Resistance to thyroid hormone induced tachycardia in RTHα syndrome.

Mutations in thyroid hormone receptor α1 (TRα1) cause Resistance to Thyroid Hormone α (RTHα), a disorder characterized by hypothyroidism in TRα1-expressing tissues including the heart. Surprisingly, we report that treatment of RTHα patients with thyroxine to overcome tissue hormone resistance does not elevate their heart rate. Cardiac telemetry in male, TRα1 mutant, mice indicates that such persistent bradycardia is caused by an intrinsic cardiac defect and not due to altered autonomic control. Transcriptomic analyses show preserved, thyroid hormone (T3)-dependent upregulation of pacemaker channels (Hcn2, Hcn4), but irreversibly reduced expression of several ion channel genes controlling heart rate. Exposure of TRα1 mutant male mice to higher maternal T3 concentrations in utero, restores altered expression and DNA methylation of ion channels, including Ryr2. Our findings indicate that target genes other than Hcn2 and Hcn4 mediate T3-induced tachycardia and suggest that treatment of RTHα patients with thyroxine in high dosage without concomitant tachycardia, is possible.

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. Fitness was estimated as maximal oxygen consumption (ml⋅min-1⋅kg-1) from an exercise test. Associations between RHR and fitness were evaluated while adjusting for age, sex, adiposity, and physical activity. In longitudinal analyses (6,589 participant subsample), we re-assessed RHR and fitness after a median of 6 years and evaluated the association between within-person change in RHR and fitness. During the coronavirus disease-2019 pandemic, we used a smartphone application to remotely and serially measure RHR (1,914 participant subsample, August 2020 to April 2021) and examined differences in RHR dynamics by pre-pandemic fitness level. RESULTS: Mean RHR while seated, supine, and during sleep was 67, 64, and 57 bpm. Age-adjusted associations (beta coefficients) between RHR and fitness were -0.26, -0.29, and -0.21 ml⋅kg-1⋅beat-1 in women and -0.27, -0.31, and -0.19 ml⋅kg-1⋅beat-1 in men. Adjustment for adiposity and physical activity attenuated the RHR-to-fitness relationship by 10% and 50%, respectively. Longitudinally, a 1-bpm increase in supine RHR was associated with a 0.23 ml⋅min-1⋅kg-1 decrease in fitness. During the pandemic, RHR increased in those with low pre-pandemic fitness but was stable in others. CONCLUSIONS: RHR is a valid population-level biomarker of cardiorespiratory fitness. Physical activity and adiposity attenuate the relationship between RHR and fitness.

Shorter sleep among adolescents is associated with lower fruit and vegetable consumption the following day.

BACKGROUND: Insufficient sleep has been associated with weight gain and metabolic dysregulation, with one suggested mechanism being through reduction in diet quality. Experimental evidence supports a causal effect of sleep timings on diet but this may not be applicable to a free-living adolescent population. In this analysis we use daily measures of sleep timings and diet quality, to examine the effect of sleep duration and timing on diet quality the following day among free-living adolescents. METHODS: The ROOTS study is a prospective cohort recruited from secondary schools in Cambridgeshire and Suffolk (UK). Participants (n = 815) at mean age 15.0y (SD 0.3y) completed a diet diary and wore a combined heart rate and accelerometer device over 4 consecutive days. Sleep duration and timing (midpoint) were derived from acceleration and heart rate traces, while daily energy density and fruit and vegetable intake were calculated from dietary data. Analyses were performed at day-level (1815 person-days). Multilevel random effects models were used to test associations between sleep each night and subsequent day diet, with daily sleep and diet measures nested within individuals and schools, and adjusted for day-level and individual-level confounding variables. RESULTS: Adolescents slept a mean of 7.88 hrs (SD 1.10) per night, reporting a mean energy density of 2.12 kcal/g (SD 0.48) and median energy-adjusted daily fruit and vegetable intake of 137.3 g (IQR 130.4). One hour shorter sleep duration was associated with lower intake of fruit and vegetables (-6.42 g, 95%CI -1.84, -10.99) the following day. An association with higher dietary energy density (0.016 kcal/g, 95%CI 0.034, -0.002) the following day was observed but did not reach statistical significance. Sleep timing was not associated with either fruit and vegetable intake (-2.52 g/d, 95%CI -7.66, 2.62) or dietary energy density (-0.001 kcal/g, 95%CI -0.022, 0.020). CONCLUSIONS: Our observational findings from a free-living adolescent population support the experimental evidence for a causal role of sleep on diet, with shorter sleep duration at night leading to a small decrease in diet quality the following day. These findings support experimental evidence to suggest inclusion of sleep duration as one component of interventions designed to improve diet quality and weight status in adolescents.

