A lifecourse mendelian randomization study highlights the long-term influence of childhood body size on later life heart structure.

Children with obesity typically have larger left ventricular heart dimensions during adulthood. However, whether this is due to a persistent effect of adiposity extending into adulthood is challenging to disentangle due to confounding factors throughout the lifecourse. We conducted a multivariable mendelian randomization (MR) study to separate the independent effects of childhood and adult body size on 4 magnetic resonance imaging (MRI) measures of heart structure and function in the UK Biobank (UKB) study. Strong evidence of a genetically predicted effect of childhood body size on all measures of adulthood heart structure was identified, which remained robust upon accounting for adult body size using a multivariable MR framework (e.g., left ventricular end-diastolic volume (LVEDV), Beta = 0.33, 95% confidence interval (CI) = 0.23 to 0.43, P = 4.6 × 10-10). Sensitivity analyses did not suggest that other lifecourse measures of body composition were responsible for these effects. Conversely, evidence of a genetically predicted effect of childhood body size on various other MRI-based measures, such as fat percentage in the liver (Beta = 0.14, 95% CI = 0.05 to 0.23, P = 0.002) and pancreas (Beta = 0.21, 95% CI = 0.10 to 0.33, P = 3.9 × 10-4), attenuated upon accounting for adult body size. Our findings suggest that childhood body size has a long-term (and potentially immutable) influence on heart structure in later life. In contrast, effects of childhood body size on other measures of adulthood organ size and fat percentage evaluated in this study are likely explained by the long-term consequence of remaining overweight throughout the lifecourse.

Apolipoprotein Proteomics for Residual Lipid-Related Risk in Coronary Heart Disease.

BACKGROUND: Recognition of the importance of conventional lipid measures and the advent of novel lipid-lowering medications have prompted the need for more comprehensive lipid panels to guide use of emerging treatments for the prevention of coronary heart disease (CHD). This report assessed the relevance of 13 apolipoproteins measured using a single mass-spectrometry assay for risk of CHD in the PROCARDIS case-control study of CHD (941 cases/975 controls). METHODS: The associations of apolipoproteins with CHD were assessed after adjustment for established risk factors and correction for statin use. Apolipoproteins were grouped into 4 lipid-related classes [lipoprotein(a), low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides] and their associations with CHD were adjusted for established CHD risk factors and conventional lipids. Analyses of these apolipoproteins in a subset of the ASCOT trial (Anglo-Scandinavian Cardiac Outcomes Trial) were used to assess their within-person variability and to estimate a correction for statin use. The findings in the PROCARDIS study were compared with those for incident cardiovascular disease in the Bruneck prospective study (n=688), including new measurements of Apo(a). RESULTS: Triglyceride-carrying apolipoproteins (ApoC1, ApoC3, and ApoE) were most strongly associated with the risk of CHD (2- to 3-fold higher odds ratios for top versus bottom quintile) independent of conventional lipid measures. Likewise, ApoB was independently associated with a 2-fold higher odds ratios of CHD. Lipoprotein(a) was measured using peptides from the Apo(a)-kringle repeat and Apo(a)-constant regions, but neither of these associations differed from the association with conventionally measured lipoprotein(a). Among HDL-related apolipoproteins, ApoA4 and ApoM were inversely related to CHD, independent of conventional lipid measures. The disease associations with all apolipoproteins were directionally consistent in the PROCARDIS and Bruneck studies, with the exception of ApoM. CONCLUSIONS: Apolipoproteins were associated with CHD independent of conventional risk factors and lipids, suggesting apolipoproteins could help to identify patients with residual lipid-related risk and guide personalized approaches to CHD risk reduction.

Childhood adiposity underlies numerous adult brain traits commonly attributed to midlife obesity.

