimed to investigate the potential impact of differential exposure and susceptibility between South Asian, Black, and White individuals. Methods This is a population-based prospective cohort study of UK Biobank participants with a median follow-up of 11.3 years. The association between ethnic group and CVD risk was studied. Additional risk factors were then adjusted to examine mediations. Moderation analysis was conducted to identify whether risk factors had a stronger association in the ethnic minority groups. Population attributable fractions were also calculated to quantify the relative contributions of risk factors for each ethnic group. Results When adjusted for only age and sex, there was a higher risk of CVD among South Asian (n=8815; HR [95% CI] 1.69 [1.59–1.79]) and Black (n=7526; HR [95% CI] 1.12 [1.03–1.22]) compared with White participants (n=434,809). The excess risk of Black participants was completely attenuated following adjustment for deprivation. Compared with White participants, the associations of BMI, triglycerides, and HbA1c with CVD were stronger in South Asians. Adiposity was attributable to the highest proportion of CVD regardless of ethnicity. Smoking had the second largest contribution to CVD among White and Black participants, and HbA1c among South Asian participants. Conclusions Adiposity is an important risk factor for CVD regardless of ethnicity. Ethnic inequalities in CVD incidence may be best tackled by targeting interventions according to ethnic differences in risk profiles.

Abstract In patients with heart failure (HF) who suffered in-hospital cardiac arrest (IHCA), little is known about the characteristics, survival and neurological outcome. We used the Swedish Registry of Cardiopulmonary Resuscitation to study this, including patients aged ≥ 18 years suffering IHCA (2008–2019), categorised as HF alone, HF with acute myocardial infarction (AMI), AMI alone, or other. Odds ratios (OR) for 30-day survival, trends in 30-day survival, and the implication of HF phenotype was studied. 6378 patients had HF alone, 2111 had HF with AMI, 4210 had AMI alone. Crude 5-year survival was 9.6% for HF alone, 12.9% for HF with AMI and 34.6% for AMI alone. The 5-year survival was 7.9% for patients with HF and left ventricular ejection fraction (LVEF) ≥ 50%, 15.4% for LVEF

Background We investigated the associations of healthcare worker status with multisystem illness trajectory in hospitalised post-COVID-19 individuals.Methods and results One hundred and sixty-eight patients were evaluated 28–60 days after the last episode of hospital care. Thirty-six (21%) were healthcare workers. Compared with non-healthcare workers, healthcare workers were of similar age (51.3 (8.7) years vs 55.0 (12.4) years; p=0.09) more often women (26 (72%) vs 48 (38%); p

Summary: Background: We aimed to assess whether a structured weight management programme incorporating a total diet replacement (TDR) (3–5 months ∼850 kcal/day formula diet) weight loss phase is acceptable to people of South Asian ethnicity and can achieve type 2 diabetes (T2D) remissions similarly to other populations. Methods: Adults of South Asian ethnicity, aged 18–65 years, with T2D for ≤4 years, and BMI 25–45 kg/m2 were recruited from primary care and social media, and randomised to commence TDR either immediately (iTDR), or delayed (dTDR) for 3–5 months as a usual care control arm during this period. Intervention effects were tested in randomised comparisons powered to detect significant weight loss, and in an expanded observational analysis to determine remission effect size, including both iTDR and dTDR groups. Acceptability in those recruited was explored by questionnaire and weight change. Trial registration: Current Controlled Trials, ISRCTN10720065. Date of Registration 27/09/2017. Findings: Twenty-five eligible individuals were recruited. Mean baseline (SD) age was 45.8 (11.1) years, weight 88.2 (13.7) kg, BMI 32.1 (3.8) kg/m2, HbA1c 60.4 (11.3) mmol/mol, liver fat by MRI 15.6 (9.4)%. In the RCT, mean(SD) weight change after TDR was −7.7 (7.2)% in the intervention group (n = 13), and −1.2 (1.4)% in the usual-care control group (n = 12) (p = 0.005), with T2D remission achieved by 5/13, compared to 0/12 respectively (p = 0.039). In the observational study, 23/25 started TDR and 19/23 participants completed the TDR phase. Median time spent in TDR was 105 days (IQR 77–134 days). T2D remission was achieved in 10/23 (43%), and weight changes were concordant with the RCT. Overall, 8/23 (35%) lost over 10% bodyweight. Absolute liver fat proportion near halved from 15.3% at the start of TDR to 8.6% (p 10% body weight, and the mechanism underpinning T2D remission appears similar, driven by weight change with loss of excess ectopic body-fat. Funding: We gratefully acknowledge funding for the MRI scans from the, Miss MJM Smith Trust (registered charity: SC040586). No other external funds were provided for this trial. NS is supported by the British Heart Foundation Research Excellence Award (RE/18/6/34217).

