Human Gain-of-Function MC4R Variants Show Signaling Bias and Protect against Obesity.

The melanocortin 4 receptor (MC4R) is a G protein-coupled receptor whose disruption causes obesity. We functionally characterized 61 MC4R variants identified in 0.5 million people from UK Biobank and examined their associations with body mass index (BMI) and obesity-related cardiometabolic diseases. We found that the maximal efficacy of ß-arrestin recruitment to MC4R, rather than canonical Gαs-mediated cyclic adenosine-monophosphate production, explained 88% of the variance in the association of MC4R variants with BMI. While most MC4R variants caused loss of function, a subset caused gain of function; these variants were associated with significantly lower BMI and lower odds of obesity, type 2 diabetes, and coronary artery disease. Protective associations were driven by MC4R variants exhibiting signaling bias toward ß-arrestin recruitment and increased mitogen-activated protein kinase pathway activation. Harnessing ß-arrestin-biased MC4R signaling may represent an effective strategy for weight loss and the treatment of obesity-related cardiometabolic diseases.

Replacing device-measured sedentary time with physical activity is associated with lower risk of coronary heart disease regardless of genetic risk.

BACKGROUND: Excess sedentary time (ST) is recognized as an important modifiable risk factor for coronary heart disease (CHD). However, whether the associations of genetic susceptibility with CHD incidence can be modified by replacing wearable-device-measured ST with physical activity (PA) is unknown. OBJECTIVES: To examine the associations of wearable-device-measured ST replaced by PA with incident CHD across strata of genetic susceptibility. METHODS: This study included 77,500 White British (57% female) with valid wrist-worn accelerometry and without prevalent CHD/stroke from UK Biobank. Genetic susceptibility to CHD was quantified through weighted polygenic risk scores for CHD based on 300 single-nucleotide polymorphisms. Wrist-worn accelerometer data were used to derive ST, light PA, and moderate-to-vigorous PA (MVPA). RESULTS: Reallocation of 60 min/day of ST into the same amount of MVPA was associated with approximately 9% lower relative risk of CHD for all participants and across strata of genetic risk: replacement of 1 min/day of ST associated with <1% lower relative risk of CHD. No evidence of interaction (p: 0.784) was found between genetic risk and ST for CHD risk. Reallocating 60 min/day of ST into the same MVPA time was associated with greater absolute CHD risk reductions at high genetic risk (0.27%) versus low genetic risk (0.15%). CONCLUSIONS: Replacing any amount of ST with an equal amount of MVPA time is associated with a lower relative risk of CHD, irrespective of genetic susceptibility to CHD. Reductions in CHD absolute risk for replacing ST with MVPA are greater at high genetic risk versus low genetic risk.

Short-term psychosocial outcomes of adding a non-contrast abdominal computed tomography (CT) scan to the thoracic CT within lung cancer screening.

OBJECTIVES: To evaluate psychological, social, and financial outcomes amongst individuals undergoing a non-contrast abdominal computed tomography (CT) scan to screen for kidney cancer and other abdominal malignancies alongside the thoracic CT within lung cancer screening. SUBJECTS AND METHODS: The Yorkshire Kidney Screening Trial (YKST) is a feasibility study of adding a non-contrast abdominal CT scan to the thoracic CT within lung cancer screening. A total of 500 participants within the YKST, comprising all who had an abnormal CT scan and a random sample of one-third of those with a normal scan between 14/03/2022 and 24/08/2022 were sent a questionnaire at 3 and 6 months. Outcomes included the Psychological Consequences Questionnaire (PCQ), the short-form of the Spielberger State-Trait Anxiety Inventory, and the EuroQoL five Dimensions five Levels scale (EQ-5D-5L). Data were analysed using regression adjusting for participant age, sex, socioeconomic status, education, baseline quality of life (EQ-5D-5L), and ethnicity. RESULTS: A total of 380 (76%) participants returned questionnaires at 3 months and 328 (66%) at 6 months. There was no difference in any outcomes between participants with a normal scan and those with abnormal scans requiring no further action. Individuals requiring initial further investigations or referral had higher scores on the negative PCQ than those with normal scans at 3 months (standardised mean difference 0.28 sd, 95% confidence interval 0.01-0.54; P = 0.044). The difference was greater in those with anxiety or depression at baseline. No differences were seen at 6 months. CONCLUSION: Screening for kidney cancer and other abdominal malignancies using abdominal CT alongside the thoracic CT within lung cancer screening is unlikely to cause significant lasting psychosocial or financial harm to participants with incidental findings.

Interaction between plasma phospholipid odd-chain fatty acids and GAD65 autoantibodies on the incidence of adult-onset diabetes: the EPIC-InterAct case-cohort study.

