Exercise is medicine in oncology: Engaging clinicians to help patients move through cancer.

Multiple organizations around the world have issued evidence-based exercise guidance for patients with cancer and cancer survivors. Recently, the American College of Sports Medicine has updated its exercise guidance for cancer prevention as well as for the prevention and treatment of a variety of cancer health-related outcomes (eg, fatigue, anxiety, depression, function, and quality of life). Despite these guidelines, the majority of people living with and beyond cancer are not regularly physically active. Among the reasons for this is a lack of clarity on the part of those who work in oncology clinical settings of their role in assessing, advising, and referring patients to exercise. The authors propose using the American College of Sports Medicine's Exercise Is Medicine initiative to address this practice gap. The simple proposal is for clinicians to assess, advise, and refer patients to either home-based or community-based exercise or for further evaluation and intervention in outpatient rehabilitation. To do this will require care coordination with appropriate professionals as well as change in the behaviors of clinicians, patients, and those who deliver the rehabilitation and exercise programming. Behavior change is one of many challenges to enacting the proposed practice changes. Other implementation challenges include capacity for triage and referral, the need for a program registry, costs and compensation, and workforce development. In conclusion, there is a call to action for key stakeholders to create the infrastructure and cultural adaptations needed so that all people living with and beyond cancer can be as active as is possible for them.

Prospective Association of Daily Steps With Cardiovascular Disease: A Harmonized Meta-Analysis.

BACKGROUND: Taking fewer than the widely promoted "10 000 steps per day" has recently been associated with lower risk of all-cause mortality. The relationship of steps and cardiovascular disease (CVD) risk remains poorly described. A meta-analysis examining the dose-response relationship between steps per day and CVD can help inform clinical and public health guidelines. METHODS: Eight prospective studies (20 152 adults [ie, ≥18 years of age]) were included with device-measured steps and participants followed for CVD events. Studies quantified steps per day and CVD events were defined as fatal and nonfatal coronary heart disease, stroke, and heart failure. Cox proportional hazards regression analyses were completed using study-specific quartiles and hazard ratios (HR) and 95% CI were meta-analyzed with inverse-variance-weighted random effects models. RESULTS: The mean age of participants was 63.2±12.4 years and 52% were women. The mean follow-up was 6.2 years (123 209 person-years), with a total of 1523 CVD events (12.4 per 1000 participant-years) reported. There was a significant difference in the association of steps per day and CVD between older (ie, ≥60 years of age) and younger adults (ie, <60 years of age). For older adults, the HR for quartile 2 was 0.80 (95% CI, 0.69 to 0.93), 0.62 for quartile 3 (95% CI, 0.52 to 0.74), and 0.51 for quartile 4 (95% CI, 0.41 to 0.63) compared with the lowest quartile. For younger adults, the HR for quartile 2 was 0.79 (95% CI, 0.46 to 1.35), 0.90 for quartile 3 (95% CI, 0.64 to 1.25), and 0.95 for quartile 4 (95% CI, 0.61 to 1.48) compared with the lowest quartile. Restricted cubic splines demonstrated a nonlinear association whereby more steps were associated with decreased risk of CVD among older adults. CONCLUSIONS: For older adults, taking more daily steps was associated with a progressively decreased risk of CVD. Monitoring and promoting steps per day is a simple metric for clinician-patient communication and population health to reduce the risk of CVD.

Observational and genetic associations between cardiorespiratory fitness and cancer: a UK Biobank and international consortia study.