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). METHODS: We used a validated submaximal exercise test to obtain CRF estimates (CRF estimated ) in 5976 women and 5316 men, residing in the East of England. CRF estimated was defined as estimated maximal oxygen consumption per kilogram total body mass (V̇O 2 max tbm ) and fat-free mass (V̇O 2 max ffm ). Descriptive statistics were computed across anthropometric and sociodemographic characteristics, and across the year. Progressive multivariable analyses were performed to examine associations with physical activity energy expenditure (PAEE) and body mass index (BMI). RESULTS: Mean ± SD V̇O 2 max tbm was lower in women (35.2 ± 7.5 mL·min -1 ·kg -1 ) than men (41.7 ± 7.3 mL·min -1 ·kg -1 ) but V̇O 2 max ffm was similar (women: 59.2 ± 11.6 mL·min -1 ·kg -1 ; men: 62.0 ± 10.3 mL·min -1 ·kg -1 ). CRF estimated was inversely associated with age but not after adjustment for PAEE. People in more physically demanding jobs were fitter compared with those in sedentary jobs, but this association was attenuated in women and reversed in men after adjustment for total PAEE. Physical activity energy expenditure and BMI were positively associated with CRF estimated at all levels of adjustment when expressed relative to fat-free mass. CRF estimated was 4% higher in summer than in winter among women, but did not differ by season among men. CONCLUSIONS: CRF estimated was inversely associated with age but less steeply than anticipated, suggesting older generations are comparatively fitter than younger generations. Physical activity energy expenditure and BMI were stronger determinants of the variance in CRF estimated than other characteristic including age. This emphasizes the importance of modifiable physical activity behaviors in public health interventions.

Cardiorespiratory fitness assessment using risk-stratified exercise testing and dose-response relationships with disease outcomes.

Cardiorespiratory fitness (CRF) is associated with mortality and cardiovascular disease, but assessing CRF in the population is challenging. Here we develop and validate a novel framework to estimate CRF (as maximal oxygen consumption, VO2max) from heart rate response to low-risk personalised exercise tests. We apply the method to examine associations between CRF and health outcomes in the UK Biobank study, one of the world's largest and most inclusive studies of CRF, showing that risk of all-cause mortality is 8% lower (95%CI 5-11%, 2670 deaths among 79,981 participants) and cardiovascular mortality is 9% lower (95%CI 4-14%, 854 deaths) per 1-metabolic equivalent difference in CRF. Associations obtained with the novel validated CRF estimation method are stronger than those obtained using previous methodology, suggesting previous methods may have underestimated the importance of fitness for human health.

Descriptive epidemiology of physical activity energy expenditure in UK adults (The Fenland study).

BACKGROUND: Physical activity (PA) plays a role in the prevention of a range of diseases including obesity and cardiometabolic disorders. Large population-based descriptive studies of PA, incorporating precise measurement, are needed to understand the relative burden of insufficient PA levels and to inform the tailoring of interventions. Combined heart and movement sensing enables the study of physical activity energy expenditure (PAEE) and intensity distribution. We aimed to describe the sociodemographic correlates of PAEE and moderate-to-vigorous physical activity (MVPA) in UK adults. METHODS: The Fenland study is a population-based cohort study of 12,435 adults aged 29-64 years-old in Cambridgeshire, UK. Following individual calibration (treadmill), participants wore a combined heart rate and movement sensor continuously for 6 days in free-living, from which we derived PAEE (kJ•day- 1•kg- 1) and time in MVPA (> 3 & > 4 METs) in bouts greater than 1 min and 10 min. Socio-demographic information was self-reported. Stratum-specific summary statistics and multivariable analyses were performed. RESULTS: Women accumulated a mean (sd) 50(20) kJ•day- 1•kg- 1 of PAEE, and 83(67) and 33(39) minutes•day- 1 of 1-min bouted and 10-min bouted MVPA respectively. By contrast, men recorded 59(23) kJ•day- 1•kg- 1, 124(84) and 60(58) minutes•day- 1. Age and BMI were also important correlates of PA. Association with age was inverse in both sexes, more strongly so for PAEE than MVPA. Obese individuals accumulated less PA than their normal-weight counterparts, whether considering PAEE or allometrically-scaled PAEE (- 10 kJ•day- 1•kg- 1 or - 15 kJ•day- 1•kg-2/3 in men). Higher income and manual work were associated with higher PA; manual workers recorded 13-16 kJ•kg- 1•day- 1 more PAEE than sedentary counterparts. Overall, 86% of women and 96% of men accumulated a daily average of MVPA (> 3 METs) corresponding to 150 min per week. These values were 49 and 74% if only considering bouts > 10 min (15 and 31% for > 4 METs). CONCLUSIONS: PA varied by age, sex and BMI, and was higher in manual workers and those with higher incomes. Light physical activity was the main driver of PAEE; a component of PA that is currently not quantified as a target in UK guidelines.