AIMS/HYPOTHESIS: Islet autoimmunity may progress to adult-onset diabetes. We investigated whether circulating odd-chain fatty acids (OCFA) 15:0 and 17:0, which are inversely associated with type 2 diabetes, interact with autoantibodies against GAD65 (GAD65Ab) on the incidence of adult-onset diabetes. METHODS: We used the European EPIC-InterAct case-cohort study including 11,124 incident adult-onset diabetes cases and a subcohort of 14,866 randomly selected individuals. Adjusted Prentice-weighted Cox regression estimated HRs and 95% CIs of diabetes in relation to 1 SD lower plasma phospholipid 15:0 and/or 17:0 concentrations or their main contributor, dairy intake, among GAD65Ab-negative and -positive individuals. Interactions between tertiles of OCFA and GAD65Ab status were estimated by proportion attributable to interaction (AP). RESULTS: Low concentrations of OCFA, particularly 17:0, were associated with a higher incidence of adult-onset diabetes in both GAD65Ab-negative (HR 1.55 [95% CI 1.48, 1.64]) and GAD65Ab-positive (HR 1.69 [95% CI 1.34, 2.13]) individuals. The combination of low 17:0 and high GAD65Ab positivity vs high 17:0 and GAD65Ab negativity conferred an HR of 7.51 (95% CI 4.83, 11.69), with evidence of additive interaction (AP 0.25 [95% CI 0.05, 0.45]). Low dairy intake was not associated with diabetes incidence in either GAD65Ab-negative (HR 0.98 [95% CI 0.94, 1.02]) or GAD65Ab-positive individuals (HR 0.97 [95% CI 0.79, 1.18]). CONCLUSIONS/INTERPRETATION: Low plasma phospholipid 17:0 concentrations may promote the progression from GAD65Ab positivity to adult-onset diabetes.

Associations between trajectories of obesity prevalence in English primary school children and the UK soft drinks industry levy: An interrupted time series analysis of surveillance data.

BACKGROUND: Sugar-sweetened beverages (SSBs) are the primary source of dietary added sugars in children, with high consumption commonly observed in more deprived areas where obesity prevalence is also highest. Associations between SSB consumption and obesity in children have been widely reported. In March 2016, a two-tier soft drinks industry levy (SDIL) on drinks manufacturers to encourage reformulation of SSBs in the United Kingdom was announced and then implemented in April 2018. We examined trajectories in the prevalence of obesity at ages 4 to 5 years and 10 to 11 years, 19 months after the implementation of SDIL, overall and by sex and deprivation. METHODS AND FINDINGS: Data were from the National Child Measurement Programme and included annual repeat cross-sectional measurement of over 1 million children in reception (4 to 5 years old) and year 6 (10 to 11 years old) in state-maintained English primary schools. Interrupted time series (ITS) analysis of monthly obesity prevalence data from September 2013 to November 2019 was used to estimate absolute and relative changes in obesity prevalence compared to a counterfactual (adjusted for temporal variations in obesity prevalence) estimated from the trend prior to SDIL announcement. Differences between observed and counterfactual estimates were examined in November 2019 by age (reception or year 6) and additionally by sex and deprivation quintile. In year 6 girls, there was an overall absolute reduction in obesity prevalence (defined as >95th centile on the UK90 growth charts) of 1.6 percentage points (PPs) (95% confidence interval (CI): 1.1, 2.1), with greatest reductions in the two most deprived quintiles (e.g., there was an absolute reduction of 2.4 PP (95% CI: 1.6, 3.2) in prevalence of obesity in the most deprived quintile). In year 6 boys, there was no change in obesity prevalence, except in the least deprived quintile where there was a 1.6-PP (95% CI: 0.7, 2.5) absolute increase. In reception children, relative to the counterfactual, there were no overall changes in obesity prevalence in boys (0.5 PP (95% CI: 1.0, -0.1)) or girls (0.2 PP (95% CI: 0.8, -0.3)). This study is limited by use of index of multiple deprivation of the school attended to assess individual socioeconomic disadvantage. ITS analyses are vulnerable to unidentified cointerventions and time-varying confounding, neither of which we can rule out. CONCLUSIONS: Our results suggest that the SDIL was associated with decreased prevalence of obesity in year 6 girls, with the greatest differences in those living in the most deprived areas. Additional strategies beyond SSB taxation will be needed to reduce obesity prevalence overall, and particularly in older boys and younger children. TRIAL REGISTRATION: ISRCTN18042742.

Correction: Anticipatory changes in British household purchases of soft drinks associated with the announcement of the Soft Drinks Industry Levy: A controlled interrupted time series analysis.

[This corrects the article DOI: 10.1371/journal.pmed.1003269.].

A nutritional biomarker score of the Mediterranean diet and incident type 2 diabetes: Integrated analysis of data from the MedLey randomised controlled trial and the EPIC-InterAct case-cohort study.

