Background: Adolescent depression is associated with adverse social, academic, and health outcomes. This study compared depression-related primary care visits among adolescents before, during, and after COVID-19, and identified affected age and sex groups across countries. Methods: Retrospective repeated cross-sectional study using routinely collected data from primary care settings in Australia, Brazil, Canada, Israel, Norway, Peru, Singapore, Spain, Sweden, the UK, and the USA. Depression-related visits among adolescents aged 10–19 years from 2018–2023 were compared across pre-pandemic (Jan 2018–Mar 2020), pandemic (Apr 2020–Dec 2021), and recovery (Jan 2022–Dec 2023) periods. Negative binomial regression estimated rate ratios (RRs) and 95% confidence intervals (CIs), overall and stratified by sex and age group (10–14 and 15–19 years). Findings: Among 145·3 million adolescent visits, 1·7 million (1·2%) were depression related. Most countries showed increases in depression-related visit rates during the pandemic compared with the pre-pandemic period, ranging from RR 1·14 (95% CI 1·04–1·25) in Spain to RR 2·23 (95% CI 1·97–2·52) in Singapore. Recovery-period rates remained higher than pre-pandemic rates in several countries. Females and older adolescents had the highest visit rates. Larger relative increases during the pandemic among younger adolescents were observed in Australia, Brazil, Canada, and the USA, in both sexes. Interpretation: Depression-related visits increased during the pandemic and often remained above pre-pandemic levels. Larger relative increases among younger adolescents highlight the need for targeted strategies.

INTRODUCTION:Type 2 diabetes is a complex condition with a multifactorial pathogenesis. The pathogenesis is considered to be polygenic due to complex interactions between genetic/epigenetic and environmental factors. The aim of this study is to determine the genetic, environmental and lifestyle factors associated with the development of type 2 diabetes amongst sibling pairs (sib-pairs) in the South-South region of Nigeria and determine which is more prominent. METHODS:This multicentre cross-sectional, comparative exploratory study will recruit 250 sib-pairs living with type 2 diabetes using a simple consecutive sampling method. Participants will be assessed for bio-psycho-social and environmental risk factors that may put them at risk of developing type 2 diabetes using a structured survey instrument. Blood samples collected for multi-omic studies will be analysed for genetic and environmental factors associated with the development of type 2 diabetes. RESULTS:It is expected that the most common genetic factors associated with the development of type 2 diabetes in sib-pairs will be explored and it will be determined to what extent they are responsible for the development of type 2 diabetes when compared to lifestyle and environmental factors. CONCLUSION:While there is a strong genetic component to the development of type 2 diabetes, it is often triggered by lifestyle or environmental factors. Understanding the genetics that lead to the development of type 2 diabetes in sib-pairs when compared to the inherent environmental and lifestyle risk factors may lead to the development of new therapeutic and preventive strategies.

Introduction A proportion of adrenal adenomata exhibit autonomous cortisol secretion, now termed mild autonomous cortisol secretion (MACS), as defined by post-1mg overnight dexamethasone suppression test (ONDST) cortisol 51-137 nmol/l. Here, we characterized the cardiometabolic profile of MACS. Methods Clinical records of 98 individuals with adrenal adenomata were examined. Subcategorization into MACS1 (ONDST cortisol of 50-137 nmol/l) and MACS2 (ONDST cortisol of >137 nmol/l was created to take account of individuals with ONDST cortisol of more than 137 nmol/l and no diagnosis of Cushing's syndrome. Results Diagnosis of MACS1 associated with a higher diagnosis rate of cardiovascular disease (CVD) (17.7% MACS1) vs. non-MACS = nonfunctioning adenoma (NFA) (3.7%) (P = 0.009) and higher rates of prescription of lipid-lowering agents (51.6%) vs. (29.6%) (P = 0.01). ONDST cortisol levels in MACS1 patients correlated with a more adverse lipid profile (for higher low-density lipoprotein cholesterol, r(2) = 0.404, P = 0.007; high-density lipoprotein cholesterol r(2) = -0.346, P = 0.023; for higher serum triglycerides r(2) = 0.282, P = 0.02) in spite of higher rates of statin prescribing. There was a gradient of increasing numbers of antihypertensives prescribed, going from non-MACS NFA to MACS1 to MACS2. Dunn's post hoc analysis indicated an overall more adverse lipid profile in MACS1. Conclusion The positive direction of associations between serum cortisol and lipid measures highlights that MACS carries a metabolically adverse lipid profile. Diagnosis of MACS was associated with a higher diagnosis rate of CVD and appropriately higher rates of prescription of lipid-lowering agents and a greater number of antihypertensive agents prescribed. The question remains about whether a specific directed treatment of MACS should be offered beyond risk-factor-mitigating management.

