Physical Activity and Mortality Across Levels of Adiposity: A Prospective Cohort Study From the UK Biobank

ObjectiveTo examine the combined and stratified associations of physical activity and adiposity measures, modelled as body mass index (BMI), abdominal adiposity (waist circumference), and body fat percentage (BF) with all-cause mortality.Patients and MethodsUsing the UK Biobank cohort, we extracted quintiles of self-reported weekly physical activity. Categories of measured BMI, waist circumference, and BF were generated. Joint associations between physical activity-adiposity categories and mortality were examined using Cox proportional hazards models adjusted for demographic, behavioral, and clinical covariates. Physical activity-mortality associations were also examined within adiposity strata. Participants were followed from baseline (2006 to 2010) through January 31, 2018.ResultsA total of 295,917 participants (median follow-up, 8.9 years, during which 6684 deaths occurred) were included. High physical activity was associated with lower risk of premature mortality in all strata of adiposity except for those with BMI ≥35 kg/m². Highest risk (HR, 1.54; 95% CI; 1.33 to 1.79) was observed in individuals with low physical activity and high BF as compared with the high physical activity–low BF referent. High physical activity attenuated the risk of high adiposity when using BF (HR, 1.24; 95% CI; 1.04 to 1.49), but the association was weaker with BMI (HR, 1.45; 95% CI; 1.21 to 1.73). Physical activity also attenuated the association between mortality and high waist circumference.ConclusionLow physical activity and adiposity were both associated with a higher risk of premature mortality, but high physical activity attenuated the increased risk with adiposity irrespective of adiposity metric, except in those with a BMI ≥35 kg/m².     

Cardiometabolic Health Outcomes Associated With Discordant Visceral and Liver Fat Phenotypes: Insights From the Dallas Heart Study and UK Biobank

ObjectiveTo evaluate the cardiometabolic outcomes associated with discordant visceral adipose tissue (VAT) and liver fat (LF) phenotypes in 2 cohorts.Patients and MethodsParticipants in the Dallas Heart Study underwent baseline imaging from January 1, 2000, through December 31, 2002, and were followed for incident cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) through 2013. Associations between VAT-LF groups (low-low, high-low, low-high, and high-high) and outcomes were assessed using multivariable-adjusted regression and were replicated in the independent UK Biobank.ResultsThe Dallas Heart Study included 2064 participants (mean ± SD age, 44±9 years; 54% female; 47% black). High VAT–high LF and high VAT–low LF were associated with prevalent atherosclerosis, whereas low VAT–high LF was not. Of 1731 participants without CVD/T2DM, 128 (7.4%) developed CVD and 95 (5.5%) T2DM over a median of 12 years. High VAT–high LF and high VAT–low LF were associated with increased risk of CVD (hazard ratios [HRs], 2.0 [95% CI, 1.3 to 3.2] and 2.4 [95% CI, 1.4 to 4.1], respectively) and T2DM (odds ratios [ORs], 7.8 [95% CI, 3.8 to 15.8] and 3.3 [95% CI, 1.4 to 7.8], respectively), whereas low VAT–high LF was associated with T2DM (OR, 2.7 [95% CI, 1.1 to 6.7]). In the UK Biobank (N=22,354; April 2014-May 2020), only high VAT–low LF remained associated with CVD after multivariable adjustment for age and body mass index (HR, 1.5 [95% CI, 1.2 to 1.9]).ConclusionAlthough VAT and LF are each associated with cardiometabolic risk, these observations demonstrate the importance of separating their cardiometabolic implications when there is presence or absence of either or both in an individual.     