Obese adults are often reported to have smaller brain volumes than their non-obese peers. Whether this represents evidence of accelerations in obesity-driven atrophy or is instead a legacy of developmental differences established earlier in the lifespan remains unclear. This study aimed to investigate whether early-life differences in adiposity explain differences in numerous adult brain traits commonly attributed to mid-life obesity. We utilised a two-sample lifecourse Mendelian randomization study in 37,501 adults recruited to UK Biobank (UKB) imaging centers from 2014, with secondary analyses in 6,996 children assessed in the Adolescent Brain Cognitive Development Study (ABCD) recruited from 2018. Exposures were genetic variants for childhood (266 variants) and adult (470 variants) adiposity derived from a GWAS of 407,741 UKB participants. Primary outcomes were adult total brain volume; grey matter volume, thickness, and surface area; white matter volume and hyperintensities; and hippocampus, amygdala, and thalamus volumes at mean age 55 in UKB. Secondary outcomes were equivalent childhood measures collected at mean age 10 in ABCD. In UKB, individuals who were genetically-predicted to have had higher levels of adiposity in childhood were found to have multiple smaller adult brain volumes relative to intracranial volume (e.g. z-score difference in normalised brain volume per category increase in adiposity [95%CI] = -0.20 [-0.28, -0.12]; p = 4 × 10-6). These effect sizes remained essentially unchanged after accounting for birthweight or current adult obesity in multivariable models, whereas most observed adult effects attenuated towards null (e.g. adult z-score [95%CI] for total volume = 0.06 [-0.05,0.17]; p = 0.3). Observational analyses in ABCD showed a similar pattern of changes already present in those with a high BMI by age 10 (z-score [95%CI] = -0.10 [-0.13, -0.07]; p = 8 × 10-13), with follow-up genetic risk score analyses providing some evidence for a causal effect already at this early age. Sensitivity analyses revealed that many of these effects were likely due to the persistence of larger head sizes established in those who gained excess weight in childhood (childhood z-score [95%CI] for intracranial volume = 0.14 [0.05,0.23]; p = 0.002), rather than smaller brain sizes per se. Our data suggest that persistence of early-life developmental differences across the lifecourse may underlie numerous neuroimaging traits commonly attributed to obesity-related atrophy in later life.

Device-measured physical activity and cardiometabolic health: the Prospective Physical Activity, Sitting, and Sleep (ProPASS) consortium.

BACKGROUND AND AIMS: Physical inactivity, sedentary behaviour (SB), and inadequate sleep are key behavioural risk factors of cardiometabolic diseases. Each behaviour is mainly considered in isolation, despite clear behavioural and biological interdependencies. The aim of this study was to investigate associations of five-part movement compositions with adiposity and cardiometabolic biomarkers. METHODS: Cross-sectional data from six studies (n = 15 253 participants; five countries) from the Prospective Physical Activity, Sitting and Sleep consortium were analysed. Device-measured time spent in sleep, SB, standing, light-intensity physical activity (LIPA), and moderate-vigorous physical activity (MVPA) made up the composition. Outcomes included body mass index (BMI), waist circumference, HDL cholesterol, total:HDL cholesterol ratio, triglycerides, and glycated haemoglobin (HbA1c). Compositional linear regression examined associations between compositions and outcomes, including modelling time reallocation between behaviours. RESULTS: The average daily composition of the sample (age: 53.7 ± 9.7 years; 54.7% female) was 7.7 h sleeping, 10.4 h sedentary, 3.1 h standing, 1.5 h LIPA, and 1.3 h MVPA. A greater MVPA proportion and smaller SB proportion were associated with better outcomes. Reallocating time from SB, standing, LIPA, or sleep into MVPA resulted in better scores across all outcomes. For example, replacing 30 min of SB, sleep, standing, or LIPA with MVPA was associated with -0.63 (95% confidence interval -0.48, -0.79), -0.43 (-0.25, -0.59), -0.40 (-0.25, -0.56), and -0.15 (0.05, -0.34) kg/m2 lower BMI, respectively. Greater relative standing time was beneficial, whereas sleep had a detrimental association when replacing LIPA/MVPA and positive association when replacing SB. The minimal displacement of any behaviour into MVPA for improved cardiometabolic health ranged from 3.8 (HbA1c) to 12.7 (triglycerides) min/day. CONCLUSIONS: Compositional data analyses revealed a distinct hierarchy of behaviours. Moderate-vigorous physical activity demonstrated the strongest, most time-efficient protective associations with cardiometabolic outcomes. Theoretical benefits from reallocating SB into sleep, standing, or LIPA required substantial changes in daily activity.

Relationship of device measured physical activity type and posture with cardiometabolic health markers: pooled dose-response associations from the Prospective Physical Activity, Sitting and Sleep Consortium.