Introduction and Objective: Epigenetic modifications, such as DNA methylation(DNAm), can provide a composite measurement of environmental/genetic influence on gene expression. A significant gap remains in defining DNAm profiles in diabetes, prior to DKD diagnosis. We determined blood-derived DNAm profiles, in type-2 diabetes(T2D) people with normal kidney function, that were predictive of DKD incidence in the DARE cohort. Methods: Blood-derived DNAm was measured at 850,000 genomic loci (CpGs) using the Infinium EPIC V2-BeadChip (Illumina), in 42 people with T2D, with >10 years detailed clinical follow up data, including renal function. All had normal ACR at baseline. The ‘ChAMP package’ in R was used to identify differentially methylated CpGs in T2D individuals who developed urine ACR>3mg/mmol)) vs no increase in ACR (n=21), after 10 years. Age range was 42-79 years (20 female/22 male), with equal split between case/control groups. Bulk RNA sequencing data from the human kidney was extracted from the ‘Nephroseq’ database. Results: Our Epigenome-wide Association study (EWAS) identified 127 differentially methylated CpG sites (p<9x10-5) associated with UACR>3mg/mmol incidence in the DARE cohort, after adjustment for age/sex. Cross-tissue comparisons identified associations between methylation at cg08494812 (sitting within 200bp of AF1B transcription start site) and UACR>3mg/mmol consistent between both blood-derived and kidney-derived DNA. RNA sequencing data (‘Nephroseq’) indicated that TAF1B expression in the kidney tubule was reduced in DKD, and suggested that kidney TAF1B expression correlated with renal function preservation. Conclusion: Our pilot study identified pre-diagnosis DNAm changes predictive of albuminuria incidence and highlights that increased methylation at the TAF1B gene (cg08494812) is associated with decreased TAF1B expression in kidney and rise in ACR. Future work aims to confirm the significance of these findings and to extend our EWAS to the larger DARE cohort. A.C. Lay: None. A.H. Heald: None. J.M. Gibson: None. P. Kalra: Speaker's Bureau; Pharmacosmos. Advisory Panel; Medice, CSL Vifor.

Weight gain has come to define the life experience of many individuals with schizophrenia and other severe enduring mental illnesses (SMI). In this clinical intervention study, we aimed to determine whether weekly treatment with the glucagon-like peptide-1 (GLP-1) agonist, semaglutide, as part of usual care, is feasible and acceptable to individuals in a psychiatric inpatient setting. Fifteen inpatients (11 men/4 women) in a secure care environment, diagnosed with schizophrenia or schizoaffective disorder and with body mass index (BMI) of at least 30 kg/m2 were commenced on weekly subcutaneous semaglutide as per standard of care. BMI and glycated haemoglobin (HbA1c) were measured at baseline and monthly follow-up to 6 months, and quality of life (QOL) was surveyed at baseline and 6 months. Analysis was based on intention-to-treat. Mean age of patients was 37 years (range 23–63). Time since diagnosis varied from 2 to 25 years. Mean initial BMI was 48.7 kg/m2 for women and 37.2 kg/m2 for men. Duration of semaglutide treatment ranged from 2–6 months. EuroQol 5-Dimensional Questionnaire, 5-Level Version Visual Analogue Scale (EQ5D5L QOL VAS) showed a mean improvement of + 7.5 (from 60 to 67.5) points. Improvement in QOL was overall significantly greater in those who remained on semaglutide (+ 9.5) than those who discontinued. Six patients discontinued semaglutide before the study end, including two who were discharged and no longer able to receive the intervention, and four who withdrew due to medical concerns. Individual percentage weight change varied from + 1 to − 12