Shift Work,Genetic Factors,and the Risk of Heart Failure: A Prospective Study of the UK Biobank

ObjectiveTo quantify the association of combined shift work and genetic factors with the incidence of heart failure (HF).Participants and MethodsThis study included 242,754 participants with complete shift work information in the UK Biobank. Participants were followed from baseline (2006 to 2010) through January 31, 2018. The association between shift work and HF incidence was investigated separately in males and females using a Cox proportional hazards model adjusted for covariates. In addition, we established a polygenic risk score and assessed whether shift work alters genetic susceptibility to HF.ResultsThe results showed a significant association of permanent night shift work with incident HF among females (hazard ratio, 2.25; 95% CI, 1.34 to 3.76; P=.002) after adjusting for age, and the association was attenuated in the fully adjusted model. Among men, we did not detect an association between shift work and HF. In addition, we observed that the association between the risk of HF and shift work was strengthened by high genetic risk. Permanent night shift work paired with high genetic risk, compared with low genetic risk, was suggested to be associated with the risk of HF in females (hazard ratio, 2.89; 95% CI, 1.05 to 7.94) but not in males.ConclusionShift work, particularly permanent night shift work, may increase the risk of HF in females, especially in those with high genetic risk.     

Association of Lifestyle Behaviors With Hearing Loss: The UK Biobank Cohort Study

ObjectiveTo examine the combined association of five healthy lifestyle behaviors with hearing loss (HL) in the UK Biobank cohort, established between 2006 and 2010 in the United Kingdom.MethodsThis longitudinal analysis included 61,958 participants aged 40 to 70 years from April 2007 to December 2016. The healthy behaviors examined were: never smoking, high level of physical activity, high diet quality, moderate alcohol intake, and optimal sleep. Hearing loss was self-reported at baseline and in any physical exam during the follow-up.ResultsOver a median follow-up of 3.9±2.5 years, 3072 (5.0%) participants reported incident HL. After adjustment for potential confounders, including age, social factors, exposure to high-intensity noise, ototoxic medication, and comorbidity, the HRs of HL associated with having 1, 2, 3, and 4 to 5 vs 0 behaviors were: 0.85 (95% CI, 0.75 to 0.96), 0.85 (95% CI, 0.75 to 0.96), 0.82 (95% CI, 0.71 to 0.94), and 0.80 (95% CI, 0.67 to 0.97), respectively (P for trend, 0.02). We estimated that the population attributable risk percent for not adhering to any five low-risk lifestyle behaviors was 15.6%.ConclusionIn this large study, an increasing number of healthy behaviors was associated with decreased risk of HL.     

Adherence to a Healthy Sleep Pattern and Risk of Chronic Kidney Disease: The UK Biobank Study

ObjectiveTo examine the association of a healthy sleep pattern, characterized by sleep of 7 to 8 h/d, morning person, no insomnia, no frequent snoring, and no daytime sleepiness, with the risk of chronic kidney disease (CKD).MethodsWe included 392,218 European adults, aged 38 to 73 years, who were free of CKD at recruitment between March 13, 2006, and October 1, 2010, from the UK Biobank study. Data on sleep behaviors were collected through questionnaires at recruitment. Cox proportional hazards regression models were used to assess the relations between the healthy sleep score and risk of CKD.ResultsWe identified 18,842 incident CKD cases after a mean follow-up of 11.1 (SD 2.2) years. The healthy sleep score was inversely associated with the risk of CKD in a dose-dependent manner (P for trend, <.001). Compared with the participants with a poor sleep pattern (score of 0-1), the multivariate adjusted hazard ratio of CKD was 0.77 (95% CI, 0.71 to 0.84) for those with the healthiest sleep pattern (score of 5). In addition, we found that the inverse association was stronger in individuals without history of hypertension compared with individuals with hypertension at baseline (P for interaction, .003) and in those 60 years of age or younger compared with their older counterparts (P for interaction, <.001).ConclusionOur data suggest that adherence to an overall healthy sleep pattern is associated with a lower risk of CKD, especially for individuals without history of hypertension and those who are younger.     