BACKGROUND: Self-reported adherence to the Mediterranean diet has been modestly inversely associated with incidence of type 2 diabetes (T2D) in cohort studies. There is uncertainty about the validity and magnitude of this association due to subjective reporting of diet. The association has not been evaluated using an objectively measured biomarker of the Mediterranean diet. METHODS AND FINDINGS: We derived a biomarker score based on 5 circulating carotenoids and 24 fatty acids that discriminated between the Mediterranean or habitual diet arms of a parallel design, 6-month partial-feeding randomised controlled trial (RCT) conducted between 2013 and 2014, the MedLey trial (128 participants out of 166 randomised). We applied this biomarker score in an observational study, the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study, to assess the association of the score with T2D incidence over an average of 9.7 years of follow-up since the baseline (1991 to 1998). We included 22,202 participants, of whom 9,453 were T2D cases, with relevant biomarkers from an original case-cohort of 27,779 participants sampled from a cohort of 340,234 people. As a secondary measure of the Mediterranean diet, we used a score estimated from dietary-self report. Within the trial, the biomarker score discriminated well between the 2 arms; the cross-validated C-statistic was 0.88 (95% confidence interval (CI) 0.82 to 0.94). The score was inversely associated with incident T2D in EPIC-InterAct: the hazard ratio (HR) per standard deviation of the score was 0.71 (95% CI: 0.65 to 0.77) following adjustment for sociodemographic, lifestyle and medical factors, and adiposity. In comparison, the HR per standard deviation of the self-reported Mediterranean diet was 0.90 (95% CI: 0.86 to 0.95). Assuming the score was causally associated with T2D, higher adherence to the Mediterranean diet in Western European adults by 10 percentiles of the score was estimated to reduce the incidence of T2D by 11% (95% CI: 7% to 14%). The study limitations included potential measurement error in nutritional biomarkers, unclear specificity of the biomarker score to the Mediterranean diet, and possible residual confounding. CONCLUSIONS: These findings suggest that objectively assessed adherence to the Mediterranean diet is associated with lower risk of T2D and that even modestly higher adherence may have the potential to reduce the population burden of T2D meaningfully. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12613000602729 https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=363860.

Supporting Weight Management during COVID-19 (SWiM-C): twelve-month follow-up of a randomised controlled trial of a web-based, ACT-based, guided self-help intervention.

OBJECTIVES: We developed a guided self-help intervention (Supporting Weight Management during COVID-19, "SWiM-C") to support adults with overweight or obesity in their weight management during the COVID-19 pandemic. This parallel, two-group trial (ISRCTN12107048) evaluated the effect of SWiM-C on weight and determinants of weight management over twelve months. METHODS: Participants (≥18 years, body-mass-index ≥25 kg/m2) were randomised to the SWiM-C intervention or to a standard advice group (unblinded). Participants completed online questionnaires at baseline, four months, and twelve months. The primary outcome was change in self-reported weight from baseline to twelve months; secondary outcomes were eating behaviour (uncontrolled eating, emotional eating, cognitive restraint of food intake), experiential avoidance, depression, anxiety, stress, wellbeing and physical activity. INTERVENTIONS: SWiM-C is based on acceptance and commitment therapy (ACT). Participants had access to an online web platform with 12 weekly modules and email and telephone contact with a trained, non-specialist coach. Standard advice was a leaflet on managing weight and mood during the COVID-19 pandemic. RESULTS: 388 participants were randomised (SWiM-C: n = 192, standard advice: n = 196). The baseline-adjusted difference in weight change between SWiM-C (n = 119) and standard advice (n = 147) was -0.81 kg (95% CI: -2.24 to 0.61 kg). SWiM-C participants reported a reduction in experiential avoidance (-2.45 [scale:10-70], 95% CI: -4.75 to -0.15), uncontrolled eating (-3.36 [scale: 0-100], 95% CI: -5.66 to -1.06), and emotional eating (-4.14 [scale:0-100], 95% CI: -7.25 to -1.02) and an increase in physical activity (8.96 [MET-min/week], 95% CI: 0.29 to 17.62) compared to standard advice participants. We found no evidence of an effect on remaining outcomes. No adverse events/side effects were reported. CONCLUSIONS: Whilst we were unable to conclude that the intervention had an effect on weight, SWiM-C improved eating behaviours, experiential avoidance and physical activity. Further refinement of the intervention is necessary to ensure meaningful effects on weight prior to implementation in practice. TRIAL REGISTRATION NUMBER: ISRCTN 12107048.

Kilocalorie labelling in the out-of-home sector: an observational study of business practices and consumer behaviour prior to implementation of the mandatory calorie labelling policy in England, 2022.