AIMS/HYPOTHESIS: The aim of this study was to examine the dose-response associations of device-measured physical activity types and postures (sitting and standing time) with cardiometabolic health. METHODS: We conducted an individual participant harmonised meta-analysis of 12,095 adults (mean ± SD age 54.5±9.6 years; female participants 54.8%) from six cohorts with thigh-worn accelerometry data from the Prospective Physical Activity, Sitting and Sleep (ProPASS) Consortium. Associations of daily walking, stair climbing, running, standing and sitting time with a composite cardiometabolic health score (based on standardised z scores) and individual cardiometabolic markers (BMI, waist circumference, triglycerides, HDL-cholesterol, HbA1c and total cholesterol) were examined cross-sectionally using generalised linear modelling and cubic splines. RESULTS: We observed more favourable composite cardiometabolic health (i.e. z score <0) with approximately 64 min/day walking (z score [95% CI] -0.14 [-0.25, -0.02]) and 5 min/day stair climbing (-0.14 [-0.24, -0.03]). We observed an equivalent magnitude of association at 2.6 h/day standing. Any amount of running was associated with better composite cardiometabolic health. We did not observe an upper limit to the magnitude of the dose-response associations for any activity type or standing. There was an inverse dose-response association between sitting time and composite cardiometabolic health that became markedly less favourable when daily durations exceeded 12.1 h/day. Associations for sitting time were no longer significant after excluding participants with prevalent CVD or medication use. The dose-response pattern was generally consistent between activity and posture types and individual cardiometabolic health markers. CONCLUSIONS/INTERPRETATION: In this first activity type-specific analysis of device-based physical activity, ~64 min/day of walking and ~5.0 min/day of stair climbing were associated with a favourable cardiometabolic risk profile. The deleterious associations of sitting time were fully attenuated after exclusion of participants with prevalent CVD and medication use. Our findings on cardiometabolic health and durations of different activities of daily living and posture may guide future interventions involving lifestyle modification.

Updating the study protocol: Insight 46 - a longitudinal neuroscience sub-study of the MRC National Survey of Health and Development - phases 2 and 3.

BACKGROUND: Although age is the biggest known risk factor for dementia, there remains uncertainty about other factors over the life course that contribute to a person's risk for cognitive decline later in life. Furthermore, the pathological processes leading to dementia are not fully understood. The main goals of Insight 46-a multi-phase longitudinal observational study-are to collect detailed cognitive, neurological, physical, cardiovascular, and sensory data; to combine those data with genetic and life-course information collected from the MRC National Survey of Health and Development (NSHD; 1946 British birth cohort); and thereby contribute to a better understanding of healthy ageing and dementia. METHODS/DESIGN: Phase 1 of Insight 46 (2015-2018) involved the recruitment of 502 members of the NSHD (median age = 70.7 years; 49% female) and has been described in detail by Lane and Parker et al. 2017. The present paper describes phase 2 (2018-2021) and phase 3 (2021-ongoing). Of the 502 phase 1 study members who were invited to a phase 2 research visit, 413 were willing to return for a clinic visit in London and 29 participated in a remote research assessment due to COVID-19 restrictions. Phase 3 aims to recruit 250 study members who previously participated in both phases 1 and 2 of Insight 46 (providing a third data time point) and 500 additional members of the NSHD who have not previously participated in Insight 46. DISCUSSION: The NSHD is the oldest and longest continuously running British birth cohort. Members of the NSHD are now at a critical point in their lives for us to investigate successful ageing and key age-related brain morbidities. Data collected from Insight 46 have the potential to greatly contribute to and impact the field of healthy ageing and dementia by combining unique life course data with longitudinal multiparametric clinical, imaging, and biomarker measurements. Further protocol enhancements are planned, including in-home sleep measurements and the engagement of participants through remote online cognitive testing. Data collected are and will continue to be made available to the scientific community.

APOE ε4 carriage associates with improved myocardial performance from adolescence to older age.

