How do lifestyle factors modify the association between genetic predisposition and obesity-related phenotypes? A 4-way decomposition analysis using UK Biobank.

BACKGROUND: Obesity and central obesity are multifactorial conditions with genetic and non-genetic (lifestyle and environmental) contributions. There is incomplete understanding of whether lifestyle modifies the translation from respective genetic risks into phenotypic obesity and central obesity, and to what extent genetic predisposition to obesity and central obesity is mediated via lifestyle factors. METHODS: This is a cross-sectional study of 201,466 (out of approximately 502,000) European participants from UK Biobank and tested for interactions and mediation role of lifestyle factors (diet quality; physical activity levels; total energy intake; sleep duration, and smoking and alcohol intake) between genetic risk for obesity and central obesity. BMI-PRS and WHR-PRS are exposures and obesity and central obesity are outcomes. RESULTS: Overall, 42.8% of the association between genetic predisposition to obesity and phenotypic obesity was explained by lifestyle: 0.9% by mediation and 41.9% by effect modification. A significant difference between men and women was found in central obesity; the figures were 42.1% (association explained by lifestyle), 1.4% (by mediation), and 40.7% (by modification) in women and 69.6% (association explained by lifestyle), 3.0% (by mediation), and 66.6% (by modification) in men. CONCLUSIONS: A substantial proportion of the association between genetic predisposition to obesity/central obesity and phenotypic obesity/central obesity was explained by lifestyles. Future studies with repeated measures of obesity and lifestyle would be needed to clarify causation.

Association of Stair Use With Risk of Major Chronic Diseases.

INTRODUCTION: Physical inactivity is associated with a higher risk of chronic diseases. Regular stair use can contribute to increasing physical activity in the population. This study aimed to investigate the association between flights of stairs used daily at home and all-cause mortality and cause-specific incidence and mortality. METHODS: Of the 502,628 UK Biobank participants recruited between 2007 and 2010, 442,027 (mean age, 56±8 years) had available data and were included in the analyses conducted in 2023. Participants were categorized on the basis of flights of stairs climbed daily (1-5, 6-10, 11-15, >15). The disease-specific outcomes were cardiovascular disease, respiratory disease, cancer, type 2 diabetes, and all-cause dementia. Cox proportional hazard models, adjusted for sociodemographic, lifestyle, and health-related confounding factors, were used to analyze the associations between stair use frequency and health outcomes. RESULTS: Participants were followed up for a median of 10.9 years. Climbing stairs >15 times per day was associated with a lower risk of 8 of the 9 outcomes analyzed than not using stairs. The magnitude of association ranged from 3% (95% CI=0.94, 0.99) lower risk for all-cause cancer to 51% (95% CI=0.39, 0.60) lower risk of chronic obstructive pulmonary disease. Findings were similar for mortality outcomes, with the hazard ratios ranging from 0.82 (95% CI=0.77, 0.87) for all-cause cancer to 0.46 (95% CI=0.23, 0.92) for chronic obstructive pulmonary disease mortality. CONCLUSIONS: Stair use was associated with a lower risk of all-cause mortality and cause-specific incidence and mortality independent of confounding factors, including adiposity and multimorbidity.

Different Sources of Fiber Intake and Risk of 17 Specific Cancers and All Cancers Combined: Prospective Study of 364,856 Participants in the UK Biobank.

Inverse associations between dietary fiber (DF) and colorectal cancer risk are well-established. However, evidence is limited in relation to other cancer sites. This study, of 364,856 participants from the UK Biobank, aimed to evaluate the associations between total and source-specific partial DF and risk of 17 specific cancers and all cancers combined. Partial DF was derived from baseline touchscreen questionnaire data on cereal, bread, fruit, and vegetable intake. The outcomes were incident cancer at 17 sites and all cancers combined. Cox proportional hazards models were applied. Over a median 8.8-year follow-up period, 30,725 people were diagnosed with cancer. After adjusting for sociodemographic and lifestyle factors, those in the highest quintile of partial DF compared with the lowest quintile (<9.6 vs ≥19.1 g/day) had 10% lower risk of cancer overall, with the greatest risk reductions observed for cervical (hazard ratio (HR) = 0.33, 95% confidence interval (CI): 0.14; 0.82), esophageal (HR = 0.66, 95% CI: 0.52; 0.84), lung (HR = 0.67, 95% CI: 0.59; 0.76), bladder (HR = 0.72, 95% CI: 0.56; 0.91), and kidney (HR = 0.75, 95% CI: 0.61; 0.92) cancers. Associations between DF and lung cancer were observed only in current and former smokers. Higher DF intake, in particular cereal fiber and fruit and vegetable fiber, was associated with a lower risk of overall and multiple site-specific cancers.