Introduction and Objective: Uptake for community-based screening for T2D is inadequate with delays in diagnosis. Patients attending hospital can be screened for diabetes for early treatment. The aim of this study was to identify people with undiagnosed diabetes attending an Accident and Emergency (A&E) department Methods: Screening was undertaken using HbA1c. Prediabetes was defined as HbA1c 39-47 and T2D ≥48 mmol/mol. The Finnish Diabetes Risk Score (FINDRISC) score was calculated for all patients. Results: 4620 patients (mean age 52.1 years, 41.8% males) were included. Normal glucose tolerance was seen in 2749 (59.5%), pre-DM in 1534 (33.2%) and T2D in 337 (7.3%); mean (SE) age: 49.3 (0.27), 56.3 (0.34) and 56.0 (0.76) years; HbA1c: 33.9 (0.09), 41.5 (0.12), 56.8 (0.25) mmol/mol; BMI: 28.2(0.13), 29.1 (0.17) and 31.5 (0.37); FINDRISC score: 8.3 (0.1), 10.0 (0.1), 11.6 (0.2), respectively (all p<0.0001). Relative risk ratios (RRR) indicated that each unit increase in the FINDRISC score was associated with a 9% increased risk for pre-DM (RRR (95% CI) 1.09 (1.07, 1.11) and a 17% increased risk for T2D (1.17 (1.14, 1.20) compared to normoglycaemia. After adjusting for age (13% (7-18%), sex (45% lower in women), ethnicity and smoking, there was little effect modification for diabetes risk at 16% (1.16 (1.13-2.72). Ethnic minorities had higher incidence of Pre-DM and T2D compared to Whites (42.65% vs 37.8%) and twice as likely to have Pre-DM (2.17 (1.72-2.76) or T2D (3.21 (2.21-4.64). Comparing different age groups, individuals over 45 years had higher prevalence of pre-DM and T2D and higher CVD risk factors. Conclusion: Individuals attending A&E have a high incidence of unknown glucose intolerance. HbA1c is a valid and simple method to diagnose diabetes and can be a simple test to identify those with diabetes so that treatment can be instituted early. The FINDRISC score can be used to identify those at risk. Patients admitted to hospital should be screened for diabetes using the HbA1c test. Older age had greater risk of being diagnosed with T2D/Pre-DM. E.B. Jude: Research Support; Abbott Diagnostics. Speaker's Bureau; AstraZeneca, A. Menarini Diagnostics, Novo Nordisk. Research Support; Sanofi. A.H. Heald: None. S.G. Anderson: None.

OBJECTIVE:The ability to reproduce the work of others is an essential part of the scientific disciplines. Replicating observational studies using electronic health record (EHR) data can be challenging due to complexities in data access, variations in EHR systems across institutions, and the potential for unaccounted confounding variables. Our aim is to identify the barriers to methods reproducibility for replication studies using EHR data. METHODS:We replicated a study that examined the risk of hospitalisation following a positive COVID-19 test in individuals with diabetes. Using EHR data from the NHS England's Secure Data Environment (SDE) covering the whole of England, UK (population 57m), we sought to replicate findings from the original study, which used data from Greater Manchester (a large urban region in the UK, population 2.9m). Both analyses were conducted in Trusted Research Environments (TREs) or SDEs, containing linked primary and secondary care data, however methods reproducibility was not straightforward. Differences between the environments that contributed to the difficulties were documented, categorized into themes, and converted into a list of recommendations for TRE/SDEs. RESULTS:Small differences between the environments and the data sources led to several challenges in methods reproducibility. Our recommendations of TRE/SDEs should facilitate future replication studies. The recommendations include: a need for improved machine-readable metadata for EHR data; standardization of governance processes to facilitate federated analysis; mandating of code sharing; and for environments to have a support structure for data engineers and analysts. We also propose a new theme for research, "data reproducibility", as the ability to prepare, extract and clean data from a different database for a replication study. CONCLUSION:Even with perfect code sharing, data reproducibility remains a challenge. Our recommendations have the potential to reduce the barriers to replication studies and therefore enhance the potential of observational studies using EHR data.