Abstract Background Infection with SARS-CoV-2 virus (COVID-19) impacts disadvantaged groups most. Lifestyle factors are also associated with adverse COVID-19 outcomes. To inform COVID-19 policy and interventions, we explored effect modification of socioeconomic-status (SES) on associations between lifestyle and COVID-19 outcomes. Methods Using data from UK-Biobank, a large prospective cohort of 502,536 participants aged 37–73 years recruited between 2006 and 2010, we assigned participants a lifestyle score comprising nine factors. Poisson regression models with penalised splines were used to analyse associations between lifestyle score, deprivation (Townsend), and COVID-19 mortality and severe COVID-19. Associations between each exposure and outcome were examined independently before participants were dichotomised by deprivation to examine exposures jointly. Models were adjusted for sociodemographic/health factors. Results Of 343,850 participants (mean age > 60 years) with complete data, 707 (0.21%) died from COVID-19 and 2506 (0.76%) had severe COVID-19. There was evidence of a nonlinear association between lifestyle score and COVID-19 mortality but limited evidence for nonlinearity between lifestyle score and severe COVID-19 and between deprivation and COVID-19 outcomes. Compared with low deprivation, participants in the high deprivation group had higher risk of COVID-19 outcomes across the lifestyle score. There was evidence for an additive interaction between lifestyle score and deprivation. Compared with participants with the healthiest lifestyle score in the low deprivation group, COVID-19 mortality risk ratios (95% CIs) for those with less healthy scores in low versus high deprivation groups were 5.09 (1.39–25.20) and 9.60 (4.70–21.44), respectively. Equivalent figures for severe COVID-19 were 5.17 (2.46–12.01) and 6.02 (4.72–7.71). Alternative SES measures produced similar results. Conclusions Unhealthy lifestyles are associated with higher risk of adverse COVID-19, but risks are highest in the most disadvantaged, suggesting an additive influence between SES and lifestyle. COVID-19 policy and interventions should consider both lifestyle and SES. The greatest public health benefit from lifestyle focussed COVID-19 policy and interventions is likely to be seen when greatest support for healthy living is provided to the most disadvantaged groups.

Abstract The aims of the current study, therefore, were to compare (1) free-living MPS and (2) muscle and metabolic adaptations to resistance exercise in South Asian and white European adults. Eighteen South Asian and 16 White European men were enrolled in the study. Free-living muscle protein synthesis was measured at baseline. Muscle strength, body composition, resting metabolic rate, VO2max and metabolic responses (insulin sensitivity) to a mixed meal were measured at baseline and following 12 weeks of resistance exercise training. Free-living muscle protein synthesis was not different between South Asians (1.48 ± 0.09%/day) and White Europeans (1.59 ± 0.15%/day) (p = 0.522). In response to resistance exercise training there were no differences, between South Asians and White Europeans, muscle mass, lower body strength or insulin sensitivity. However, there were differences between the ethnicities in response to resistance exercise training in body fat, resting carbohydrate and fat metabolism, blood pressure, VO2max and upper body strength with responses less favourable in South Asians. In this exploratory study there were no differences in muscle protein synthesis or anabolic and metabolic responses to resistance exercise, yet there were less favourable responses in several outcomes. These findings require further investigation.