BACKGROUND: Although APOE ε4 allele carriage confers a risk for coronary artery disease, its persistence in humans might be explained by certain survival advantages (antagonistic pleiotropy). METHODS: Combining data from ~ 37,000 persons from three older age British cohorts (1946 National Survey of Health and Development [NSHD], Southall and Brent Revised [SABRE], and UK Biobank) and one younger age cohort (Avon Longitudinal Study of Parents and Children [ALSPAC]), we explored whether APOE ε4 carriage associates with beneficial or unfavorable left ventricular (LV) structural and functional metrics by echocardiography and cardiovascular magnetic resonance (CMR). RESULTS: Compared to the non-APOE ε4 group, APOE ε4 carriers had similar cardiac phenotypes in terms of LV ejection fraction, E/e', posterior wall and interventricular septal thickness, and LV mass. However, they had improved myocardial performance resulting in greater LV stroke volume generation per 1 mL of myocardium (higher myocardial contraction fraction). In NSHD (n = 1467) and SABRE (n = 1187), ε4 carriers had a 4% higher MCF (95% CI 1-7%, p = 0.016) using echocardiography. Using CMR data, in UK Biobank (n = 32,972), ε4 carriers had a 1% higher MCF 95% (CI 0-1%, p = 0.020) with a dose-response relationship based on the number of ε4 alleles. In addition, UK Biobank ε4 carriers also had more favorable radial and longitudinal strain rates compared to non APOE ε4 carriers. In ALSPAC (n = 1397), APOE ε4 carriers aged < 24 years had a 2% higher MCF (95% CI 0-5%, p = 0.059). CONCLUSIONS: By triangulating results in four independent cohorts, across imaging modalities (echocardiography and CMR), and in ~ 37,000 individuals, our results point towards an association between ε4 carriage and improved cardiac performance in terms of LV MCF. This potentially favorable cardiac phenotype adds to the growing number of reported survival advantages attributed to the pleiotropic effects APOE ε4 carriage that might collectively explain its persistence in human populations.

Common infections and neuroimaging markers of dementia in three UK cohort studies.

INTRODUCTION: We aimed to investigate associations between common infections and neuroimaging markers of dementia risk (brain volume, hippocampal volume, white matter lesions) across three population-based studies. METHODS: We tested associations between serology measures (pathogen serostatus, cumulative burden, continuous antibody responses) and outcomes using linear regression, including adjustments for total intracranial volume and scanner/clinic information (basic model), age, sex, ethnicity, education, socioeconomic position, alcohol, body mass index, and smoking (fully adjusted model). Interactions between serology measures and apolipoprotein E (APOE) genotype were tested. Findings were meta-analyzed across cohorts (Nmain  = 2632; NAPOE-interaction  = 1810). RESULTS: Seropositivity to John Cunningham virus associated with smaller brain volumes in basic models (ß = -3.89 mL [-5.81, -1.97], Padjusted  < 0.05); these were largely attenuated in fully adjusted models (ß = -1.59 mL [-3.55, 0.36], P = 0.11). No other relationships were robust to multiple testing corrections and sensitivity analyses, but several suggestive associations were observed. DISCUSSION: We did not find clear evidence for relationships between common infections and markers of dementia risk. Some suggestive findings warrant testing for replication.

Arterial pulse wave modeling and analysis for vascular-age studies: a review from VascAgeNet.

Arterial pulse waves (PWs) such as blood pressure and photoplethysmogram (PPG) signals contain a wealth of information on the cardiovascular (CV) system that can be exploited to assess vascular age and identify individuals at elevated CV risk. We review the possibilities, limitations, complementarity, and differences of reduced-order, biophysical models of arterial PW propagation, as well as theoretical and empirical methods for analyzing PW signals and extracting clinically relevant information for vascular age assessment. We provide detailed mathematical derivations of these models and theoretical methods, showing how they are related to each other. Finally, we outline directions for future research to realize the potential of modeling and analysis of PW signals for accurate assessment of vascular age in both the clinic and in daily life.

Correction: Lipoprotein signatures of cholesteryl ester transfer protein and HMG-CoA reductase inhibition.

[This corrects the article DOI: 10.1371/journal.pbio.3000572.].

Developing a medical device-grade T2 phantom optimized for myocardial T2 mapping by cardiovascular magnetic resonance.