Validating the SMART2 Score in a Racially Diverse High-Risk Nationwide Cohort of Patients Receiving Coronary Artery Bypass Grafting.

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.

Association Between the AHA Life's Essential 8 Score and Incident All-Cause Dementia: A Prospective Cohort Study from UK Biobank.

This study aimed to investigate the association between the Life's Essential 8 (LE8) score and incident all-cause dementia (including Alzheimer's disease [AD] and vascular dementia) in UK Biobank. A total of 259,718 participants were included in this prospective study. Smoking, non-HDL cholesterol, blood pressure, body mass index, HbA1c, physical activity, diet, and sleep were used to create the Life's Essential 8 (LE8) score. Associations between the score (both continuous and as quartiles) and outcomes were investigated using adjusted Cox proportional hazard models. The potential impact fractions of 2 scenarios and the rate advancement periods were also calculated. Over a median follow-up of 10.6 years, 4958 participants were diagnosed with any dementia. Higher LE8 scores were associated with lower risk of all-cause and vascular dementia in an exponential decay pattern. Compared with individuals in the healthiest quartile, those in the least healthy quartile had a higher risk of all-cause dementia (HR: 1.50 [95% CI: 1.37-1.65] and vascular dementia (HR: 1.86 [1.44-2.42]). A targeted intervention that increased the score by 10-points among individuals in the lowest quartile could have prevented 6.8% of all-cause dementia cases. Individuals in the least healthy LE8 quartile might develop all-cause dementia 2.45 years earlier than their counterparts. In conclusion, individuals with higher LE8 scores had lower risk of all-cause and vascular dementia. Because of nonlinear associations, interventions targeted at the least healthy individuals might produce greater population-level benefits.

Educational outcomes in childhood cancer survivors: A Scotland-wide record-linkage study of 766,217 schoolchildren.

BACKGROUND: A cancer diagnosis during childhood greatly disrupts the lives of those affected, causing physical and psychological challenges. We aim to investigate educational outcomes among schoolchildren with a previous cancer diagnosis compared to their peers. METHODS: Individual records from four national education databases and three national health databases were linked to construct a cohort of all singleton schoolchildren born in Scotland attending Scottish local-authority schools between 2009-2013. Pupils previously diagnosed with any cancer, haematological cancers, and central nervous system (CNS) cancers, were compared to their unaffected peers with respect to five educational outcomes: special educational need (SEN), absenteeism, school exclusion, academic attainment, and unemployment. Analyses were adjusted for sociodemographic and maternity factors and chronic conditions. RESULTS: Of 766,217 pupils, 1,313 (0.17%) had a previous cancer diagnosis. Children with any cancer had increased odds of SEN (OR 3.26, 95% CI 2.86-3.71), absenteeism (IRR 1.82, 95% CI 1.70-1.94), and low attainment (OR 2.15, 95% CI 1.52-3.03) compared to their peers. Similar findings were observed for haematological (SEN OR 2.62, 95% CI 2.12-3.24; absenteeism IRR 2.04, 95% CI 1.85-2.25; low attainment OR 2.17, 95% CI 1.31-3.61) and CNS (SEN OR 6.44, 95% CI 4.91-8.46; absenteeism IRR 1.75, 95% CI 1.51-2.04; low attainment OR 3.33, 95% CI 1.52-7.30) cancers. Lower exclusions were observed among children with any cancer (IRR 0.51, 95% CI 0.31-0.83) and CNS cancer (IRR 0.20, 95% CI 0.06-0.61). No associations were observed with unemployment. CONCLUSIONS: This study highlights the wider impacts of childhood cancer on educational outcomes. These children need to be supported, as poor educational outcomes can further impact later health.

Genetic architecture of DCC and influence on psychological, psychiatric and cardiometabolic traits in multiple ancestry groups in UK Biobank.

BACKGROUND: People with severe mental illness have a higher risk of cardiometabolic disease than the general population. Traditionally attributed to sociodemographic, behavioural factors and medication effects, recent genetic studies have provided evidence of shared biological mechanisms underlying mental illness and cardiometabolic disease. We aimed to determine whether signals in the DCC locus, implicated in psychiatric and cardiometabolic traits, were shared or distinct. METHODS: In UK Biobank, we systematically assessed genetic variation in the DCC locus for association with metabolic, cardiovascular and psychiatric-related traits in unrelated "white British" participants (N = 402,837). Logistic or linear regression were applied assuming an additive genetic model and adjusting for age, sex, genotyping chip and population structure. Bonferroni correction for the number of independent variants was applied. Conditional analyses (including lead variants as covariates) and trans-ancestry analyses were used to investigate linkage disequilibrium between signals. RESULTS: Significant associations were observed between DCC variants and smoking, anhedonia, body mass index (BMI), neuroticism and mood instability. Conditional analyses and linkage disequilibrium structure suggested signals for smoking and BMI were distinct from each other and the mood traits, whilst individual mood traits were inter-related in a complex manner. LIMITATIONS: Restricting analyses in non-"white British" individuals to the phenotypes significant in the "white British" sample is not ideal, but the smaller samples sizes restricted the phenotypes possible to analyse. CONCLUSIONS: Genetic variation in the DCC locus had distinct effects on BMI, smoking and mood traits, and therefore is unlikely to contribute to shared mechanisms underpinning mental and cardiometabolic traits.