BACKGROUND: Regulations mandating kilocalorie (kcal) labelling for large businesses in the out-of-home food sector (OHFS) came into force on 6th April 2022 as a policy to reduce obesity in England. To provide indicators of potential reach and impact, kcal labelling practices were studied in the OHFS, and customer purchasing and consumption behaviours prior to implementation of the mandatory kcal labelling policy in England. METHODS: From August-December 2021, large OHFS businesses subject to the kcal labelling regulations were visited prior to regulations coming into force on 6th April 2022. 3308 customers were recruited from 330 outlets and collected survey information on the number of kcal purchased and consumed by customers, customers' knowledge of the kcal content of their purchases, and customers noticing and use of kcal labelling. In a subset of 117 outlets, data was collected on nine recommended kcal labelling practices. RESULTS: The average number of kcals purchased (1013 kcal, SD = 632 kcal) was high with 69% of purchases exceeding the recommendation of a maximum of 600 kcal per meal. Participants underestimated the energy content of their purchased meals by on average 253 kcal (SD = 644 kcals). In outlets providing kcal labelling in which customer survey data was collected, a minority of customers reported noticing (21%) or using (20%) kcal labelling. Out of the 117 outlets assessed for kcal labelling practices, 24 (21%) provided any in-store kcal labelling. None of the outlets met all nine aspects of recommended labelling practices. CONCLUSIONS: Prior to implementation of 2022 kcal labelling policy, the majority of sampled OHFS large business outlets in England did not provide kcal labelling. Few customers noticed or used the labels and on average customers purchased and consumed substantially more energy than recommended in public health guidelines. The findings suggest that reliance on voluntary action for kcal labelling implementation failed to produce widespread, consistent, and adequate kcal labelling practices.

Engagement With mHealth COVID-19 Digital Biomarker Measurements in a Longitudinal Cohort Study: Mixed Methods Evaluation.

BACKGROUND: The COVID-19 pandemic accelerated the interest in implementing mobile health (mHealth) in population-based health studies, but evidence is lacking on engagement and adherence in studies. We conducted a fully remote study for ≥6 months tracking COVID-19 digital biomarkers and symptoms using a smartphone app nested within an existing cohort of adults. OBJECTIVE: We aimed to investigate participant characteristics associated with initial and sustained engagement in digital biomarker collection from a bespoke smartphone app and if engagement changed over time or because of COVID-19 factors and explore participants' reasons for consenting to the smartphone substudy and experiences related to initial and continued engagement. METHODS: Participants in the Fenland COVID-19 study were invited to the app substudy from August 2020 to October 2020 until study closure (April 30, 2021). Participants were asked to complete digital biomarker modules (oxygen saturation, body temperature, and resting heart rate [RHR]) and possible COVID-19 symptoms in the app 3 times per week. Participants manually entered the measurements, except RHR that was measured using the smartphone camera. Engagement was categorized by median weekly frequency of completing the 3 digital biomarker modules (categories: 0, 1-2, and ≥3 times per week). Sociodemographic and health characteristics of those who did or did not consent to the substudy and by engagement category were explored. Semistructured interviews were conducted with 35 participants who were purposively sampled by sex, age, educational attainment, and engagement category, and data were analyzed thematically; 63% (22/35) of the participants consented to the app substudy, and 37% (13/35) of the participants did not consent. RESULTS: A total of 62.61% (2524/4031) of Fenland COVID-19 study participants consented to the app substudy. Of those, 90.21% (2277/2524) completed the app onboarding process. Median time in the app substudy was 34.5 weeks (IQR 34-37) with no change in engagement from 0 to 3 months or 3 to 6 months. Completion rates (≥1 per week) across the study between digital biomarkers were similar (RHR: 56,517/77,664, 72.77%; temperature: 56,742/77,664, 73.06%; oxygen saturation: 57,088/77,664, 73.51%). Older age groups and lower managerial and intermediate occupations were associated with higher engagement, whereas working, being a current smoker, being overweight or obese, and high perceived stress were associated with lower engagement. Continued engagement was facilitated through routine and personal motivation, and poor engagement was caused by user error and app or equipment malfunctions preventing data input. From these results, we developed key recommendations to improve engagement in population-based mHealth studies. CONCLUSIONS: This mixed methods study demonstrated both high initial and sustained engagement in a large mHealth COVID-19 study over a ≥6-month period. Being nested in a known cohort study enabled the identification of participant characteristics and factors associated with engagement to inform future applications in population-based health research.

Genetic susceptibility, screen-based sedentary activities and incidence of coronary heart disease.