INTRODUCTION: A long T2 relaxation time can reflect oedema, and myocardial inflammation when combined with increased plasma troponin levels. Cardiovascular magnetic resonance (CMR) T2 mapping therefore has potential to provide a key diagnostic and prognostic biomarkers. However, T2 varies by scanner, software, and sequence, highlighting the need for standardization and for a quality assurance system for T2 mapping in CMR. AIM: To fabricate and assess a phantom dedicated to the quality assurance of T2 mapping in CMR. METHOD: A T2 mapping phantom was manufactured to contain 9 T1 and T2 (T1|T2) tubes to mimic clinically relevant native and post-contrast T2 in myocardium across the health to inflammation spectrum (i.e., 43-74 ms) and across both field strengths (1.5 and 3 T). We evaluated the phantom's structural integrity, B0 and B1 uniformity using field maps, and temperature dependence. Baseline reference T1|T2 were measured using inversion recovery gradient echo and single-echo spin echo (SE) sequences respectively, both with long repetition times (10 s). Long-term reproducibility of T1|T2 was determined by repeated T1|T2 mapping of the phantom at baseline and at 12 months. RESULTS: The phantom embodies 9 internal agarose-containing T1|T2 tubes doped with nickel di-chloride (NiCl2) as the paramagnetic relaxation modifier to cover the clinically relevant spectrum of myocardial T2. The tubes are surrounded by an agarose-gel matrix which is doped with NiCl2 and packed with high-density polyethylene (HDPE) beads. All tubes at both field strengths, showed measurement errors up to ≤ 7.2 ms [< 14.7%] for estimated T2 by balanced steady-state free precession T2 mapping compared to reference SE T2 with the exception of the post-contrast tube of ultra-low T1 where the deviance was up to 16 ms [40.0%]. At 12 months, the phantom remained free of air bubbles, susceptibility, and off-resonance artifacts. The inclusion of HDPE beads effectively flattened the B0 and B1 magnetic fields in the imaged slice. Independent temperature dependency experiments over the 13-38 °C range confirmed the greater stability of shorter vs longer T1|T2 tubes. Excellent long-term (12-month) reproducibility of measured T1|T2 was demonstrated across both field strengths (all coefficients of variation < 1.38%). CONCLUSION: The T2 mapping phantom demonstrates excellent structural integrity, B0 and B1 uniformity, and reproducibility of its internal tube T1|T2 out to 1 year. This device may now be mass-produced to support the quality assurance of T2 mapping in CMR.

Technical development and feasibility of a reusable vest to integrate cardiovascular magnetic resonance with electrocardiographic imaging.

BACKGROUND: Electrocardiographic imaging (ECGI) generates electrophysiological (EP) biomarkers while cardiovascular magnetic resonance (CMR) imaging provides data about myocardial structure, function and tissue substrate. Combining this information in one examination is desirable but requires an affordable, reusable, and high-throughput solution. We therefore developed the CMR-ECGI vest and carried out this technical development study to assess its feasibility and repeatability in vivo. METHODS: CMR was prospectively performed at 3T on participants after collecting surface potentials using the locally designed and fabricated 256-lead ECGI vest. Epicardial maps were reconstructed to generate local EP parameters such as activation time (AT), repolarization time (RT) and activation recovery intervals (ARI). 20 intra- and inter-observer and 8 scan re-scan repeatability tests. RESULTS: 77 participants were recruited: 27 young healthy volunteers (HV, 38.9 ± 8.5 years, 35% male) and 50 older persons (77.0 ± 0.1 years, 52% male). CMR-ECGI was achieved in all participants using the same reusable, washable vest without complications. Intra- and inter-observer variability was low (correlation coefficients [rs] across unipolar electrograms = 0.99 and 0.98 respectively) and scan re-scan repeatability was high (rs between 0.81 and 0.93). Compared to young HV, older persons had significantly longer RT (296.8 vs 289.3 ms, p = 0.002), ARI (249.8 vs 235.1 ms, p = 0.002) and local gradients of AT, RT and ARI (0.40 vs 0.34 ms/mm, p = 0,01; 0.92 vs 0.77 ms/mm, p = 0.03; and 1.12 vs 0.92 ms/mm, p = 0.01 respectively). CONCLUSION: Our high-throughput CMR-ECGI solution is feasible and shows good reproducibility in younger and older participants. This new technology is now scalable for high throughput research to provide novel insights into arrhythmogenesis and potentially pave the way for more personalised risk stratification. CLINICAL TRIAL REGISTRATION: Title: Multimorbidity Life-Course Approach to Myocardial Health-A Cardiac Sub-Study of the MRC National Survey of Health and Development (NSHD) (MyoFit46). National Clinical Trials (NCT) number: NCT05455125. URL: https://clinicaltrials.gov/ct2/show/NCT05455125?term=MyoFit&draw=2&rank=1.