Polygenic risk of major depressive disorder as a risk factor for venous thromboembolism.

Major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ) are associated with an increased risk of cardiovascular diseases, including venous thromboembolism (VTE). The reasons for this are complex and include obesity, smoking, and use of hormones and psychotropic medications. Genetic studies have increasingly provided evidence of the shared genetic risk of psychiatric and cardiometabolic illnesses. This study aimed to determine whether a genetic predisposition to MDD, BD, or SCZ is associated with an increased risk of VTE. Genetic correlations using the largest genome-wide genetic meta-analyses summary statistics for MDD, BD, and SCZ (Psychiatric Genetics Consortium) and a recent genome-wide genetic meta-analysis of VTE (INVENT Consortium) demonstrated a positive association between VTE and MDD but not BD or SCZ. The same summary statistics were used to construct polygenic risk scores for MDD, BD, and SCZ in UK Biobank participants of self-reported White British ancestry. These were assessed for impact on self-reported VTE risk (10 786 cases, 285 124 controls), using logistic regression, in sex-specific and sex-combined analyses. We identified significant positive associations between polygenic risk for MDD and the risk of VTE in men, women, and sex-combined analyses, independent of the known risk factors. Secondary analyses demonstrated that this association was not driven by those with lifetime experience of mental illness. Meta-analyses of individual data from 6 additional independent cohorts replicated the sex-combined association. This report provides evidence for shared biological mechanisms leading to MDD and VTE and suggests that, in the absence of genetic data, a family history of MDD might be considered when assessing the risk of VTE.

Infant feeding method and special educational need in 191,745 Scottish schoolchildren: A national, population cohort study.

BACKGROUND: While special educational needs (SEN) are increasingly recorded among schoolchildren, infant breastfeeding has been associated with reduced incidence of childhood physical and mental health problems. This study investigated relationships between infant feeding method and risk of all-cause and cause-specific SEN. METHODS AND FINDINGS: A population cohort of schoolchildren in Scotland was constructed by linking together health (maternity, birth, and health visitor records) and education (annual school pupil census) databases. Inclusion was restricted to singleton children, born in Scotland from 2004 onwards with available breastfeeding data and who attended local authority mainstream or special schools between 2009 and 2013. Generalised estimating equation models with a binomial distribution and logit link function investigated associations between infant feeding method at 6 to 8 weeks and all-cause and cause-specific SEN, adjusting for sociodemographic and maternity factors. Of 191,745 children meeting inclusion criteria, 126,907 (66.2%) were formula-fed, 48,473 (25.3%) exclusively breastfed, and 16,365 (8.5%) mixed-fed. Overall, 23,141 (12.1%) children required SEN. Compared with formula feeding, mixed feeding and exclusive breastfeeding, respectively, were associated with decreased all-cause SEN (OR 0.90, 95% CI [0.84,0.95], p < 0.001 and 0.78, [0.75,0.82], p < 0.001), and SEN attributed to learning disabilities (0.75, [0.65,0.87], p < 0.001 and 0.66, [0.59,0.74], p < 0.001), and learning difficulties (0.85, [0.77,0.94], p = 0.001 and 0.75, [0.70,0.81], p < 0.001). Compared with formula feeding, exclusively breastfed children had less communication problems (0.81, [0.74,0.88], p = 0.001), social-emotional-behavioural difficulties (0.77, [0.70,0.84], p = 0.001), sensory impairments (0.79, [0.65,0.95], p = 0.01), physical motor disabilities (0.78, [0.66,0.91], p = 0.002), and physical health conditions (0.74, [0.63,0.87], p = 0.01). There were no significant associations for mixed-fed children (communication problems (0.94, [0.83,1.06], p = 0.312), social-emotional-behavioural difficulties (0.96, [0.85,1.09], p = 0.541), sensory impairments (1.07, [0.84,1.37], p = 0.579), physical motor disabilities (0.97, [0.78,1.19], p = 0.754), and physical health conditions (0.93, [0.74,1.16], p = 0.504)). Feeding method was not significantly associated with mental health conditions (exclusive 0.58 [0.33,1.03], p = 0.061 and mixed 0.74 [0.36,1.53], p = 0.421) or autism (exclusive 0.88 [0.77,1.01], p = 0.074 and mixed 1.01 [0.84,1.22], p = 0.903). Our study was limited since only 6- to 8-week feeding method was available precluding differentiation between never-breastfed infants and those who stopped breastfeeding before 6 weeks. Additionally, we had no data on maternal and paternal factors such as education level, IQ, employment status, race/ethnicity, or mental and physical health. CONCLUSIONS: In this study, we observed that both breastfeeding and mixed feeding at 6 to 8 weeks were associated with lower risk of all-cause SEN, and SEN attributed to learning disabilities and learning difficulty. Many women struggle to exclusively breastfeed for the full 6 months recommended by WHO; however, this study provides evidence that a shorter duration of nonexclusive breastfeeding could nonetheless be beneficial with regard to the development of SEN. Our findings augment the existing evidence base concerning the advantages of breastfeeding and reinforce the importance of breastfeeding education and support.