Abstract Background Previous cohort studies have investigated the relationship between self-reported physical activity (PA) and dementia. Evidence from objective device-measured PA data is lacking. This study aimed to explore the association of device-measured PA with the risk of dementia incidence and common subtypes (Alzheimer’s disease [AD] and vascular dementia) using the UK Biobank study. Methods 84,854 participants (55.8% women), invited to participate in the device-measured PA between 2013 and 2015, were included in this prospective cohort study. Wrist accelerometers were used to measure light, moderate, vigorous, moderate-to-vigorous PA (MVPA) and total PA intensity and duration (MET/min/week). Incident dementia (fatal and non-fatal) was extracted from hospital episodes records for incidence and death register for mortality. Incidence follow-up was carried out until the end of March 2021in England and Scotland and the end of March 2018 in Wales. Mortality data were available until February 2021. Nonlinear associations were first investigated using penalised cubic splines fitted in the Cox proportional hazard models. In addition, using MVPA, five categories were created. Associations of these categories with the outcomes were investigated using Cox proportional hazard models. Analyses were adjusted for sociodemographic, lifestyle and health-related factors. Results After a median follow-up of 6.3 years, 678 individuals were diagnosed with dementia. Evidence of nonlinearity was observed for all PA modes and all-cause dementia. For categories of MVPA, there was a significant trend towards a low risk of overall dementia when higher levels of MVPA were achieved (HRtrend 0.66 [95% CI 0.62 to 0.70]. The lowest risk was identified in individuals who performed more than 1200 MET/min/week, those who had 84% (95% CI 0.12 to 0.21) lower risk of incident dementia compared to those who performed

Abstract Background Increased physical activity (PA), reduced time spent sedentary (SED), healthier diet and reduced body weight may all have a positive impact on cardiometabolic risk. The relative importance of change in each of these variables on cardiometabolic risk, however, is unclear. We therefore sought to investigate the relative contributions of changes in PA, SED, diet and body weight on cardiometabolic risk. Methods This is a secondary analysis of data collected from the EuroFIT randomised controlled trial, which was a 12-week group-based lifestyle intervention for overweight middle-aged men delivered by coaches in football club stadia aiming to improve PA, SED, diet, and body weight. PA and SED were assessed by accelerometry, diet using the Dietary Instrument for Nutrition Education (DINE). An overall cardiometabolic risk score was derived from combining z-scores for glucose, HbA1c, insulin, lipids and blood pressure. In total, 707 men (from the overall cohort of 1113) with complete data for these variables at baseline and 12-month follow-up were included in the multivariable linear regression analyses. Results In multivariable analyses, change in number of steps (explaining 5.1% of R2) and dietary factors (less alcohol, fatty and sugary food, and more fruit and vegetables) (together explaining 4.5% of R2), but not changes in standing time or SED, were significantly associated with change in body weight. Changes in number of steps (R2 = 1.7%), fatty food score (R2 = 2.4%), and sugary food score (R2 = 0.4%) were significantly associated with change in cardiometabolic risk score in univariable models. However, in multivariable models which included changes in weight as well as changes in steps and dietary variables, change in weight explained a substantially larger proportion of the change in cardiometabolic risk score, explaining 14.1% of R2 (out of an overall model R2 of 19.0%). When baseline (as well as change) values were also included in the model, 38.8% of R2 for change in cardiometabolic risk score was explained overall, with 14.1% of R2 still explained by change in weight. Conclusion Change in body weight, together with baseline cardiometabolic risk explained most of the change in cardiometabolic risk. Thus, the benefits of increasing physical activity and improving diet on cardiometabolic risk appear to act largely via an effect on changes in body weight. Trial registration International Standard Randomised Controlled Trials, ISRCTN-81935608. Registered 06052015. https://www.isrctn.com/ISRCTN81935608?q=&filters=recruitmentCountry:Portugal&sort=&offset=7&totalResults=92&page=1&pageSize=10&searchType=basic-search