Adverse childhood experiences and the development of multimorbidity across adulthood-a national 70-year cohort study.

AIM: To examine impact of adverse childhood experiences (ACE) on rates and development of multimorbidity across three decades in adulthood. METHODS: Sample: Participants from the 1946 National Survey of Health and Development, who attended the age 36 assessment in 1982 and follow-up assessments (ages 43, 53, 63, 69; N = 3,264, 51% males). Prospectively collected data on nine ACEs was grouped into (i) psychosocial, (ii) parental health and (iii) childhood health. For each group, we calculated cumulative ACE scores, categorised into 0, 1 and ≥2 ACEs. Multimorbidity was estimated as the total score of 18 health disorders.Serial cross-sectional linear regression was used to estimate associations between grouped ACEs and multimorbidity during follow-up. Longitudinal analysis of ACE-associated changes in multimorbidity trajectories across follow-up was estimated using linear mixed-effects modelling for ACE groups (adjusted for sex and childhood socioeconomic circumstances). FINDINGS: Accumulation of psychosocial and childhood health ACEs were associated with progressively higher multimorbidity scores throughout follow-up. For example, those with ≥2 psychosocial ACEs experienced 0.20(95% CI 0.07, 0.34) more disorders at age 36 than those with none, rising to 0.61(0.18, 1.04) disorders at age 69.All three grouped ACEs were associated with greater rates of accumulation and higher multimorbidity trajectories across adulthood. For example, individuals with ≥2 psychosocial ACEs developed 0.13(-0.09, 0.34) more disorders between ages 36 and 43, 0.29(0.06, 0.52) disorders between ages 53 and 63, and 0.30(0.09, 0.52) disorders between ages 63 and 69 compared with no psychosocial ACEs. INTERPRETATIONS: ACEs are associated with widening inequalities in multimorbidity development in adulthood and early old age. Public health policies should aim to reduce these disparities through individual and population-level interventions.

Assessment of Microvascular Disease in Heart and Brain by MRI: Application in Heart Failure with Preserved Ejection Fraction and Cerebral Small Vessel Disease.

The objective of this review is to investigate the commonalities of microvascular (small vessel) disease in heart failure with preserved ejection fraction (HFpEF) and cerebral small vessel disease (CSVD). Furthermore, the review aims to evaluate the current magnetic resonance imaging (MRI) diagnostic techniques for both conditions. By comparing the two conditions, this review seeks to identify potential opportunities to improve the understanding of both HFpEF and CSVD.

Association between carotid atherosclerosis and brain activation patterns during the Stroop task in older adults: An fNIRS investigation.

There is an increasing body of evidence suggesting that vascular disease could contribute to cognitive decline and overt dementia. Of particular interest is atherosclerosis, as it is not only associated with dementia, but could be a potential mechanism through which cardiovascular disease directly impacts brain health. In this work, we evaluated the differences in functional near infrared spectroscopy (fNIRS)-based measures of brain activation, task performance, and the change in central hemodynamics (mean arterial pressure (MAP) and heart rate (HR)) during a Stroop color-word task in individuals with atherosclerosis, defined as bilateral carotid plaques (n = 33) and healthy age-matched controls (n = 33). In the healthy control group, the left prefrontal cortex (LPFC) was the only region showing evidence of activation when comparing the incongruous with the nominal Stroop test. A smaller extent of brain activation was observed in the Plaque group compared with the healthy controls (1) globally, as measured by oxygenated hemoglobin (p = 0.036) and (2) in the LPFC (p = 0.02) and left sensorimotor cortices (LMC)(p = 0.008) as measured by deoxygenated hemoglobin. There were no significant differences in HR, MAP, or task performance (both in terms of the time required to complete the task and number of errors made) between Plaque and control groups. These results suggest that carotid atherosclerosis is associated with altered functional brain activation patterns despite no evidence of impaired performance of the Stroop task or central hemodynamic changes.