Validity and reliability of an online self-report 24-h dietary recall method (Intake24): a doubly labelled water study and repeated-measures analysis.

Online self-reported 24-h dietary recall systems promise increased feasibility of dietary assessment. Comparison against interviewer-led recalls established their convergent validity; however, reliability and criterion-validity information is lacking. The validity of energy intakes (EI) reported using Intake24, an online 24-h recall system, was assessed against concurrent measurement of total energy expenditure (TEE) using doubly labelled water in ninety-eight UK adults (40-65 years). Accuracy and precision of EI were assessed using correlation and Bland-Altman analysis. Test-retest reliability of energy and nutrient intakes was assessed using data from three further UK studies where participants (11-88 years) completed Intake24 at least four times; reliability was assessed using intra-class correlations (ICC). Compared with TEE, participants under-reported EI by 25 % (95 % limits of agreement -73 % to +68 %) in the first recall, 22 % (-61 % to +41 %) for average of first two, and 25 % (-60 % to +28 %) for first three recalls. Correlations between EI and TEE were 0·31 (first), 0·47 (first two) and 0·39 (first three recalls), respectively. ICC for a single recall was 0·35 for EI and ranged from 0·31 for Fe to 0·43 for non-milk extrinsic sugars (NMES). Considering pairs of recalls (first two v. third and fourth recalls), ICC was 0·52 for EI and ranged from 0·37 for fat to 0·63 for NMES. EI reported with Intake24 was moderately correlated with objectively measured TEE and underestimated on average to the same extent as seen with interviewer-led 24-h recalls and estimated weight food diaries. Online 24-h recall systems may offer low-cost, low-burden alternatives for collecting dietary information.

Estimating energy expenditure from wrist and thigh accelerometry in free-living adults: a doubly labelled water study.

BACKGROUND: Many large studies have implemented wrist or thigh accelerometry to capture physical activity, but the accuracy of these measurements to infer activity energy expenditure (AEE) and consequently total energy expenditure (TEE) has not been demonstrated. The purpose of this study was to assess the validity of acceleration intensity at wrist and thigh sites as estimates of AEE and TEE under free-living conditions using a gold-standard criterion. METHODS: Measurements for 193 UK adults (105 men, 88 women, aged 40-66 years, BMI 20.4-36.6 kg m-2) were collected with triaxial accelerometers worn on the dominant wrist, non-dominant wrist and thigh in free-living conditions for 9-14 days. In a subsample (50 men, 50 women) TEE was simultaneously assessed with doubly labelled water (DLW). AEE was estimated from non-dominant wrist using an established estimation model, and novel models were derived for dominant wrist and thigh in the non-DLW subsample. Agreement with both AEE and TEE from DLW was evaluated by mean bias, root mean squared error (RMSE), and Pearson correlation. RESULTS: Mean TEE and AEE derived from DLW were 11.6 (2.3) MJ day-1 and 49.8 (16.3) kJ day-1 kg-1. Dominant and non-dominant wrist acceleration were highly correlated in free-living (r = 0.93), but less so with thigh (r = 0.73 and 0.66, respectively). Estimates of AEE were 48.6 (11.8) kJ day-1 kg-1 from dominant wrist, 48.6 (12.3) from non-dominant wrist, and 46.0 (10.1) from thigh; these agreed strongly with AEE (RMSE ~12.2 kJ day-1 kg-1, r ~ 0.71) with small mean biases at the population level (~6%). Only the thigh estimate was statistically significantly different from the criterion. When combining these AEE estimates with estimated REE, agreement was stronger with the criterion (RMSE ~1.0 MJ day-1, r ~ 0.90). CONCLUSIONS: In UK adults, acceleration measured at either wrist or thigh can be used to estimate population levels of AEE and TEE in free-living conditions with high precision.

Erratum: Validity and reliability of an online self-report 24-hour dietary recall method (Intake24): A doubly-labelled water study and repeated measures analysis - CORRIGENDUM.

[This corrects the article DOI: 10.1017/jns.2019.20.].