Abstract Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome‐wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow‐up following heart failure diagnosis ranged from 2 to 116 months. Forty‐nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34–90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low‐frequency variants (allele frequency 0.01–0.05) at P

Introduction By applying on two-sample Mendelian randomization and systematic review and meta-analysis we investigated the association between caffeine and coffee intake with prevalent CKD and markers of renal function. Material and methods For the individual data analysis we analysed the NHANES data on renal function markers and caffeine intake. MR was implemented by using summary-level data from the largest ever GWAS conducted on coffee intake (N=91,462) and kidney function. Results Finally, we included the data of 18,436 participants, 6.9% had prevalent CKD (based on eGFR). Caffeine intake for general population was 131.1±1.1 mg. The percentage of participants with CKD, by caffeine quartile was 16.6% in the first (lowest) quartile, 13.9% in the second, 12.2% in the third and 11.0% in the top quartile (p 0.234). In fully adjusted logistic regression models, there was no significant difference in chances of CKD prevalence (p-trend=0.745). In the same line, results of MR showed no impact of coffee intake on CKD (IVW=β: -0.0191, SE: 0.069, p=0.781), on eGFR (overall= IVW= β: -0.0005, SE: 0.005, p=0.926) both in diabetic (IVW= β: -0.006, SE: 0.009, p=0.478), and non-diabetic patients (IVW= β: -6.772, SE: 0.006, p=0.991). Results from the meta-analysis indicted that coffee consumption was not significantly associated with CKD (OR: 0.85, 95%CI 0.71-1.02, p=0.090, n=6 studies, I2=0.32). Conclusions By implementing on different strategies, we have highlighted no significant association between coffee consumption with renal function and chance of CKD.

Abstract Background Observational studies suggest interconnections between thyroid status, metabolism, and risk of coronary artery disease (CAD), but causality remains to be proven. The present study aimed to investigate the potential causal relationship between thyroid status and cardiovascular disease and to characterize the metabolomic profile associated with thyroid status. Methods Multi-cohort two-sample Mendelian randomization (MR) was performed utilizing genome-wide significant variants as instruments for standardized thyrotropin (TSH) and free thyroxine (fT4) within the reference range. Associations between TSH and fT4 and metabolic profile were investigated in a two-stage manner: associations between TSH and fT4 and the full panel of 161 metabolomic markers were first assessed hypothesis-free, then directional consistency was assessed through Mendelian randomization, another metabolic profile platform, and in individuals with biochemically defined thyroid dysfunction. Results Circulating TSH was associated with 52/161 metabolomic markers, and fT4 levels were associated with 21/161 metabolomic markers among 9432 euthyroid individuals (median age varied from 23.0 to 75.4 years, 54.5% women). Positive associations between circulating TSH levels and concentrations of very low-density lipoprotein subclasses and components, triglycerides, and triglyceride content of lipoproteins were directionally consistent across the multivariable regression, MR, metabolomic platforms, and for individuals with hypo- and hyperthyroidism. Associations with fT4 levels inversely reflected those observed with TSH. Among 91,810 CAD cases and 656,091 controls of European ancestry, per 1-SD increase of genetically determined TSH concentration risk of CAD increased slightly, but not significantly, with an OR of 1.03 (95% CI 0.99–1.07; p value 0.16), whereas higher genetically determined fT4 levels were not associated with CAD risk (OR 1.00 per SD increase of fT4; 95% CI 0.96–1.04; p value 0.59). Conclusions Lower thyroid status leads to an unfavorable lipid profile and a somewhat increased cardiovascular disease risk.