The UK Coronavirus Job Retention Scheme and diet, physical activity, and sleep during the COVID-19 pandemic: evidence from eight longitudinal population surveys.

BACKGROUND: In March 2020, the UK implemented the Coronavirus Job Retention Scheme (furlough) to minimise job losses. Our aim was to investigate associations between furlough and diet, physical activity, and sleep during the early stages of the COVID-19 pandemic. METHODS: We analysed data on 25,092 participants aged 16-66 years from eight UK longitudinal studies. Changes in employment, including being furloughed, were based on employment status before and during the first lockdown. Health behaviours included fruit and vegetable consumption, physical activity, and sleep. Study-specific estimates obtained using modified Poisson regression, adjusting for socio-demographic characteristics and pre-pandemic health and health behaviours, were statistically pooled using random effects meta-analysis. Associations were also stratified by sex, age, and education. RESULTS: Across studies, between 8 and 25% of participants were furloughed. Compared to those who remained working, furloughed workers were slightly less likely to be physically inactive (RR = 0.85; [95% CI 0.75-0.97]; I 2 = 59%) and did not differ overall with respect to low fruit and vegetable consumption or atypical sleep, although findings for sleep were heterogenous (I 2 = 85%). In stratified analyses, furlough was associated with lower fruit and vegetable consumption among males (RR = 1.11; [1.01-1.22]; I 2 = 0%) but not females (RR = 0.84; [0.68-1.04]; I 2 = 65%). Considering changes in quantity, furloughed workers were more likely than those who remained working to report increases in fruit and vegetable consumption, exercise, and hours of sleep. CONCLUSIONS: Those furloughed exhibited similar health behaviours to those who remained in employment during the initial stages of the pandemic. There was little evidence to suggest that adoption of such social protection policies in the post-pandemic recovery period and during future economic crises had adverse effects on population health behaviours.

The UK Coronavirus Job Retention Scheme and smoking, alcohol consumption and vaping during the COVID-19 pandemic: evidence from eight longitudinal population surveys.

BACKGROUND: Employment disruptions can impact smoking and alcohol consumption. During the COVID-19 pandemic, many countries implemented furlough schemes to prevent job loss. We examine how furlough was associated with smoking, vaping and alcohol consumption in the UK. METHODS: Data from 27,841 participants in eight UK adult longitudinal surveys were analysed. Participants self-reported employment status and current smoking, current vaping and alcohol consumption (>4 days/week or 5+ drinks per typical occasion) both before and during the early stages of the pandemic (April-July 2020). Risk ratios were estimated within each study using modified Poisson regression, adjusting for a range of potential confounders, including pre-pandemic behaviour. Findings were synthesised using random effects meta-analysis. RESULTS: Compared to stable employment and after adjustment for pre-pandemic characteristics, furlough was not associated with smoking (ARR = 1.05; 95% CI: 0.95-1.16; I2: 10%), vaping (ARR = 0.89; 95% CI: 0.74-1.08; I2: 0%) or drinking (ARR = 1.03; 95% CI: 0.94-1.13; I2: 48%). There were similar findings for no longer being employed, and stable unemployment, though this varied by sex: stable unemployment was associated with smoking for women (ARR = 1.35; 95% CI: 1.00-1.82; I2: 47%) but not men (0.84; 95% CI: 0.67-1.05; I2: 0%). No longer being employed was associated with vaping among women (ARR = 2.74; 95% CI: 1.59-4.72; I2: 0%) but not men (ARR = 1.25; 95% CI: 0.83-1.87; I2: 0%). CONCLUSIONS: We found no clear evidence of furlough or unemployment having adverse impacts on smoking, vaping or drinking behaviours during the early stages of the COVID-19 pandemic in the UK. Differences in risk compared to those who remained employed were largely explained by pre-pandemic characteristics.

Lipoprotein signatures of cholesteryl ester transfer protein and HMG-CoA reductase inhibition.