BACKGROUND: Whether the associations of time spent in screen-based sedentary activities with CHD vary by genetic susceptibility is currently unknown. The objective of this study was to examine the interplay of genetic susceptibility to CHD and two prevalent types of screen-based sedentary activities (television [TV] viewing and computer use) for CHD incidence. METHODS: This prospective cohort study included 373,026 individuals of European ancestry without prevalent CHD/stroke from UK Biobank data. Genetic susceptibility to CHD was assessed using weighted polygenic risk scores, calculated by summing the number of risk-increasing alleles among 300 single-nucleotide polymorphisms, multiplied by their corresponding effect estimates. TV viewing and computer use were assessed through touch-screen questionnaires. CHD incidence (n=9185) was adjudicated over a median 12.6-year follow-up. RESULTS: Compared with ≥4h/day of TV viewing, the hazard ratio of CHD was 0.84 (95% confidence interval [CI] 0.79-0.90) and 0.94 (0.90-0.99) for ≤1h/day and 2-3h/day of TV viewing, respectively, after adjusting for confounders including the genetic risk. CHD hazards were higher for medium and high genetic risk than for low genetic risk. Across all levels of genetic risk including high-genetic risk, ≤1h/day of TV viewing had lower CHD hazards, compared with ≥4h/day: no evidence of interaction between genetic risk and TV viewing (p value: 0.362). Estimates of the population attributable fraction (PAF) suggested that 10.9% (95% CI 6.1-15.3%) of CHD could be prevented if TV viewing time were reduced to ≤1h/day, assuming causality. The PAF values were relatively larger for medium-to-high genetic risk than for low genetic risk, although the CIs were wide and overlapping. No associations were observed for computer use. CONCLUSIONS: Less TV viewing time was associated with lower CHD risk independently of genetic risk. Clinical trials targeted at individuals with high genetic susceptibility should consider reducing TV viewing as as a behavioural target for prevention of an early onset of cardiovascular events.

Risk models for recurrence and survival after kidney cancer: a systematic review.

OBJECTIVE: To systematically identify and compare the performance of prognostic models providing estimates of survival or recurrence of localized renal cell cancer (RCC) in patients treated with surgery with curative intent. MATERIALS AND METHODS: We performed a systematic review (PROSPERO CRD42019162349). We searched Medline, EMBASE and the Cochrane Library from 1 January 2000 to 12 December 2019 to identify studies reporting the performance of one or more prognostic model(s) that predict recurrence-free survival (RFS), cancer-specific survival (CSS) or overall survival (OS) in patients who have undergone surgical resection for localized RCC. For each outcome we summarized the discrimination of each model using the C-statistic and performed multivariate random-effects meta-analysis of the logit transformed C-statistic to rank the models. RESULTS: Of a total of 13 549 articles, 57 included data on the performance of 22 models in external populations. C-statistics ranged from 0.59 to 0.90. Several risk models were assessed in two or more external populations and had similarly high discriminative performance. For RFS, these were the Sorbellini, Karakiewicz, Leibovich and Kattan models, with the UCLA Integrated Staging System model also having similar performance in European/US populations. All had C-statistics ≥0.75 in at least half of the validations. For CSS, they the models with the highest discriminative performance in two or more external validation studies were the Zisman, Stage, Size, Grade and Necrosis (SSIGN), Karakiewicz, Leibovich and Sorbellini models (C-statistic ≥0.80 in at least half of the validations), and for OS they were the Leibovich, Karakiewicz, Sorbellini and SSIGN models. For all outcomes, the models based on clinical features at presentation alone (Cindolo and Yaycioglu) had consistently lower discrimination. Estimates of model calibration were only infrequently included but most underestimated survival. CONCLUSION: Several models had good discriminative ability, with there being no single 'best' model. The choice from these models for each setting should be informed by both the comparative performance and availability of factors included in the models. All would need recalibration if used to provide absolute survival estimates.

Impacts of new cycle infrastructure on cycling levels in two French cities: an interrupted time series analysis.

BACKGROUND: Cities globally have started to make substantial investment in more sustainable forms of transportation. We aimed to evaluate whether the construction of new cycling infrastructure in Paris and Lyon, France, affected population cycling activity along new or improved routes. METHODS: Routinely collected cycle count data from January 2014 to March 2020 were acquired for the cities of Paris and Lyon. Improvements were identified at 15 locations with 6 months of pre- and post-intervention data. Comparison streets were chosen within Paris or Lyon for which pre-intervention trends in cycling were similar to those at intervention sites. Controlled interrupted time series analyses and autocorrelation were performed adjusting for seasonality. Random-effects meta-analysis combined results across streets within each city and overall. RESULTS: On average, cycling counts/day increased on both intervention and control streets in Paris and Lyon. In general, results of the ITS analysis indicated no significant change in the level or trend as a result of the improvements in either city. Meta-analysis suggested that intervention streets in Paris had a larger positive pooled effect size for level change (218 cycle counts, 95% CI -189, 626, I2 = 0%) compared to Lyon (34, 95% CI -65, 133, I2 = 14%); however, confidence intervals for both cities were wide and included no effect. CONCLUSIONS: The findings suggest that improving or constructing new cycle lanes may be necessary but not sufficient to induce significant changes in cycling levels. There is a need to understand how context, intervention design and other complementary interventions can improve the effectiveness of new cycling infrastructure.