Dose-Response Associations of Dietary Inflammatory Potential With Health Outcomes: A Prospective Cohort Study of 198,265 UK Biobank Participants.

To investigate the dose-response associations of dietary inflammatory potential with all-cause mortality and incident cardiovascular disease (CVD) and cancer. METHODS: This was a prospective cohort study of 198,265 UK Biobank participants who completed at least 1 dietary assessment. A web based 24 hours recall questionnaire was used to derive the energy-adjusted dietary inflammatory index (E-DII). All-cause mortality and incident CVD and cancer ascertained from linked records. RESULTS: After adjusting for socio-demographic and lifestyle factors, there were J-shaped associations of E-DII with all-cause mortality and CVD, and a relatively linear association with cancer. When E-DII was <0, E-DII was not associated with any of the outcomes. When E-DII was ≥0, the linear associations were strongest in all-cause mortality (HR 1.09, 95% CI, 1.05-1.13), followed by CVD (HR 1.06, 95% CI, 1.03-1.09), and cancer (HR 1.03, 95%,CI, 1.01-1.05). CONCLUSION: Dietary inflammatory potential was associated with mortality and CVD primarily when the diet is proinflammatory.

C-reactive protein partially mediates the inverse association between coffee consumption and risk of type 2 diabetes: The UK Biobank and the Rotterdam study cohorts.

BACKGROUND: Coffee is among the most consumed beverages worldwide. Coffee consumption has been associated with lower risk of type 2 diabetes mellitus (T2D), but underlying mechanisms are not well understood. We aimed to study the role of classic and novel-T2D biomarkers with anti- or pro-inflammatory activity in the association between habitual coffee intake and T2D risk. Furthermore, we studied differences by coffee types and smoking status in this association. METHODS: Using two large population-based cohorts, the UK-Biobank (UKB; n = 145,368) and the Rotterdam Study (RS; n = 7111), we investigated associations of habitual coffee consumption with incident T2D and repeated measures of insulin resistance (HOMA-IR), using Cox proportional hazards and mixed effect models, respectively. Additionally, we studied associations between coffee and subclinical inflammation biomarkers including C-reactive protein (CRP) and IL-13, and adipokines, such as adiponectin and leptin, using linear regression models. Next, we performed formal causal mediation analyses to investigate the role of coffee-associated biomarkers in the association of coffee with T2D. Finally, we evaluated effect modification by coffee type and smoking. All models were adjusted for sociodemographic, lifestyle and health-related factors. RESULTS: During a median follow-up of 13.9 (RS) and 7.4 (UKB) years, 843 and 2290 incident T2D cases occurred, respectively. A 1 cup/day increase in coffee consumption was associated with 4% lower T2D risk (RS, HR = 0.96 [95%CI 0.92; 0.99], p = 0.045; UKB, HR = 0.96 [0.94; 0.98], p < 0.001), with lower HOMA-IR (RS, log-transformed ß = -0.017 [-0.024;-0.010], p < 0.001), and with lower CRP (RS, log-transformed ß = -0.014 [-0.022;-0.005], p = 0.002; UKB, ß = -0.011 [-0.012;-0.009], p < 0.001). We also observed associations of higher coffee consumption with higher serum adiponectin and IL-13 concentrations, and with lower leptin concentrations. Coffee-related CRP levels partially mediated the inverse association of coffee intake with T2D incidence (average mediation effect RS ß = 0.105 (0.014; 0.240), p = 0.016; UKB ß = 6.484 (4.265; 9.339), p < 0.001), with a proportion mediated by CRP from 3.7% [-0.012%; 24.4%] (RS) to 9.8% [5,7%; 25.8%] (UKB). No mediation effect was observed for the other biomarkers. Coffee-T2D and coffee-CRP associations were generally stronger among consumers of ground (filtered or espresso) coffee and among never and former smokers. CONCLUSIONS: Lower subclinical inflammation may partially mediate the beneficial association between coffee consumption and lower T2D risk. Consumers of ground coffee and non-smokers may benefit the most. KEYWORDS (MESH TERMS): coffee consumptions; diabetes mellitus, type 2; inflammation; adipokines; biomarkers; mediation analysis; follow-up studies.