Abstract Background Sarcopenia often co‐occurs with osteoporosis in cross‐sectional studies. However, this association has rarely been studied in prospective studies. This study aimed to investigate the association between sarcopenia categories—along with its individual components—and incident osteoporosis in both middle‐aged and older men and women from the UK Biobank study. Methods A total of 168,682 participants (48.8% women, aged 37 to 70 years at baseline) were included in this prospective study. Categories of sarcopenia (pre‐sarcopenia and sarcopenia), and its individual components, were defined according to the EWGSOP2 criteria (2019). Associations with incident osteoporosis by sex were investigated using Cox‐proportional hazard models adjusted for socio‐demographic, lifestyle and health‐related factors, and morbidity count. Associations between categories of sarcopenia and incident osteoporosis were also investigated by age‐groups and subtype of osteoporosis (with and without pathological fractures). Results After a median follow‐up of 7.4 years, 6296 participants were diagnosed with osteoporosis. When the analyses were adjusted for a range of relevant confounding factors, pre‐sarcopenia was associated with 1.3‐times higher risk of osteoporosis in men (HR: 1.30 [95% CI: 1.03 to 1.63]) but not in women, and sarcopenia was associated with 1.66‐times increased osteoporosis risk in women (HR: 1.66 [95% CI: 1.33 to 2.08]) but not in men compared with people without sarcopenia or pre‐sarcopenia. A similar magnitude of associations was found in osteoporosis without pathological fractures but weaker for those with pathological fractures. Within the individual components, low muscle mass (HRwomen: 1.36 [95% CI: 1.22 to 1.51] and HRmen: 3.07 [95% CI: 1.68 to 5.59]), followed by slow gait speed (HRwomen: 1.30 [95% CI: 1.17 to 1.45] and HRmen: 1.70 [95% CI: 1.43 to 2.02]), were associated with a higher risk of incident osteoporosis in both sexes. Low grip strength was associated with a higher risk of incident osteoporosis in men (HR: 1.38 [95% CI: 1.15 to 1.65]), but not in women. No significant interaction between the exposures and incident osteoporosis by age groups were identified. Conclusions Our findings demonstrated that pre‐sarcopenic men and sarcopenic women had a higher risk of developing osteoporosis even after adjustment for a large range of potential confounders. Considering that sarcopenia could be prevented, health interventions to improve physical capability may delay or prevent the onset of osteoporosis.

Objective To assess the independent association of maternal lipid levels with birth weight and cord blood insulin (CBI) level.Setting The Born in Guangzhou Cohort Study, Guangzhou, China.Participants Women who delivered between January 2015 and June 2016 and with umbilical cord blood retained were eligible for this study. Those with prepregnancy health conditions, without an available fasting blood sample in the second trimester, or without demographic and glycaemic information were excluded. After random selection, data from 1522 mother–child pairs were used in this study.Exposures and outcome measures Additive Bayesian network analysis was used to investigate the interdependency of lipid profiles with other metabolic risk factors (prepregnancy body mass index (BMI), fasting glucose and early gestational weight gain) in association with birth weight and CBI, along with multivariable linear regression models.Results In multivariable linear regressions, maternal triglyceride was associated with increased birth weight (adjusted β=67.46, 95% CI 41.85 to 93.06 g per mmol/L) and CBI (adjusted β=0.89, 95% CI 0.06 to 1.72 μU/mL per mmol/L increase), while high-density lipoprotein cholesterol was associated with decreased birth weight (adjusted β=−45.29, 95% CI −85.49 to −5.09 g per mmol/L). After considering the interdependency of maternal metabolic risk factors in the Network analysis, none of the maternal lipid profiles was independently associated with birth weight and CBI. Instead, prepregnancy BMI was the global strongest factor for birth weight and CBI directly and indirectly.Conclusions Gestational dyslipidaemia appears to be secondary to metabolic dysfunction with no clear association with metabolic adverse outcomes in neonates. Maternal prepregnancy overweight/obesity appears the most influential upstream metabolic risk factor for both maternal and neonatal metabolic health; these data imply weight management may need to be addressed from the preconception period and during early pregnancy.