Abstract Background Frailty has both health + health economic consequences. There are however few data concerning occurrence of frailty in different ethnic groups in the United Kingdom (UK). The aim of this analysis was to determine frailty prevalence across an ethnically diverse city and to explore the influence of age/social-disadvantage/ethnicity on occurrence. We looked also at frailty related risk of severe illness in relation to COVID-19 infection. Methods Using data from the Greater Manchester Health Record (GMCR), we defined frailty index based on the presence/absence of up to 36 deficits scaled 0–1. We defined frailty based on those with 9 or more deficits (out of total = 36) and electronic frailty index (eFi) as the total number of deficits present, divided by 36 (range 0–1). Results There were 534,567 people aged 60 + years on 1January2020 in Greater Manchester. There was noticeable variation in frailty prevalence across general practices. The majority were white (84%) with 4.7% self-describing as Asian/Asian British, and 1.3% Black/Black British. The prevalence of moderate to severe frailty (eFI > 0.24) was 22.1%. Prevalence was higher in women than men (25.3% vs 18.5%) and increased with age. Compared to the prevalence of frailty in Whites (22.5%) prevalence was higher in Asian/Asian British ethnicity people (28.1%) and lower in those of Black/Black British descent (18.7%). Prevalence increased with increasing social disadvantage (p = 0.002 for trend across disadvantage quintiles). Among those with a positive COVID-19 test those with frailty were more likely to require hospital admission within 28-days, with increased risk for Asian/Asian British descent (OR = 1.47; 95% CI 1.34–1.61) and Black/Black British descent (OR 1.86; 95% CI 1.56–2.20) people vs Whites. Conclusion There is marked variation in occurrence of frailty across Greater Manchester. Frailty is more common in Asian/Asian British people than Whites and less common among Black/Black British with a gradient that relates to social disadvantage.

Reduced stair usage has been linked to metabolic and cardiovascular diseases. The aim of our study was to investigate stair/elevator use by the National Health System (NHS) staff in the UK. Anonymised online survey of stair usage. Staff were asked if they never used the elevator (group 1), took the elevator less than 25

Systemic inflammation, which can be measured by high-sensitivity C-reactive protein (hsCRP), may play a crucial role in the progression of chronic kidney disease (CKD) in people with type 2 diabetes (T2D). In this study, we report longitudinal outcomes from 718 individuals with T2D, followed up for up to 24 years, to assess how hsCRP influences the development and progression of CKD, measured by urine albumin-to-creatinine ratio (uACR)/estimated glomerular filtration rate (eGFR). Longitudinal renal function analysis showed numerical trends towards greater mean eGFR decline (-20.6 ml/min in the lowest Q1 vs. -26.4 ml/min in the highest Q4 baseline hsCRP quartile) and greater fold increase in uACR (1.93 in Q1 vs. 2.91 in Q4) across hsCRP quartiles. However, in multivariate linear regression analyses, baseline hsCRP was not an independent predictor of eGFR decline (P = 0.267) or change in uACR (P = 0.884). We suggest that hsCRP may still serve as a single surrogate quantifiable analyte encompassing multiple risk/factors to denote individuals with a greater risk of rapid progression of diabetic nephropathy.

OBJECTIVES:Long COVID is characterized by a constellation of persistent symptoms following an initial infection with COVID-19 virus. The primary focus of this study was to investigate how the characteristics of people diagnosed with Long COVID differed from those of matched individuals who did not have a diagnosis of Long COVID, after at least one confirmed positive COVID-19 test. STUDY DESIGN:A retrospective observational cohort study was performed using data collected for the time period, January 1, 2020 to January 31, 2024 from a population database of 2.85 million people. METHODS:The primary outcome was a primary care coded diagnosis, or referral for treatment of Long COVID following an acute COVID-19 infection, to a Long COVID clinic. Twenty six thousand, six hundred and twenty six (26,626) individuals were identified with a diagnosis of Long COVID and at least one previous recorded COVID-19 positive test. These were matched by age and sex with 133,165 individuals (i.e. an approximate ratio of 5 controls to one case) with at least one previous recorded COVID-19 positive test but no recorded diagnosis of Long COVID. Mortality rate was also analysed in relation to having a previous confirmed acute COVID-19 infection. RESULTS:There was a higher proportion of people with 2, 3, 4 and 5 or more comorbidities in the diagnosed Long COVID group compared to those with one or no comorbidity. Black/ Black British ethnicity (+28 %) and Mixed ethnicity (+37 %) were both associated with a higher likelihood of a Long COVID diagnosis when compared to White ethnicity. Those in the most disadvantaged quintile (as measured by Townsend index) were more than twice as likely to have Long COVID than the most advantaged quintile. The risk of Long COVID increased by 5.7 % per each comorbidity, with modulation by the number of COVID-19 vaccinations. The risk of Long COVID doubled for every additional confirmed positive COVID-19 test. BMI did not have an effect when account was taken of Townsend quintile. Lastly, we analysed mortality rates following a COVID-19 infection. Female sex was associated with a lower risk of death. More disadvantaged individuals as measured by Townsend quintile were more likely to have died. This risk was nearly doubled for the most deprived quintile compared to least deprived quintile. CONCLUSIONS:In this city region wide study with individuals matched for age and sex, we have determined that being in a socially disadvantaged situation and being Black/Black British or of Mixed ethnicity increased the risk of developing Long COVID. BMI did not have an effect when account was taken of Townsend quintile. These findings can inform public health messages and public health interventions going forward, whether in relation to Long COVID or future pandemic preparedness.