Longitudinal associations between prepubertal childhood total energy and macronutrient intakes and subsequent puberty timing in UK boys and girls.

PURPOSE: Early puberty is associated with adverse health outcomes. To identify potential modifiable factors for puberty timing, we examined the associations of prepubertal childhood macronutrient intakes with puberty timing in boys and girls. METHODS: In the Avon Longitudinal Study of Parents and Children, macronutrient intakes at age 6 years were predicted using random intercepts linear regression models of dietary data at 3, 4, 7 (assessed by food frequency questionnaires) and 7.5 years (by 3-day food diaries). Timings of puberty onset (Tanner stage 2 genital or breast (B2) development) and puberty completion (voice breaking (VB) or menarche) were calculated from annual parental and child reports at 8-17 years. Age at peak height velocity (PHV) was derived from repeated height measurements at 5-20 years. Linear regression models were fit to estimate the associations of total energy (TEI) and macronutrient intakes (carbohydrate, fat, protein) with puberty timing traits, adjusting for maternal and infant characteristics. RESULTS: Among 3811 boys, higher TEI, but no macronutrient, was associated with earlier VB. Among 3919 girls, higher TEI was associated with earlier ages at B2, PHV, and menarche. Higher protein intake but not carbohydrate or fat intake (in energy partition models) and substitution of dietary protein for carbohydrate (in nutrient density and residual models) was associated with earlier B2, PHV, and menarche in girls. Findings were not attenuated on additional adjustment for body fat percentage during adolescence. CONCLUSIONS: These findings suggest habitual total energy intakes in children, and protein intakes in girls, as potential modifiable determinants of puberty timing.

Independent and combined associations between fast-food outlet exposure and genetic risk for obesity: a population-based, cross-sectional study in the UK.

BACKGROUND: Characteristics of the built environment, such as neighbourhood fast-food outlet exposure, are increasingly recognised as risk factors for unhealthy diet and obesity. Obesity also has a genetic component, with common genetic variants explaining a substantial proportion of population-level obesity susceptibility. However, it is not known whether and to what extent associations between fast-food outlet exposure and body weight are modified by genetic predisposition to obesity. METHODS: We used data from the Fenland Study, a population-based sample of 12,435 UK adults (mean age 48.6 years). We derived a genetic risk score associated with BMI (BMI-GRS) from 96 BMI-associated single nucleotide polymorphisms. Neighbourhood fast-food exposure was defined as quartiles of counts of outlets around the home address. We used multivariable regression models to estimate the associations of each exposure, independently and in combination, with measured BMI, overweight and obesity, and investigated interactions. RESULTS: We found independent associations between BMI-GRS and risk of overweight (RR = 1.34, 95% CI 1.23-1.47) and obesity (RR = 1.73, 95% CI 1.55-1.93), and between fast-food outlet exposure and risk of obesity (highest vs lowest quartile RR = 1.58, 95% CI 1.21-2.05). There was no evidence of an interaction of fast-food outlet exposure and genetic risk on BMI (P = 0.09), risk of overweight (P = 0.51), or risk of obesity (P = 0.27). The combination of higher BMI-GRS and highest fast-food outlet exposure was associated with 2.70 (95% CI 1.99-3.66) times greater risk of obesity. CONCLUSIONS: Our study demonstrated independent associations of both genetic obesity risk and neighbourhood fast-food outlet exposure with adiposity. These important drivers of the obesity epidemic have to date been studied in isolation. Neighbourhood fast-food outlet exposure remains a potential target of policy intervention to prevent obesity and promote the public's health.

Promoting physical activity in a multi-ethnic population at high risk of diabetes: the 48-month PROPELS randomised controlled trial.