Background: Studies on risk factors for severe COVID-19 in people of working age have generally not included non-working persons or established population attributable fractions (PAFs) for occupational and other factors. Objectives: We describe the effect of job-related, sociodemographic, and other exposures on the incidence, relative risks and PAFs of severe COVID-19 in individuals aged 18–64. Methods: We conducted a registry-based study in Swedish citizens aged 18–64 from 1 January 2020 to 1 February 2021 with respect to COVID-19-related hospitalizations and death. Results: Of 6,205,459 persons, 272,043 (7.5%) were registered as infected, 3399 (0.05%) needed intensive care, and 620 (0.01%) died, with an estimated case fatality rate of 0.06% over the last 4-month period when testing was adequate. Non-Nordic origin was associated with a RR for need of intensive care of 3·13, 95%CI 2·91–3·36, and a PAF of 32·2% after adjustment for age, sex, work, region and comorbidities. In a second model with occupation as main exposure, and adjusted for age, sex, region, comorbidities and origin, essential workers had an RR of 1·51, 95%CI, 1·35–1·6, blue-collar workers 1·18, 95%CI 1·06–1·31, school staff 1·21, 95%CI 1·01–1·46, and health and social care workers 1·89, 95%CI 1·67–2·135) compared with people able to work from home, with altogether about 13% of the PAF associated with these occupations. Essential workers and blue-collar workers, but no other job categories had higher risk of death, adjusted RRs of 1·79, 95%CI 1·34–2·38 and 1·37, 95%CI 1·04–1·81, with adjusted PAFs of altogether 9%. Conclusion: Among people of working age in Sweden, overall mortality and case fatality were low. Occupations that require physical presence at work were associated with elevated risk of needing intensive care for COVID-19, with 14% cases attributable to this factor, and 9% of deaths.

Purpose The Scottish Diabetes Research Network (SDRN)-diabetes research platform was established to combine disparate electronic health record data into research-ready linked datasets for diabetes research in Scotland. The resultant cohort, ‘The SDRN-National Diabetes Dataset (SDRN-NDS)’, has many uses, for example, understanding healthcare burden and socioeconomic trends in disease incidence and prevalence, observational pharmacoepidemiology studies and building prediction tools to support clinical decision making.Participants We estimate that >99% of those diagnosed with diabetes nationwide are captured into the research platform. Between 2006 and mid-2020, the cohort comprised 472 648 people alive with diabetes at any point in whom there were 4 million person-years of follow-up. Of the cohort, 88.1% had type 2 diabetes, 8.8% type 1 diabetes and 3.1% had other types (eg, secondary diabetes). Data are captured from all key clinical encounters for diabetes-related care, including diabetes clinic, primary care and podiatry and comprise clinical history and measurements with linkage to blood results, microbiology, prescribed and dispensed drug and devices, retinopathy screening, outpatient, day case and inpatient episodes, birth outcomes, cancer registry, renal registry and causes of death.Findings to date There have been >50 publications using the SDRN-NDS. Examples of recent key findings include analysis of the incidence and relative risks for COVID-19 infection, drug safety of insulin glargine and SGLT2 inhibitors, life expectancy estimates, evaluation of the impact of flash monitors on glycaemic control and diabetic ketoacidosis and time trend analysis showing that diabetic ketoacidosis (DKA) remains a major cause of death under age 50 years. The findings have been used to guide national diabetes strategy and influence national and international guidelines.Future plans The comprehensive SDRN-NDS will continue to be used in future studies of diabetes epidemiology in the Scottish population. It will continue to be updated at least annually, with new data sources linked as they become available.