Association of Self-reported Walking Pace With Type 2 Diabetes Incidence in the UK Biobank Prospective Cohort Study

ObjectiveTo investigate the association between self-reported walking pace and type 2 diabetes (T2D) incidence and whether it differed by physical activity levels and walking time.MethodsThere were 162,155 participants (mean age, 57.1 years; 54.9% women) from the UK Biobank prospective study, recruited between 2006 and 2010, included in the study. Walking pace was self-reported and classified as brisk, average, or slow. Total physical activity and walking time were self-reported using the International Physical Activity Questionnaire. Association between walking pace and T2D incidence and the potential moderating role of physical activity and walking time were investigated using Cox proportional hazards models.ResultsThe median follow-up was 7.4 (interquartile range, 6.7 to 8.2) years. There were 4442 participants in whom T2D developed during the follow-up period. In the fully adjusted model (sociodemographic factors, diet, body mass index, and physical activity), average walking pace (hazard ratio [HR], 1.28; 95% CI, 1.14 to 1.44) and slow walking pace (HR, 1.91; 95% CI, 1.62 to 2.24) were associated with a higher T2D risk compared with brisk walking among women. Among men, average walking pace (HR, 1.28; 95% CI, 1.17 to 1.40) and slow walking pace (HR, 1.73; 95% CI, 1.50 to 1.99) were also associated with higher T2D risk. Compared with slow walkers, brisk walkers have the same diabetes incidence rate 18.6 and 16.0 years later, for women and men, respectively.ConclusionAverage and slow walking pace was associated with a higher risk of incident T2D in both men and women, independent of major confounding factors. The associations were consistent across different physical activity levels and walking time.     

Comparative Relevance of Physical Fitness and Adiposity on Life Expectancy: A UK Biobank Observational Study

ObjectiveTo investigate the extent to which 2 measures of physical fitness—walking pace and handgrip strength—are associated with life expectancy across different levels of adiposity, as the relative importance of physical fitness and adiposity on health outcomes is still debated.Patients and MethodsUsual walking pace (self-defined as slow, steady/average, brisk), dynamometer-assessed handgrip strength, body mass index (BMI), waist circumference, and body-fat percentage determined at baseline in the UK Biobank prospective cohort study (March 13, 2006, to January 31, 2016). Life expectancy was estimated at 45 years of age.ResultsThe median age and BMI of the 474,919 participants included in this analysis were 58.2 years and 26.7 kg/m², respectively; over a median follow-up of 6.97 years, 12,823 deaths occurred. Participants reporting brisk walking pace had longer life expectancies across all levels of BMIs, ranging from 86.7 to 87.8 years in women and 85.2 to 86.8 years in men. Conversely, subjects reporting slow walking pace had shorter life expectancies, being the lowest observed in slow walkers with a BMI less than 20 kg/m² (women: 72.4 years; men: 64.8 years). Smaller, less consistent differences in life expectancy were observed between participants with high and low handgrip strength, particularly in women. The same pattern of results was observed for waist circumference or body-fat percentage.ConclusionBrisk walkers were found to have longer life expectancies, which was constant across different levels and indices of adiposity. These findings could help clarify the relative importance of physical fitness and adiposity on mortality.     

Effect of Omega-3 Dosage on Cardiovascular Outcomes: An Updated Meta-Analysis and Meta-Regression of Interventional Trials

ObjectivesTo quantify the effect of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids on cardiovascular disease (CVD) prevention and the effect of dosage.MethodsThis study is designed as a random effects meta-analysis and meta-regression of randomized control trials with EPA/DHA supplementation. This is an update and expanded analysis of a previously published meta-analysis which covers all randomized control trials with EPA/DHA interventions and cardiovascular outcomes published before August 2019. The outcomes included are myocardial infarction (MI), coronary heart disease (CHD) events, CVD events (a composite of MI, angina, stroke, heart failure, peripheral arterial disease, sudden death, and non-scheduled cardiovascular surgical interventions), CHD mortality and fatal MI. The strength of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation framework.ResultsA total of 40 studies with a combined 135,267 participants were included. Supplementation was associated with reduced risk of MI (relative risk [RR], 0.87; 95% CI, 0.80 to 0.96), high certainty number needed to treat (NNT) of 272; CHD events (RR, 0.90; 95% CI, 0.84 to 0.97), high certainty NNT of 192; fatal MI (RR, 0.65; 95% CI, 0.46 to 0.91]), moderate certainty NNT = 128; and CHD mortality (RR, 0.91; 95% CI, 0.85 to 0.98), low certainty NNT = 431, but not CVD events (RR, 0.95; 95% CI, 0.90 to 1.00). The effect is dose dependent for CVD events and MI.ConclusionCardiovascular disease remains the leading cause of death worldwide. Supplementation with EPA and DHA is an effective lifestyle strategy for CVD prevention, and the protective effect probably increases with dosage.     

