Redefining ALS: Large-scale proteomic profiling reveals a prolonged pre-diagnostic phase with immune, muscular, metabolic, and brain involvement.

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with a largely unknown duration and pathophysiology of the pre-diagnostic phase, especially for the common non-monogenic form.

Methods: We leveraged the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort with up to 30 years of follow-up to identify incident ALS cases across five European countries. Pre-diagnostic plasma samples from initially healthy participants underwent high-throughput proteomic profiling (7,285 protein markers, SomaScan).

Trends in mortality and hospitalisations for cardiovascular, kidney and liver disease in people with type 2 diabetes in England, 2009-2019.

Aims: To assess longitudinal trends in total and cause-specific mortality rates and in hospitalisation rates for diabetes complications among people with type 2 diabetes in England between 2009 and 2019; and to assess how trends differ by patient characteristics.

Materials And Methods: A sequential cohort study of people with type 2 diabetes aged ≥20 years was performed using data from the National Diabetes Audit. Discretised Poisson regression models, adjusted for age, sex, ethnicity, socio-economic deprivation and diabetes duration, were used to calculate total and cause-specific mortality rates, as well as hospitalisation rates for myocardial infarction, stroke, heart failure, kidney and liver disease.

Large-scale plasma proteomics uncovers preclinical molecular signatures of Parkinson's disease and overlap with other neurodegenerative disorders.

Parkinson's disease (PD) remains incurable, with a long preclinical phase currently undetectable by existing methods. In the largest proteomic study in neurodegenerative diseases to date, we analyzed blood samples from ~74,000 individuals across discovery and validation cohorts. In the EPIC4PD discovery case-cohort, large-scale profiling of 7,285 proteins (SomaScan-7K) in 4,538 initially unaffected participants (574 incident cases) identified 17 proteins that predict PD up to 28 years before diagnosis.

Associations of proteomic age with mortality and incident chronic diseases in the European Prospective Investigation into Cancer and Nutrition (EPIC).

Assessment of biological ageing using proteomic clocks may enhance risk prediction and elucidate the molecular links between ageing and chronic diseases. Within a pre-diagnostic cohort of 17,473 Europeans with up to 28 years of follow-up, we examined associations of plasma SomaScan-based proteomic clocks, including organ-specific clocks, with 24 incident chronic diseases, all-cause mortality, and lifestyle risk factors. Global proteomic age gap (a composite biological age acceleration score combining previously published clocks) showed the strongest positive association of all tested clocks with all-cause mortality.

Impact of supervised aerobic exercise training on habitual physical activity in healthy older adults: the Hertfordshire physical activity randomised controlled trial.

Objectives: Physical activity is important for health, but the influence of structured, supervised aerobic exercise sessions on habitual physical activity in healthy older adults is unclear.

Methods: We evaluated habitual physical activity in the Hertfordshire Physical Activity Trial, where healthy older adults were randomised to 36 supervised 1-hour gymnasium sessions on a cycle ergometer at moderate intensity over 12 weeks or to a control group with no intervention. We estimated physical activity energy expenditure (PAEE) and time spent in sedentary behaviour and light and moderate or vigorous physical activity over 7 days at three time points (before, during and immediately after the intervention) with individually calibrated combined heart rate and movement sensing.

Trends in hospitalization for cardio-renal disease and mortality in people with type 1 diabetes in England, 2009-2019.

Aim: To assess mortality and complication trends in people with type 1 diabetes during the 11 years before the SARS-CoV2 pandemic (2009-2019).

Materials And Methods: Sequential cohorts of people in England with type 1 diabetes aged ≥20 years from the National Diabetes Audit (2006/2007 to 2016/2017) were analysed. Discretized Poisson regression models, adjusted for age, sex, ethnicity, socioeconomic deprivation and duration of diabetes, were used to calculate mortality and hospitalization rates.

Proteomic analysis of cardiorespiratory fitness for prediction of mortality and multisystem disease risks.

Despite the wide effects of cardiorespiratory fitness (CRF) on metabolic, cardiovascular, pulmonary and neurological health, challenges in the feasibility and reproducibility of CRF measurements have impeded its use for clinical decision-making. Here we link proteomic profiles to CRF in 14,145 individuals across four international cohorts with diverse CRF ascertainment methods to establish, validate and characterize a proteomic CRF score. In a cohort of around 22,000 individuals in the UK Biobank, a proteomic CRF score was associated with a reduced risk of all-cause mortality (unadjusted hazard ratio 0.

Relationship between HLA genetic variations, COVID-19 vaccine antibody response, and risk of breakthrough outcomes.

The rapid global distribution of COVID-19 vaccines, with over a billion doses administered, has been unprecedented. However, in comparison to most identified clinical determinants, the implications of individual genetic factors on antibody responses post-COVID-19 vaccination for breakthrough outcomes remain elusive. Here, we conducted a population-based study including 357,806 vaccinated participants with high-resolution HLA genotyping data, and a subset of 175,000 with antibody serology test results.

Protein-truncating variants in BSN are associated with severe adult-onset obesity, type 2 diabetes and fatty liver disease.

Obesity is a major risk factor for many common diseases and has a substantial heritable component. To identify new genetic determinants, we performed exome-sequence analyses for adult body mass index (BMI) in up to 587,027 individuals. We identified rare loss-of-function variants in two genes (BSN and APBA1) with effects substantially larger than those of well-established obesity genes such as MC4R.