Cholesteryl ester transfer protein (CETP) inhibition reduces vascular event risk, but confusion surrounds its effects on low-density lipoprotein (LDL) cholesterol. Here, we clarify associations of genetic inhibition of CETP on detailed lipoprotein measures and compare those to genetic inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). We used an allele associated with lower CETP expression (rs247617) to mimic CETP inhibition and an allele associated with lower HMGCR expression (rs12916) to mimic the well-known effects of statins for comparison. The study consists of 65,427 participants of European ancestries with detailed lipoprotein subclass profiling from nuclear magnetic resonance spectroscopy. Genetic associations were scaled to 10% reduction in relative risk of coronary heart disease (CHD). We also examined observational associations of the lipoprotein subclass measures with risk of incident CHD in 3 population-based cohorts totalling 616 incident cases and 13,564 controls during 8-year follow-up. Genetic inhibition of CETP and HMGCR resulted in near-identical associations with LDL cholesterol concentration estimated by the Friedewald equation. Inhibition of HMGCR had relatively consistent associations on lower cholesterol concentrations across all apolipoprotein B-containing lipoproteins. In contrast, the associations of the inhibition of CETP were stronger on lower remnant and very-low-density lipoprotein (VLDL) cholesterol, but there were no associations on cholesterol concentrations in LDL defined by particle size (diameter 18-26 nm) (-0.02 SD LDL defined by particle size; 95% CI: -0.10 to 0.05 for CETP versus -0.24 SD, 95% CI -0.30 to -0.18 for HMGCR). Inhibition of CETP was strongly associated with lower proportion of triglycerides in all high-density lipoprotein (HDL) particles. In observational analyses, a higher triglyceride composition within HDL subclasses was associated with higher risk of CHD, independently of total cholesterol and triglycerides (strongest hazard ratio per 1 SD higher triglyceride composition in very large HDL 1.35; 95% CI: 1.18-1.54). In conclusion, CETP inhibition does not appear to affect size-specific LDL cholesterol but is likely to lower CHD risk by lowering concentrations of other atherogenic, apolipoprotein B-containing lipoproteins (such as remnant and VLDLs). Inhibition of CETP also lowers triglyceride composition in HDL particles, a phenomenon reflecting combined effects of circulating HDL, triglycerides, and apolipoprotein B-containing particles and is associated with a lower CHD risk in observational analyses. Our results reveal that conventional composite lipid assays may mask heterogeneous effects of emerging lipid-altering therapies.

Multiphysics Modelling and Simulation of Thrombolysis via Activated Platelet-Targeted Nanomedicine.

PURPOSE: This study establishes a multiphysics simulation platform for both conventional and targeted thrombolysis using tissue plasminogen activator (tPA). Based on our computational results, the effects of therapeutic parameters on the dynamics of thrombolysis and the risk of side effects are investigated. METHODS: The model extends our previously developed one-dimensional(1D) mathematical models for fibrinolysis by incorporating targeted thrombolysis. It consists of two parts: (i) a coupled mathematical model of systemic pharmacokinetics (PK) and pharmacodynamics (PD) and local PD in a 1D occluded artery, and (ii) a mechanistic model for a targeted thrombolytic system via activated platelet-targeted tPA-loaded nanovesicles (tPA-NV), with model parameters derived from our in vitro experiments. A total of 16 therapeutic scenarios are simulated by varying the clot location and composition as well as the dosing regimen with free tPA or tPA-NV. RESULTS: Our simulation results indicate that tPA-NV offers several advantages over free tPA for thrombolysis. It reduces systemic exposure of tPA, thereby minimising the risk of bleeding complications. Simulations with different tPA-NV doses reveal that tPA-NV at 10% of the recommended dose can be as effective as the standard regimen with the full recommended dose of free tPA, demonstrating the potential of our tPA-NV as a new thrombolytic strategy with a reduced tPA dose. Moreover, faster recanalisation can be achieved with tPA-NV, especially for platelet-rich(or fibrin-poor) clots. CONCLUSIONS: Our simulation platform for thrombolysis with well-tuned model parameters can be used to evaluate and optimise treatment regimens of existing and new thrombolytic therapies via benefit/risk assessment under various therapeutic scenarios.

Distinct Body Mass Index Trajectories to Young-Adulthood Obesity and Their Different Cardiometabolic Consequences.

[Figure: see text].