Diet-Related Inflammation Is Associated with Worse COVID-19 Outcomes in the UK Biobank Cohort.

Diet, the most important modulator of inflammatory and immune responses, may affect COVID-19 incidence and disease severity. Data from 196,154 members of the UK biobank had at least one 24 h dietary recall. COVID-19 outcomes were based on PCR testing, hospital admissions, and death certificates. Adjusted Poisson regression analyses were performed to estimate the risk ratios (RR) and their 95% confidence intervals (CI) for dietary inflammatory index (DII)/energy-adjusted DII (E-DII) scores. Models were adjusted for sociodemographic factors, comorbidities, smoking status, physical activity, and sleep duration. Between January 2020 and March 2021, there were 11,288 incident COVID-19 cases, 1270 COVID-19-related hospitalizations, and 315 COVID-19-related deaths. The fully adjusted model showed that participants in the highest (vs. lowest) DII/E-DII quintile were at 10-17% increased risk of COVID-19 (DII: RR Q5 vs. Q1 = 1.10, 95% CI 1.04-1.17, Ptrend < 0.001; E-DII: RR Q5 vs. Q1 = 1.17, 95% CI 1.10-1.24, Ptrend < 0.001) and ≈40% higher risk was observed for disease severity (DII: RR Q5 vs. Q1 = 1.40, 95% CI 1.18-1.67, Ptrend < 0.001; E-DII: RR Q5 vs. Q1 = 1.39, 95% CI 1.16-1.66, Ptrend < 0.001). There was a 43% increased risk of COVID-19-related death in the highest DII quintile (RR Q5 vs. Q1 = 1.43, 95% CI 1.01-2.01, Ptrend = 0.04). About one-quarter of the observed positive associations between DII and COVID-19-related outcomes were mediated by body mass index (25.8% for incidence, 21.6% for severity, and 19.8% for death). Diet-associated inflammation increased the risk of COVID-19 infection, severe disease, and death.

Associations of Physical Activity With Breast Cancer Risk: Findings From the UK Biobank Prospective Cohort Study.

PURPOSE: Although physical activity (PA) has been consistently associated with breast cancer, existing evidence is limited to self-reported physical activity, which is prone to dilution bias. Therefore, this aims to examine the associations of device-measured PA domains with breast cancer risk and whether it differs by menopausal status. METHODS: Prospective cohort study. Data from 48,286 women from the UK Biobank cohort were analyzed. A wrist triaxial accelerometer was used to collect physical activity data for light, moderate, vigorous, moderate to vigorous, and total PA. Cox proportional models were performed to examine the association between PA domains, menopausal status, and breast cancer risk. RESULTS: Eight hundred thirty-six breast cancer cases were diagnosed during a median of 5.4 years (interquartile range: 4.7-5.9). For total PA, those in the most active quartile had a 26% lower risk of breast cancer (Hazard ratio [HR]: 0.74; 95% confidence interval [CI], 0.61-0.91) compared with those least active. Similar results were observed for light PA (HR: 0.79; 95% CI, 0.64-0.96), and moderate to vigorous PA (HR: 0.78; 95% CI, 0.64-0.96). However, moderate PA (HR: 0.73; 95% CI, 0.44-1.19) and vigorous PA (HR: 0.77; 95% CI, 0.56-1.05) was nonsignificant. No evidence of interaction between PA domains and menopause status was found (P > .10). CONCLUSION: High levels of PA are associated with a lower risk of breast cancer with similar magnitude of associations observed across different intensity domains.

Identifying the Biomarker Profile of Pre-Frail and Frail People: A Cross-Sectional Analysis from UK Biobank.