The relationship of within-individual and between-individual variation in mental health with bodyweight: An exploratory longitudinal study.

Background: Poor mental health is associated with obesity, but existing studies are either cross-sectional or have long time periods between measurements of mental health and weight. It is, therefore, unclear how small fluctuations in mental wellbeing within individuals predict bodyweight over short time periods, e.g.

The optimal healthy ranges of thyroid function defined by the risk of cardiovascular disease and mortality: systematic review and individual participant data meta-analysis.

Background: Reference intervals of thyroid-stimulating hormone (TSH) and free thyroxine (FT) are statistically defined by the 2·5-97·5th percentiles, without accounting for potential risk of clinical outcomes. We aimed to define the optimal healthy ranges of TSH and FT based on the risk of cardiovascular disease and mortality.

Methods: This systematic review and individual participant data (IPD) meta-analysis identified eligible prospective cohorts through the Thyroid Studies Collaboration, supplemented with a systematic search via Embase, MEDLINE (Ovid), Web of science, the Cochrane Central Register of Controlled Trials, and Google Scholar from Jan 1, 2011, to Feb 12, 2017 with an updated search to Oct 13, 2022 (cohorts found in the second search were not included in the IPD).

Associations between change in physical activity and sedentary time and health-related quality of life in older english adults: the EPIC-Norfolk cohort study.

Background: No previous studies have examined the associations between changes in objectively-measured physical behaviours with follow-up QoL in older adults. Based on cross-sectional evidence, it is biologically plausible that such associations exist. If so, this bolsters the case for the commissioning of activity interventions and for including QoL as an outcome in trials of such interventions.

Resting heart rate is a population-level biomarker of cardiorespiratory fitness: The Fenland Study.

Introduction: Few large studies have evaluated the relationship between resting heart rate (RHR) and cardiorespiratory fitness. Here we examine cross-sectional and longitudinal relationships between RHR and fitness, explore factors that influence these relationships, and demonstrate the utility of RHR for remote population monitoring.

Methods: In cross-sectional analyses (The UK Fenland Study: 5,722 women, 5,143 men, aged 29-65y), we measured RHR (beats per min, bpm) while seated, supine, and during sleep.

Lowering of Circulating Sclerostin May Increase Risk of Atherosclerosis and Its Risk Factors: Evidence From a Genome-Wide Association Meta-Analysis Followed by Mendelian Randomization.

Objective: In this study, we aimed to establish the causal effects of lowering sclerostin, target of the antiosteoporosis drug romosozumab, on atherosclerosis and its risk factors.

Methods: A genome-wide association study meta-analysis was performed of circulating sclerostin levels in 33,961 European individuals. Mendelian randomization (MR) was used to predict the causal effects of sclerostin lowering on 15 atherosclerosis-related diseases and risk factors.

Descriptive Epidemiology of Cardiorespiratory Fitness in UK Adults: The Fenland Study.

Introduction: Cardiorespiratory fitness (CRF) is rarely measured in population studies. Most studies of CRF do not examine differences by population subgroups or seasonal trends. We examined how estimated CRF levels vary by anthropometric, sociodemographic, and behavioral characteristics in a population-based cohort of UK adults (the Fenland Study).

Quantifying the Relationship Between Physical Activity Energy Expenditure and Incident Type 2 Diabetes: A Prospective Cohort Study of Device-Measured Activity in 90,096 Adults.

Objective: To investigate the association between accelerometer-derived physical activity energy expenditure (PAEE) and incident type 2 diabetes (T2D) in a cohort of middle-aged adults and within subgroups.

Research Design And Methods: Data were from 90,096 UK Biobank participants without prevalent diabetes (mean 62 years of age; 57% women) who wore a wrist accelerometer for 7 days. PAEE was derived from wrist acceleration using a population-specific method validated against doubly labeled water.

Effectiveness of digital and remote provision of the Healthier You: NHS Diabetes Prevention Programme during the COVID-19 pandemic.

Aims: To assess weight change in the Healthier You: NHS Diabetes Prevention Programme (NHS DPP) delivered via video conferencing (remote) sessions or delivered via specific digital interventions through apps or websites, during the COVID-19 pandemic compared to group-based face-to-face interventions, pre-pandemic.

Methods: Prospectively collected national service-level data relating to individuals with non-diabetic hyperglycaemia (HbA 42-47 mmol/mol (6.0%-6.

Bidirectional associations of accelerometer-assessed physical activity and sedentary time with physical function among older English adults: the EPIC-Norfolk cohort study.

Unlabelled: To develop healthy ageing interventions, longitudinal associations between objectively assessed physical behaviours and physical function need to be better understood. We assessed associations between accelerometer-assessed total physical activity (PA), moderate-to-vigorous physical activity (MVPA), light physical activity (LPA), sedentary time and prolonged sedentary bout time, and clinically assessed physical function (grip strength, usual walking speed (UWS), chair stand speed) at two time-points in 3188 participants (≥ 60 years) of the EPIC-Norfolk study. Bidirectional associations were assessed using multivariable linear regression.

Mild-to-Moderate Kidney Dysfunction and Cardiovascular Disease: Observational and Mendelian Randomization Analyses.

Background: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke.

Methods: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition-Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.