Introduction Participants in randomised controlled trials (trials) are generally younger and healthier than many individuals encountered in clinical practice. Consequently, the applicability of trial findings is often uncertain. To address this, results from trials can be calibrated to more representative data sources. In a network meta-analysis, using a novel approach which allows the inclusion of trials whether or not individual-level participant data (IPD) is available, we will calibrate trials for three drug classes (sodium glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP1) receptor analogues and dipeptidyl peptidase-4 (DPP4) inhibitors) to the Scottish diabetes register.Methods and analysis Medline and EMBASE databases, the US clinical trials registry (clinicaltrials.gov) and the Chinese Clinical Trial Registry (chictr.org.cn) will be searched from 1 January 2002. Two independent reviewers will apply eligibility criteria to identify trials for inclusion. Included trials will be phase 3 or 4 trials of SGLT2 inhibitors, GLP1 receptor analogues or DPP4 inhibitors, with placebo or active comparators, in participants with type 2 diabetes, with at least one of glycaemic control, change in body weight or major adverse cardiovascular event as outcomes. Unregistered trials will be excluded.We have identified a target population from the population-based Scottish diabetes register. The chosen cohort comprises people in Scotland with type 2 diabetes who either (1) require further treatment due to poor glycaemic control where any of the three drug classes may be suitable, or (2) who have adequate glycaemic control but are already on one of the three drug classes of interest or insulin.Ethics and dissemination Ethical approval for IPD use was obtained from the University of Glasgow MVLS College Ethics Committee (Project: 200160070). The Scottish diabetes register has approval from the Scottish A Research Ethics Committee (11/AL/0225) and operates with Public Benefit and Privacy Panel for Health and Social Care approval (1617-0147).PROSPERO registration number CRD42020184174.

Introduction Oxidative stress is one of many factors suspected to promote antinuclear autoantibody (ANA) formation. Reactive oxygen species can induce changes in the antigenic structure of macromolecules, causing the immune system to treat them as “neo-antigens” and start production of autoantibodies. This study was designed to evaluate the relationship between oxidative stress markers, lifestyle factors and the detection of ANA. Material and methods We examined measures of oxidative stress indices of free-radical damage to lipids and proteins, such as total oxidant status (TOS), concentration of protein thiol groups (PSH), and malondialdehyde (MDA), activity of superoxide dismutase (SOD) in 1731 serum samples. The parameters of the non-enzymatic antioxidant system, such as total antioxidant status (TAS) and uric acid (UA) concentration, were also measured and the oxidative stress index (OSI-index) was calculated. All samples were tested for the presence of ANA using an indirect immunofluorescence assay (IIFA). Results The presence of ANA in women was associated with lower physical activity (p = 0.036), less frequent smoking (p = 0.007) and drinking of alcohol (p = 0.024) accompanied by significant changes in SOD isoenzymes activity (p < 0.001) and a higher uric acid (UA) concentration (p < 0.001). In ANA positive males we observed lower concentrations of PSH (p = 0.046) and increased concentrations of MDA (p = 0.047). Conclusions The results indicate that local oxidative stress may be associated with increased probability of ANA formation in a sex-specific manner.