The presentation,etiologies, pathophysiology,and treatment of pulmonary renal syndrome: A review of the literature

Pulmonary renal syndrome (PRS) is a constellation of different disorders that cause both rapidly progressive glomerulonephritis and diffuse alveolar hemorrhage. While antineutrophil cytoplasmic antibody associated vasculitis and anti-glomerular basement membrane disease are the predominant causes of PRS, numerous other mechanisms have been shown to cause this syndrome, including thrombotic microangiopathies, drug exposures, and infections, among others. This syndrome has high morbidity and mortality, and early diagnosis and treatment is imperative to improve outcomes. Treatment generally involves glucocorticoids and immunosuppressive agents, but treatment targeted to the underlying disorder can improve outcomes and mitigate side effects. Familiarity with the wide range of possible causes of PRS can aid the clinician in workup, diagnosis and early initiation of treatment. This review provides a summary of the clinical presentation, etiologies, pathophysiology, and treatment of PRS.     

Osteoporosis and Its Association With Cardiovascular Disease,Respiratory Disease,and Cancer: Findings From the UK Biobank Prospective Cohort Study

ObjectiveTo investigate sex-specific associations of osteoporosis with incidence of and mortality from cardiovascular disease (CVD), respiratory disease, and cancer as well as with all-cause mortality.MethodsIn total, 305,072 participants (53% [161,383] women) of UK Biobank were included in this study (2007-2010). Self-reported diagnosis of osteoporosis at baseline was the exposure of interest. The outcomes were CVD, respiratory disease, chronic obstructive pulmonary disease (COPD), all cancer, and prostate and breast cancer incidence and mortality and all-cause mortality. Associations between osteoporosis and outcomes were investigated using Cox proportional hazards models.ResultsIn men, osteoporosis was associated with a higher incident risk of all respiratory diseases (hazard ratio [HR], 1.26; 95% CI, 1.06 to 1.50) including COPD (HR, 1.82; 95% CI, 1.38 to 2.40). Men with osteoporosis also had a higher mortality risk from all causes (HR, 1.71; 95% CI, 1.38 to 2.11), CVD (HR, 1.68; 95% CI, 1.19 to 2.37), respiratory disease (HR, 2.35; 95% CI, 1.70 to 3.24), and COPD (HR, 3.64; 95% CI, 2.24 to 5.91). These associations persisted after adjustment for age, body mass index, and comorbidities. Women with osteoporosis had a higher risk of incident CVD (HR, 1.24; 95% CI, 1.97 to 1.44), respiratory disease (HR, 1.23; 95% CI, 1.13 to 1.33), and COPD (HR, 1.29; 95% CI, 1.10 to 1.52). Women with osteoporosis also had a higher mortality risk from respiratory disease (HR, 1.31; 95% CI, 1.00 to 1.72) and breast cancer (HR, 1.60; 95% CI, 1.14 to 2.26).ConclusionCompared with women, men with osteoporosis had a higher risk of all-cause mortality, mortality from respiratory diseases including COPD, and cancer incidence. Osteoporosis was strongly associated with respiratory disease and COPD in both sexes, even after full adjustment for covariates, although men with osteoporosis experienced a higher risk of adverse outcomes.     