AIMS:Chronic kidney disease (CKD) is a serious and common complication of type 1 diabetes (T1D). Despite improvements in diabetes management, the prevalence of CKD in people with T1D remains high. However, large-scale, real-world data from the UK are limited. This study aimed to provide contemporary estimates of CKD incidence and its associated risk factors in a population with T1D in Salford, Greater Manchester. METHODS:We conducted a retrospective cohort study using anonymised electronic health records from the Salford Integrated Record Research Database between 2010 and 2023. Adults with T1D were assessed for CKD, defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 and/or albuminuria (urine albumin-to-creatinine ratio ≥3 mg/mmol), confirmed by two readings at least 90 days apart. Competing risk regression models (accounting for death as a competing event) were used to identify associations with demographic and clinical risk factors, including age, sex, ethnicity, deprivation, smoking, body mass index (BMI), HbA1c and use of ACE inhibitors or ARBs. RESULTS:Among 1106 adults with T1D, 38.5% developed reduced eGFR, 47.2% had albuminuria, and 23.8% met both criteria for CKD. Older age was strongly associated with reduced eGFR: compared to those aged 18-28 years, the sub-distribution hazard ratio (sHR) was 3.1 (95% CI: 2.0-5.0) for ages 42-54 and 8.6 (95% CI: 5.4-13.9) for ≥55 years. Other significant predictors included missing ethnicity data (sHR 1.5), higher BMI (sHR 1.1 per kg/m2), higher HbA1c (sHR 1.1 per mmol/mol) and not being prescribed an ACE inhibitor or ARB (sHR 1.4). For albuminuria, increased risk was associated with female sex (sHR 1.3), missing ethnicity (sHR 1.4), higher HbA1c (sHR 1.1), current smoking (sHR 1.5), living in the second most deprived quintile (sHR 1.9) and being prescribed ACE inhibitors or ARBs (sHR 2.1). CONCLUSION:This large UK cohort study highlights a high burden of CKD among adults with T1D. Key risk factors included older age, higher BMI, poor glycaemic control, smoking and deprivation. Although ACE inhibitors and ARBs were commonly prescribed, the uptake of newer reno-protective treatments was low. These findings point to a need for earlier detection, targeted interventions and broader implementation of effective therapies to reduce kidney disease burden in this population.

Introduction:People with serious mental illness (SMI) have a higher than average cardiovascular event rate/shortened life expectancy by up to 20 years. The higher incidence of cardiovascular events is not sufficiently accounted for by traditional risk factors. It has been established that aortic stiffness assessed with pulse wave velocity (PWV) correlates with vascular inflammation/increased risk for cardiovascular events. Methods:We measured PWV/central blood pressure by photoplethysmography in 15 long-term psychiatry inpatients on a specialist inpatient ward, during a 5-min period of rest with the pOpmètre. The pOpmètre is a class IIa medical device, noninvasive and nonoperator dependent. Results:Mean age was 59.2 years (range: 26-79 years). Mean body (SD) BMI was 33.1 (7.7) kg/m2. 46% of individuals were taking antihypertensive medication, and 60% lipid-lowering medication. 27% were diagnosed with type 2 diabetes and 20% with nondiabetic hyperglycaemia. Of the 11 men/four women, 60% took oral antipsychotics and 40% were on depot-antipsychotic medication. Mean (SD) estimated vascular age (63.7 years) was higher than chronological age (59.2 years) in two-thirds of people, with a greater propensity for this differential in older people. For PWV, the range was 4.0-17.5 m/s. In 10 of the 15 individuals, this was above the 90th centile for their age decade and sex. Central blood pressure was pathologically elevated (≥140 mmHg) in 40% of cases. Conclusion:We describe differences in major arterial vessel health that may account for some of the excess cardiovascular event rate/excess mortality in people with SMI.