BACKGROUND: Physical activity is associated with a reduced risk of type 2 diabetes and cardiovascular disease but limited evidence exists for the sustained promotion of increased physical activity within diabetes prevention trials. The aim of the study was to investigate the long-term effectiveness of the Walking Away programme, an established group-based behavioural physical activity intervention with pedometer use, when delivered alone or with a supporting mHealth intervention. METHODS: Those at risk of diabetes (nondiabetic hyperglycaemia) were recruited from primary care, 2013-2015, and randomised to (1) Control (information leaflet); (2) Walking Away (WA), a structured group education session followed by annual group-based support; or (3) Walking Away Plus (WAP), comprising WA annual group-based support and an mHealth intervention delivering tailored text messages supported by telephone calls. Follow-up was conducted at 12 and 48 months. The primary outcome was accelerometer measured ambulatory activity (steps/day). Change in primary outcome was analysed using analysis of covariance with adjustment for baseline, randomisation and stratification variables. RESULTS: One thousand three hundred sixty-six individuals were randomised (median age = 61 years, ambulatory activity = 6638 steps/day, women = 49%, ethnic minorities = 28%). Accelerometer data were available for 1017 (74%) individuals at 12 months and 993 (73%) at 48 months. At 12 months, WAP increased their ambulatory activity by 547 (97.5% CI 211, 882) steps/day compared to control and were 1.61 (97.5% CI 1.05, 2.45) times more likely to achieve 150 min/week of moderate-to-vigorous physical activity. Differences were not maintained at 48 months. WA was no different to control at 12 or 48 months. Secondary anthropometric and health outcomes were largely unaltered in both intervention groups apart from small reductions in body weight in WA (~ 1 kg) at 12- and 48-month follow-up. CONCLUSIONS: Combining a pragmatic group-based intervention with text messaging and telephone support resulted in modest changes to physical activity at 12 months, but changes were not maintained at 48 months. TRIAL REGISTRATION: ISRCTN 83465245 (registered on 14 June 2012).

Associations of Total Legume, Pulse, and Soy Consumption with Incident Type 2 Diabetes: Federated Meta-Analysis of 27 Studies from Diverse World Regions.

BACKGROUND: The consumption of legumes is promoted as part of a healthy diet in many countries but associations of total and types of legume consumption with type 2 diabetes (T2D) are not well established. Analyses across diverse populations are lacking despite the availability of unpublished legume consumption data in prospective cohort studies. OBJECTIVE: To examine the prospective associations of total and types of legume intake with the risk of incident T2D. METHODS: Meta-analyses of associations between total legume, pulse, and soy consumption and T2D were conducted using a federated approach without physical data-pooling. Prospective cohorts were included if legume exposure and T2D outcome data were available and the cohort investigators agreed to participate. We estimated incidence rate ratios (IRRs) and CIs of associations using individual participant data including ≤42,473 incident cases among 807,785 adults without diabetes in 27 cohorts across the Americas, Eastern Mediterranean, Europe, and Western Pacific. Random-effects meta-analysis was used to combine effect estimates and estimate heterogeneity. RESULTS: Median total legume intake ranged from 0-140 g/d across cohorts. We observed a weak positive association between total legume consumption and T2D (IRR = 1.02, 95% CI: 1.01 to 1.04) per 20 g/d higher intake, with moderately high heterogeneity (I2 = 74%). Analysis by region showed no evidence of associations in the Americas, Eastern Mediterranean, and Western Pacific. The positive association in Europe (IRR = 1.05, 95% CI: 1.01 to 1.10, I2 = 82%) was mainly driven by studies from Germany, UK, and Sweden. No evidence of associations was observed for the consumption of pulses or soy. CONCLUSIONS: These findings suggest no evidence of an association of legume intakes with T2D in several world regions. The positive association observed in some European studies warrants further investigation relating to overall dietary contexts in which legumes are consumed, including accompanying foods which may be positively associated with T2D.

Association of weight loss and weight loss maintenance following diabetes diagnosis by screening and incidence of cardiovascular disease and all-cause mortality: An observational analysis of the ADDITION-Europe trial.

AIMS: Short-term weight loss may lead to remission of type 2 diabetes but the effect of maintained weight loss on cardiovascular disease (CVD) is unknown. We quantified the associations between changes in weight 5 years following a diagnosis of diabetes, and incident CVD events and mortality up to 10 years after diagnosis. MATERIALS AND METHODS: Observational analysis of the ADDITION-Europe trial of 2730 adults with screen-detected type 2 diabetes from the UK, Denmark and the Netherlands. We defined weight change based on the maintenance at 5 years of weight loss achieved during the year after diabetes diagnosis, and as 5-year overall change in weight. Incident CVD events (n = 229) and all-cause mortality (n = 225) from 5 to 10 years follow-up were ascertained from medical records. RESULTS: Gaining >2% weight during the year after diabetes diagnosis was associated with higher hazard of all-cause mortality versus maintaining weight [hazard ratio (95% confidence interval): 3.18 (1.30-7.82)]. Losing ≥5% weight 1 year after diagnosis was also associated with mortality, whether or not weight loss was maintained at 5 years: 2.47 (0.99-6.21) and 2.72 (1.17-6.30), respectively. Losing ≥10% weight over 5 years was associated with mortality among those with body mass index <30 kg/m2 [4.62 (1.87-11.42)]. Associations with CVD incidence were inconclusive. CONCLUSIONS: Both weight loss and weight gain after screen-detected diabetes diagnosis were associated with higher mortality, but not CVD events, particularly among participants without obesity. The clinical implications of weight loss following a diagnosis of diabetes probably depend on its magnitude and timing, and may differ by body mass index status. Personalization of weight loss advice and support may be warranted.