Background Lowering low‐density lipoprotein cholesterol (LDL‐C) levels decreases major cardiovascular events and is recommended for patients at elevated cardiovascular risk. However, appropriate doses of statin therapy are often insufficient to reduce LDL‐C in accordance with current guidelines. In such cases, treatment could be supplemented with nonstatin lipid‐lowering therapy. Methods and Results A systematic literature review and network meta‐analysis were conducted on randomized controlled trials of nonstatin lipid‐lowering therapy added to maximally tolerated statins, including statin‐intolerant patients. The primary objective was to assess relative efficacy of nonstatin lipid‐lowering therapy in reducing LDL‐C levels at week 12. Secondary objectives included the following: LDL‐C level reduction at week 24 and change in non–high‐density lipoprotein cholesterol and apolipoprotein B at week 12. There were 48 randomized controlled trials included in the primary network meta‐analysis. All nonstatin agents significantly reduced LDL‐C from baseline versus placebo, regardless of background therapy. At week 12, evolocumab, 140 mg every 2 weeks (Q2W)/420 mg once a month, and alirocumab, 150 mg Q2W, were the most efficacious regimens, followed by alirocumab, 75 mg Q2W, alirocumab, 300 mg once a month, inclisiran, bempedoic acid/ezetimibe fixed‐dose combination, and ezetimibe and bempedoic acid used as monotherapies. Primary end point results were generally consistent at week 24, and for other lipid end points at week 12. Conclusions Evolocumab, 140 mg Q2W/420 mg once a month, and alirocumab, 150 mg Q2W, were consistently the most efficacious nonstatin regimens when added to maximally tolerated statins to lower LDL‐C, non–high‐density lipoprotein cholesterol, and apolipoprotein B levels and facilitate attainment of guideline‐recommended risk‐stratified lipoprotein levels.

Objectives Informing an international task force updating the consensus statement on efficacy and safety of biological disease-modifying antirheumatic drugs (bDMARDs) selectively targeting interleukin-6 (IL-6) pathway in the context of immune-mediated inflammatory diseases.Methods A systematic literature research of all publications on IL-6 axis inhibition with bDMARDs published between January 2012 and December 2020 was performed using MEDLINE, EMBASE and Cochrane CENTRAL databases. Efficacy and safety outcomes were assessed in clinical trials including their long-term extensions and observational studies. Meeting abstracts from ACR, EULAR conferences and results on clinicaltrials.gov were taken into consideration.Results 187 articles fulfilled the inclusion criteria. Evidence for positive effect of IL-6 inhibition was available in various inflammatory diseases such as rheumatoid arthritis, juvenile idiopathic arthritis, giant cell arteritis, Takayasu arteritis, adult-onset Still’s disease, cytokine release syndrome due to chimeric antigen receptor T cell therapy and systemic sclerosis-associated interstitial lung disease. Newcomers like satralizumab and anti-IL-6 ligand antibody siltuximab have expanded therapeutic approaches for Castleman’s disease and neuromyelitis optica, respectively. IL-6 inhibition did not provide therapeutic benefits in psoriatic arthritis, ankylosing spondylitis and certain connective tissue diseases. In COVID-19, tocilizumab (TCZ) has proven to be therapeutic in advanced disease. Safety outcomes did not differ from other bDMARDs, except higher risks of diverticulitis and lower gastrointestinal perforations. Inconsistent results were observed in several studies investigating the risk for infections when comparing TCZ to TNF-inhibitors.Conclusion IL-6 inhibition is effective for treatment of several inflammatory diseases with a safety profile that is widely comparable to other bDMARDs.

Despite its increasing prevalence, nonalcoholic fatty liver disease (NAFLD) remains under-diagnosed in primary care. Timely diagnosis is critical, as NAFLD can progress to nonalcoholic steatohepatitis, fibrosis, cirrhosis, hepatocellular carcinoma, and death; furthermore, NAFLD is also a risk factor linked to cardiometabolic outcomes. Identifying patients with NAFLD, and particularly those at risk of advanced fibrosis, is important so that healthcare practitioners can optimize care delivery in an effort to prevent disease progression. This review debates the practical issues that primary care physicians encounter when managing NAFLD, using a patient case study to illustrate the challenges and decisions that physicians face. It explores the pros and cons of different diagnostic strategies and tools that physicians can adopt in primary care settings, depending on how NAFLD presents and progresses. We discuss the importance of prescribing lifestyle changes to achieve weight loss and mitigate disease progression. A diagnostic and management flow chart is provided, showing the key points of assessment for primary care physicians. The advantages and disadvantages of advanced fibrosis risk assessments in primary care settings and the factors that influence patient referral to a hepatologist are also reviewed.