OBJECTIVE: This study aimed to compare the biomarker profile of pre-frail and frail adults in the UK Biobank cohort by sex. METHODS: In total, 202,537 participants (67.8% women, aged 37 to 73 years) were included in this cross-sectional analysis. Further, 31 biomarkers were investigated in this study. Frailty was defined using a modified version of the Frailty Phenotype. Multiple linear regression analyses were performed to explore the biomarker profile of pre-frail and frail individuals categorized by sex. RESULTS: Lower concentrations of apoA1, total, LDL, and HDL cholesterol, albumin, eGFRcys, vitamin D, total bilirubin, apoB, and testosterone (differences ranged from -0.30 to -0.02 per 1-SD change), as well as higher concentrations of triglycerides, GGT, cystatin C, CRP, ALP, and phosphate (differences ranged from 0.01 to 0.53 per 1-SD change), were identified both in pre-frail and frail men and women. However, some of the associations differed by sex. For instance, higher rheumatoid factor and urate concentrations were identified in pre-frail and frail women, while lower calcium, total protein, and IGF-1 concentrations were identified in pre-frail women and frail women and men. When the analyses were further adjusted for CRP, similar results were found. CONCLUSIONS: Several biomarkers were linked to pre-frailty and frailty. Nonetheless, some of the associations differed by sex. Our findings contribute to a broader understanding of the pathophysiology of frailty as currently defined.

Implementation of a national smoke-free prison policy: an economic evaluation within the Tobacco in Prisons (TIPs) study.

OBJECTIVE: To determine the cost-effectiveness of a smoke-free prison policy in Scotland, through assessments of the trade-offs between costs (healthcare and non-healthcare-related expenditure) and outcomes (health and non-health-related non-monetary consequences) of implementing the policy. DESIGN: A health economic evaluation consisting of three analyses (cost-consequence, cost-effectiveness and cost-utility), from the perspectives of the healthcare payer, prison service, people in custody and operational staff, assessed the trade-offs between costs and outcomes. Costs associated with the implementation of the policy, healthcare resource use and personal spend on nicotine products were considered, alongside health and non-health outcomes. The cost-effectiveness of the policy was evaluated over 12-month and lifetime horizons (short term and long term). SETTING: Scotland's national prison estate. PARTICIPANTS: People in custody and operational prison staff. INTERVENTION: Implementation of a comprehensive (indoor and outdoor) smoke-free policy. MAIN OUTCOME MEASURES: Concentration of secondhand smoke, health-related quality of life (health utilities and quality-adjusted life-years (QALY)) and various non-health outcomes (eg, incidents of assaults and fires). RESULTS: The short-term analyses suggest cost savings for people in custody and staff, improvements in concentration of secondhand smoke, with no consistent direction of change across other outcomes. The long-term analysis demonstrated that implementing smoke-free policy was cost-effective over a lifetime for people in custody and staff, with approximate cost savings of £28 000 and £450, respectively, and improvement in health-related quality of life of 0.971 QALYs and 0.262, respectively. CONCLUSION: Implementing a smoke-free prison policy is cost-effective over the short term and long term for people in custody and staff.

An Opportunity for Prevention: Associations Between the Life's Essential 8 Score and Cardiovascular Incidence Using Prospective Data from UK Biobank.

To investigate the association between the Life's Essential 8 (LE8) score and the incidence of four cardiovascular outcomes (ischemic heart disease, myocardial infarction, stroke, and heart failure [HF]) - separately and as a composite outcome of major adverse cardiovascular events (MACE) - in UK Biobank. 250,825 participants were included in this prospective study. Smoking, non-HDL cholesterol, blood pressure, body mass index, HbA1c, physical activity, diet, and sleep were used to create a modified version of the LE8 score. Associations between the score (both as a continuous score and as quartiles) and outcomes were investigated using adjusted Cox proportional hazard models. The potential impact fractions of two scenarios were also calculated. Over a median follow-up of 10.4 years, there were 25,068 MACE. Compared to individuals in the highest quartile of the score (healthiest), those in the lowest quartile (least healthy) had 2.07 (95% CI: 1.99; 2.16) higher risk for MACE. The highest relative risk gradient of the individual outcomes was observed for HF (HRlowest quartile: 2.67 [95% CI: 2.42; 2.94]). The magnitude of association was stronger in participants below 50 years, women, and ethnic minorities. A targeted intervention that increased, by 10-points, the score among individuals in the lowest quartile could have prevented 9.2% of MACE. Individuals with a lower LE8 score experienced more MACE, driven especially by incident HF. Our scenarios suggested that relevant interventions targeted towards those in the lowest quartile may have a greater impact than interventions producing small equal changes across all quartiles.

Lipid Lowering in "Very High Risk" Patients Undergoing Coronary Artery Bypass Surgery and Its Projected Reduction in Risk for Recurrent Vascular Events: A Monte Carlo Stepwise Simulation Approach.