Association of Changes in Physical Activity and Adiposity With Mortality and Incidence of Cardiovascular Disease: Longitudinal Findings From the UK Biobank

ObjectiveTo examine the association of changes in physical activity and adiposity with all-cause mortality and incident cardiovascular disease (CVD).MethodsPhysical activity, body mass index (BMI), body fat percentage, waist circumference, and waist to hip ratio changes were categorized on the basis of public health and clinical guidelines. Among 29,610 participants (mean ± SD follow-up, 5.1±2.1 years), 545 deaths and 2970 CVD events occurred. Participants were observed from baseline (March 13, 2006, to October 10, 2010) and follow-up (August 1, 2012 to November 9, 2018) assessment through March 31, 2021.ResultsCompared with stable-insufficient physical activity, increasing physical activity to meet guidelines at follow-up was associated with lower all-cause mortality (hazard ratio, 0.64 [0.49 to 0.85]) and CVD (0.83 [0.72 to 0.96]) risk. This risk was similar to that of those who achieved physical activity guidelines at both time points (all-cause mortality, 0.74 [0.60 to 0.92]; CVD, 0.88 [0.79 to 0.99]). For obese and overweight participants, decreasing BMI category was associated with a lower CVD risk (0.70 [0.47 to 1.04]) similar to the risk of those who had a healthy weight at both time points (0.85 [0.76 to 0.96]). In the joint analyses, the only combination that lowered all-cause mortality and CVD risk was physical activity increase and adiposity decrease over time (eg, CVD risk: BMI, 0.64 [0.42 to 0.96]; body fat percentage, 0.76 [0.55 to 0.97]; waist circumference, 0.66 [0.48 to 0.89]; waist to hip ratio, 0.78 [0.62 to 0.97]) compared with the reference group (stable physical activity and adiposity).ConclusionIncreases in physical activity to meet guidelines lowered all-cause mortality and CVD risk equal to that of those who continually met guidelines. The risk was effectively eliminated in those who had concurrent adiposity decrease.     

Association of Timing and Balance of Physical Activity and Rest/Sleep With Risk of COVID-19: A UK Biobank Study

Behavioral lifestyle factors are associated with cardiometabolic disease and obesity, which are risk factors for coronavirus disease 2019 (COVID-19). We aimed to investigate whether physical activity, and the timing and balance of physical activity and sleep/rest, were associated with SARS-CoV-2 positivity and COVID-19 severity. Data from 91,248 UK Biobank participants with accelerometer data and complete covariate and linked COVID-19 data to July 19, 2020, were included. The risk of SARS-CoV-2 positivity and COVID-19 severity—in relation to overall physical activity, moderate-to-vigorous physical activity (MVPA), balance between activity and sleep/rest, and variability in timing of sleep/rest—was assessed with adjusted logistic regression. Of 207 individuals with a positive test result, 124 were classified as having a severe infection. Overall physical activity and MVPA were not associated with severe COVID-19, whereas a poor balance between activity and sleep/rest was (odds ratio [OR] per standard deviation: 0.71; 95% confidence interval [CI], 0.62 to 0.81]). This finding was related to higher daytime activity being associated with lower risk (OR, 0.75; 95% CI, 0.61 to 0.93) but higher movement during sleep/rest being associated with higher risk (OR, 1.26; 95% CI, 1.12 to 1.42) of severe infection. Greater variability in timing of sleep/rest was also associated with increased risk (OR, 1.21; 95% CI, 1.08 to 1.35). Results for testing positive were broadly consistent. In conclusion, these results highlight the importance of not just physical activity, but also quality sleep/rest and regular sleep/rest patterns, on risk of COVID-19. Our findings indicate the risk of COVID-19 was consistently approximately 1.2-fold greater per approximately 40-minute increase in variability in timing of proxy measures of sleep, indicative of irregular sleeping patterns.     

Evaluation of the dosimetric influence of interfractional 6D setup error in hypofractionated prostate cancer treated with IMRT and VMAT using daily kV-CBCT