Is occupational physical activity associated with mortality in UK Biobank?

BACKGROUND: Current physical activity guidelines do not distinguish between activity accumulated in different behavioural domains but some studies suggest that occupational physical activity (OPA) may not confer health benefits and could even be detrimental. The purpose of this study was to investigate associations between OPA and mortality outcomes. METHODS: From baseline (2006-2010), 460,901 UK Biobank participants (aged 40-69 years) were followed for a median 12.0 (IQR: 11.3-12.7) years. OPA was categorised by cross-tabulating degree of manual work and walking/standing work amongst those in paid employment (n = 267,765), and combined with categories of occupational status for those not in paid employment (n = 193,136). Cox proportional hazards models were used to estimate sex-stratified hazard ratios (HR) and 95% confidence intervals (CI) for mortality from all causes, CVD, and cancer by occupational group, and for working hours/week and non-occupational physical activity stratified by occupational group. Models included adjustment for age and a range of lifestyle, socio-economic and health-related covariates. RESULTS: During 5,449,989 person-years of follow-up, 28,740 deaths occurred. Compared to those reporting no heavy manual or walking/standing work (e.g. sedentary office workers) and adjusting for covariates, retirement was associated with lower mortality in women (HR = 0.62, CI: 0.53-0.72) and men (HR = 0.80, CI: 0.71-0.90), whereas unemployment was associated with higher mortality in men only (HR = 1.24, CI: 1.07-1.45). Within the working population, there was no evidence of differences in all-cause, CVD or cancer mortality by OPA group when comparing those reporting higher levels of OPA to the lowest OPA reference group for both women and men. Working < 35 h/week versus 35-40 h/week was associated with lower mortality in women (HR = 0.85, CI: 0.79-0.92) and men (HR = 0.83, CI: 0.78-0.89), with no interaction by OPA. Non-occupational physical activity was associated with lower mortality in working women (HR = 0.89 per 5 kJ/day/kg, CI: 0.84-0.95) and men (HR = 0.87 per 5 kJ/day/kg, CI: 0.84-0.91), with no interaction by OPA group. CONCLUSIONS: Jobs classified as higher levels of OPA may not be as active as reported, or the types of physical activity performed in those jobs are not health-enhancing. Irrespective of OPA category or employment status, non-occupational physical activity appears to provide health benefits.

The impact of participant mental health on attendance and engagement in a trial of behavioural weight management programmes: secondary analysis of the WRAP randomised controlled trial.

BACKGROUND: Low attendance and engagement in behavioural weight management trials are common. Mental health may play an important role, however previous research exploring this association is limited with inconsistent findings. We aimed to investigate whether mental health was associated with attendance and engagement in a trial of behavioural weight management programmes. METHODS: This is a secondary data analysis of the Weight loss referrals for adults in primary care (WRAP) trial, which randomised 1267 adults with overweight or obesity to brief intervention, WW (formerly Weight Watchers) for 12-weeks, or WW for 52-weeks. We used regression analyses to assess the association of baseline mental health (depression and anxiety (by Hospital Anxiety and Depression Scale), quality of life (by EQ5D), satisfaction with life (by Satisfaction with Life Questionnaire)) with programme attendance and engagement in WW groups, and trial attendance in all randomised groups. RESULTS: Every one unit of baseline depression score was associated with a 1% relative reduction in rate of WW session attendance in the first 12 weeks (Incidence rate ratio [IRR] 0.99; 95% CI 0.98, 0.999). Higher baseline anxiety was associated with 4% lower odds to report high engagement with WW digital tools (Odds ratio [OR] 0.96; 95% CI 0.94, 0.99). Every one unit of global quality of life was associated with 69% lower odds of reporting high engagement with the WW mobile app (OR 0.31; 95% CI 0.15, 0.64). Greater symptoms of depression and anxiety and lower satisfaction with life at baseline were consistently associated with lower odds of attending study visits at 3-, 12-, 24-, and 60-months. CONCLUSIONS: Participants were less likely to attend programme sessions, engage with resources, and attend study assessments when reporting poorer baseline mental health. Differences in attendance and engagement were small, however changes may still have a meaningful effect on programme effectiveness and trial completion. Future research should investigate strategies to maximise attendance and engagement in those reporting poorer mental health. TRIAL REGISTRATION: The original trial ( ISRCTN82857232 ) and five year follow up ( ISRCTN64986150 ) were prospectively registered with Current Controlled Trials on 15/10/2012 and 01/02/2018.