ABSTRACT: 2018 AHA guidelines provide criteria to identify patients at very high risk (VHR) for adverse vascular events and recommend an low density lipoprotein-C (LDL-C) level <1.8 mmol/L. Data regarding the 10-year risk for adverse vascular events in coronary artery bypass grafting (CABG) patients at VHR and the need for nonstatin therapies in the VHR cohort are limited. We queried a national cohort of CABG patients to answer these questions. The projected reduction of LDL-C from stepwise escalation of lipid-lowering therapy (LLT) was simulated; Monte Carlo methods were used to account for patient-level heterogeneity in treatment effects. Data on preoperative statin therapy and LDL-C levels were obtained. In the first scenario, all eligible patients not at target LDL-C received high-intensity statins, followed by ezetimibe and then alirocumab; alternatively, bempedoic acid was also used. The 10-year risk for an adverse vascular event was estimated using a validated risk score. Potential risk reduction was estimated after simulating maximal LLT. Before CABG, 8948 of 27,443 patients (median LDL-C 85 mg/dL) were at VHR. In the whole cohort, 31% were receiving high-intensity statins. With stepwise LLT escalation, the proportion of patients at target were 60%, 78%, 86%, and 97% after high-intensity statins, ezetimibe, bempedoic acid, and alirocumab, respectively. The projected 10-year risk to suffer a vascular event reduced by 4.6%. A large proportion of CABG patients who are at VHR for vascular events fail to meet 2018 AHA LDL-C targets. A stepwise approach, particularly with the use of bempedoic acid, can significantly reduce the need for more expensive proprotein convertase subtilisin kexin 9 inhibitors.

Association of birthweight centiles and early childhood development of singleton infants born from 37 weeks of gestation in Scotland: A population-based cohort study.

BACKGROUND: Birthweight centiles beyond the traditional thresholds for small or large babies are associated with adverse perinatal outcomes but there is a paucity of data about the relationship between birthweight centiles and childhood development among children born from 37 weeks of gestation. This study aims to establish the association between birthweight centiles across the whole distribution and early childhood development among children born from 37 weeks of gestation. METHODS AND FINDINGS: This is a population-based cohort study of 686,284 singleton infants born from 37 weeks of gestation. The cohort was generated by linking pregnancy and delivery data from the Scottish Morbidity Records (2003 to 2015) and the child developmental assessment at age 2 to 3.5 years. The main outcomes were child's fine motor, gross motor, communication, and social developmental concerns measured with the Ages and Stages Questionnaires-3 (ASQ-3) and Ages and Stages Questionnaire: Social & Emotional-2 (ASQ:SE-2), and for a subset of children with additional specialist tools such as the Modified Checklist for Autism in Toddlers (M-CHAT) if the ASQ3/SE indicate these are necessary. The ASQ score for each domain was categorised as "concern" and "no concern." We used multivariate cubic regression splines to model the associations between birthweight centiles and early childhood developmental concerns. We used multivariate Poisson regression models, with cluster robust errors, to estimate the relative risks (RRs) of developmental concerns below and above the established thresholds. We adjusted for maternal age, early pregnancy body mass index (BMI), parity, year of delivery, gestational age at delivery, smoking history, substance misuse in pregnancy, alcohol intake, ethnicity, residential area deprivation index, maternal clinical conditions in pregnancy (such as diabetes and pre-eclampsia), induction of labour, and child's sex. Babies born from 37 weeks of gestation with birthweight below the 25th centile, compared to those between the 25th and 74th centile, were at higher risk of developmental concerns. Those born between the 10th and 24th centile had an RR of 1.07 (95% CI: 1.03 to 1.12, p < 0.001), between the 3rd and 9th centile had an RR: 1.18 (95% CI: 1.12 to 1.25, p < 0.001), and <3rd centile had an RR of 1.37 (95% CI: 1.24 to 1.50, p < 0.001). There was no substantial increase in the risk of early childhood developmental concerns for larger birthweight categories of 75th to 89th (RR: 1.01; 95% CI: 0.97 to 1.05; p = 0.56), 90th to 96th (RR: 0.99; 95% CI: 0.94 to 1.05; p = 0.86), and ≥97th centiles (RR: 1.04; 95% CI: 0.97 to 1.12; p = 0.27), referent to birthweight between 25th and 74th centile. The percentage of developmental concerns attributable to birthweight between the 10th and 24th centile was more than that of birthweight <3rd centile (p = 0.023) because this group includes more of the population. Approximately 2.50% (95% CI: 1.26 to 3.61) of social skills concerns and 3.00% (95% CI: 1.33 to 4.67) of fine motor developmental concerns were attributable to birthweight between the 10th and 24th centile compared to 0.90% (95% CI: 0.48 to 1.26) and 2.30% (95% CI: 1.73 to 2.67) respectively for birthweight <3rd centile. We acknowledge the limitation of ASQ as a screening tool, the subjective nature of developmental assessments (particularly for speech) among young children, and inability to control for early childhood illness and upbringing factors may have an impact on our findings. CONCLUSIONS: We observed that from 37 weeks of gestation birthweight below the 25th centile was associated with child developmental concerns, with an association apparent at higher centiles above the conventional threshold defining small for gestational age (SGA, 3rd or 10th centile). Mild to moderate SGA is an unrecognised potentially important contributor to the prevalence of developmental concerns. Closer surveillance, appropriate parental counselling, and increased support during childhood may reduce the risks associated with lower birthweight centiles.