IntroductionProstate cancer is one of the most common malignant tumors in men and is usually treated with advanced intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT). Significant uncorrected interfractional 6-Dimensional setup errors could impact the delivered dose. The aim of this study was to assess the dosimetric impact of 6D interfractional setup errors in hypofractionated prostate cancer using daily kilovoltage cone-beam computed tomography (kV-CBCT).MethodsThis retrospective study comprised twenty prostate cancer patients treated with hypofractionated IMRT (8) and VMAT (12) with daily kV-CBCT image guidance. Interfraction 6D setup errors along lateral, longitudinal, vertical, pitch, roll, and yaw axes were evaluated for 400 CBCTs. For targets and organs at risk (OARs), the dosimetric impact of rotational error (R_Error), translational error (T_Error), and translational plus rotational error (T+R_Error) were evaluated on kV-CBCT images.ResultsThe single fraction maximum T_Error ranged from 12–20 mm, and the R_Error ranged from 2.8⁰–3.0⁰. The maximum mean absolute dose variation ΔD in D_98% (dose to 98% volume) of CTV-55 and PTV-55 was -0.66±0.82 and -5.94±3.8 Gy, respectively, in the T+R_Error. The maximum ΔD (%) for D_98% and D_0.035cc in CTV-55 was -4.29% and 2.49%, respectively, while in PTV-55 it was -24.9% and 2.36%. The mean dose reduction for D_98% in CTV-55 and D_98% and D_95% in PTV-55 was statistically significant (p<0.05) for T_Error and T+R_Error. The mean dose variation for D_mean and D_50% in the rectum was statistically significant (p<0.05) for T_Error and T+R_Error.ConclusionThe uncorrected interfractional 6D setup error results in significant target underdosing and OAR overdosing in prostate cancer. This emphasizes the need to correct interfractional 6D setup errors daily in IMRT and VMAT.     

Genetic Risk,Muscle Strength,and Incident Stroke: Findings From the UK Biobank Study

ObjectiveTo examine the associations of muscle strength and genetic risk for stroke with stroke incidence.Participants and MethodsWe included 284,767 white British participants of UK Biobank without genetic relatedness and stroke or myocardial infarction at baseline between March 13, 2006, and October 1, 2010. Genetic risk was assessed with polygenic risk scores, calculated by summing the risk-increasing alleles, weighted by the effect estimates. Muscle strength was assessed through grip strength tests by hand dynamometers. Incidence of overall (n= 4008), ischemic (n= 3031), and hemorrhagic (n=1073) stroke was adjudicated during 11.5-year follow-up.ResultsCompared with the bottom muscle strength tertile, hazard ratios (95% CI) of stroke were 0.81 (0.75 to 0.87) and 0.76 (0.71 to 0.82) for the middle and top muscle strength tertiles, respectively, after adjustment for confounders and genetic risk; higher genetic risk was independently associated with higher stroke incidence. Stroke hazards for the top muscle strength tertile were consistently lower across genetic risk strata, with no evidence of interaction. Compared with individuals with high muscle strength and low genetic risk, stroke hazards were higher for individuals who had medium or high genetic risk combined with low or medium muscle strength but not for those who had medium genetic risk but high muscle strength. Associations were similar for ischemic and hemorrhagic stroke (although CIs were inconclusive for some of the associations).ConclusionHigher muscle strength was associated with lower stroke incidence in all individuals, including those with high genetic susceptibility. The increased genetic risk of overall and ischemic stroke was partly attenuated through increased muscle strength.     

Effect of sample size and the traditional parametric,nonparametric, and robust methods on the establishment of reference intervals: Evidence from real world data

Sample size and statistical methods are critical for establishing reference intervals (RIs) but they tend to be overlooked. In this study, we used R (3.6.3) to stratify the reference individuals by sex, and then stratified them using the random sampling method. Fourteen sub-data sets with a sample size of 40, 80, 120, 160, 200, 500, 800, 1000, 1500, 2000, 2500, 3000, 3500, and 4000 were extracted, respectively. The sex ratios of all sub-data sets were 1:1. Transformed parametric (using log transformation), nonparametric, and robust approaches as described in the Clinical and Laboratory Standards Institute guidelines were adopted to establish the RIs and the 90% confidence interval of the thyroid-stimulating hormone (TSH) using data from the sub-data sets. The Bland-Altman plot was used to evaluate the consistency of the upper and lower limits of the RIs established using the three methods. The upper and lower limits of TSH RI tended to be stable starting from the data set with a sample size of 1500. The RIs established using the three methods were more consistent when using a sample size greater than or equal to 2000.