Trends in Prescriptions of Cardioprotective Diabetic Agents After Coronary Artery Bypass Grafting Among U.S. Veterans.

OBJECTIVE: Patients with type 2 diabetes undergoing coronary artery bypass grafting (CABG) are at risk for cardiovascular events. Sodium-glucose cotransporter 2 receptor inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1RA) are effective cardioprotective agents; however, their prescription among CABG patients is uncertain. The aims of this study were 1) to evaluate the overall use of SGLT2i/GLP-1RA after CABG and explore longitudinal trends and 2) to examine patient-related factors associated with the use of SGLT2i or GLP-1RA. RESEARCH DESIGN AND METHODS: We analyzed the nationwide Veterans Affairs (VA) database (2016-2019) to report trends and factors associated with SGLT2i or GLP-1RA prescription after CABG. RESULTS: Among 5,109 patients operated on at 40 different VA medical centers, 525 of 5,109 (10.4%), 352 of 5,109 (6.8%), and 91 of 5,109 (1.8%) were prescribed SGLT2i, GLP-1RA, and both, respectively. A substantial increase in the quarterly SGLT2i prescription rates (1.6% [first quarter of 2016 (2016Q1)], 33% [2019Q4]) was present but was lower for GLP-1RA (0.8% [2016Q1], 11.2% [2019Q4]). SGLT2i use was less likely with preexisting vascular disease (odd ratio [OR] 0.75, 95% CI 0.75, 0.94) or kidney disease (OR 0.72, 95% CI 0.58, 0.88), while GLP-1RA use was associated with obesity (OR 1.91, 95% CI 1.50, 2.46). CONCLUSIONS: The overall utilization of SGLT2i or GLP-1RA drugs in U.S. veterans with type 2 diabetes undergoing CABG is low, with SGLT2i preferred over GLP-1RA.

Muscle strength and incidence of depression and anxiety: findings from the UK Biobank prospective cohort study.

BACKGROUND: Depression and anxiety are the leading mental health problems worldwide; depression is ranked as the leading cause of global disability with anxiety disorders ranked sixth. Preventive strategies based on the identification of modifiable factors merit exploration. The aim of the present study was to investigate the associations of handgrip strength (HGS) with incident depression and anxiety and to explore how these associations differ by socio-demographic, lifestyle, and health-related factors. METHODS: The analytic sample comprised 162 167 participants (55% women), aged 38-70 years, from the UK Biobank prospective cohort study. HGS was assessed at baseline using dynamometry. Depression and anxiety were extracted from primary care and hospital admission records. Cox proportional models were applied, with a 2 year landmark analysis, to investigate the associations between HGS and incident depression and anxiety. RESULTS: Of the 162 167 participants included, 5462 (3.4%) developed depression and 6614 (4.1%) anxiety, over a median follow-up period of 10.0 years (inter-quartile range: 9.3-10.8) for depression and 9.9 (inter-quartile range: 9.0-10.8) for anxiety. In the fully adjusted model, a 5 kg lower HGS was associated with a 7% (HR: 1.07 [95% CI: 1.05, 1.10]; P < 0.001) and 8% (HR: 1.08 [95% CI: 1.06, 1.10]; P < 0.001) higher risk of depression and anxiety, respectively. Compared with participants in the sex and age-specific highest tertiles of HGS, those in the medium and lowest tertiles had an 11% (HR: 1.11 [95% CI: 1.04, 1.19]; P = 0.002) and 24% (HR: 1.24 [95% CI: 1.16, 1.33]; P < 0.001) higher risk of depression and 13% (HR: 1.13 [95% CI: 1.06, 1.20]; P < 0.001) and 27% (HR: 1.27 [95% CI: 1.19, 1.35]; P < 0.001) higher risk of anxiety, respectively. The association of HGS with depression was stronger among participants with average or brisk walking pace (vs. slow walking pace; Pinteraction  < 0.001). The association with anxiety was stronger in those participants aged ≥58 years (vs. ≤58 years; Pinteraction  = 0.002) and those living in more affluent areas (vs. deprived; Pinteraction  = 0.001). CONCLUSIONS: Handgrip strength was inversely associated with incident depression and anxiety. Because HGS is a simple, non-invasive, and inexpensive measure, it could be easily used in clinical practice to stratify patients and identify those at elevated risk of mental health problems. However, future research should assess if resistance training aimed at increasing HGS can prevent the occurrence of mental health conditions.