BACKGROUND: The association of fitness with cancer risk is not clear. METHODS: We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of lung, colorectal, endometrial, breast, and prostate cancer in a subset of UK Biobank participants who completed a submaximal fitness test in 2009-12 (N = 72,572). We also investigated relationships using two-sample Mendelian randomisation (MR), odds ratios (ORs) were estimated using the inverse-variance weighted method. RESULTS: After a median of 11 years of follow-up, 4290 cancers of interest were diagnosed. A 3.5 ml O2⋅min-1⋅kg-1 total-body mass increase in fitness (equivalent to 1 metabolic equivalent of task (MET), approximately 0.5 standard deviation (SD)) was associated with lower risks of endometrial (HR = 0.81, 95% CI: 0.73-0.89), colorectal (0.94, 0.90-0.99), and breast cancer (0.96, 0.92-0.99). In MR analyses, a 0.5 SD increase in genetically predicted O2⋅min-1⋅kg-1 fat-free mass was associated with a lower risk of breast cancer (OR = 0.92, 95% CI: 0.86-0.98). After adjusting for adiposity, both the observational and genetic associations were attenuated. DISCUSSION: Higher fitness levels may reduce risks of endometrial, colorectal, and breast cancer, though relationships with adiposity are complex and may mediate these relationships. Increasing fitness, including via changes in body composition, may be an effective strategy for cancer prevention.

Dose-response of accelerometer-measured physical activity, step count, and cancer risk in the UK Biobank: a prospective cohort analysis.

BACKGROUND: Cancer is an age-related condition, but changes to modifiable lifestyle-related behaviours, including physical activity, could impact risk. While step count is an accessible metric of activity for older adults, its association with cancer risk remains poorly understood. We investigated the association between accelerometer-measured total activity, step count, and cancer risk. METHODS: We analysed data from a prospective UK Biobank cohort of consenting participants who wore wrist-based Axivity AX3 accelerometer devices for 7 days between June 1, 2013 and Dec 23, 2015, had valid accelerometer data, and no previous cancer diagnosis at baseline. Machine learning models estimated total physical activity (vector magnitude) and step count. The primary outcome, a composite of 13 cancers previously associated with physical activity, was obtained from national registries. Hazard ratios (HR) and were calculated using Cox proportional hazard models, with attained age as the underlying timescale and adjustment for sex, ethnicity, smoking status, alcohol consumption, education, and Townsend Deprivation Index. The impact of reallocating time between behaviours was evaluated using compositional data analyses. Dose-response associations were assessed with restricted cubic splines. FINDINGS: We analysed data from 86 556 participants, who were followed up during an average of 6·1 years (age range 43-78; 48 478 [56%] female and 38 078 [44%] male; 83 830 [97%] white). 5577 incident malignant cancers occurred among these 86 556 participants. Greater total physical activity was associated with a lower risk of physical-activity-related cancer (HR per 1 SD [+8·33 milligravity per day] 0·85, 95% CI 0·81-0·89). Reallocating 30 min/day from other activities to moderate-to-vigorous physical activity behaviour was associated with lower cancer risk (HR 0·96, 0·94-0·98), as was reallocating 1 h/day to light intensity activity (HR 0·94, 0·92-0·96), compared with the mean behaviour composition among included participants. Compared with taking 5000 steps per day, taking 10 000 daily steps was associated with a significantly lower risk of physical-activity-related cancer (HR 0·81, 0·73-0·90). INTERPRETATION: In this sample from the UK Biobank, higher total physical activity and daily step count were associated with lower risk of physical-activity-related cancers. Findings suggest additional physical activity time, irrespective of intensity, may be beneficial. Increasing low intensity activity time and increasing daily step counts could be practical public health interventions to lower cancer risk, especially for aging adults. FUNDING: National Institute of Health Oxford Cambridge Scholars Program, Wellcome Trust, Swiss Re, Health Data Research UK, and Cancer Research UK.

The associations of muscle-strengthening exercise with recurrence and mortality among breast cancer survivors: a systematic review.

BACKGROUND: Our systematic review aimed to critically evaluate empirical literature describing the association of muscle-strengthening exercise (MSE) with recurrence and/or mortality among breast cancer survivors. METHODS: We included English-language empirical research studies examining the association between MSE and recurrence and/or mortality among females diagnosed with breast cancer. Seven databases (MEDLINE, PsycINFO, Embase, Scopus, Web of Science, Cochrane CENTRAL, and CINAHL) were searched in September 2023. Quality was appraised using the Mixed Methods Appraisal Tool. Results are summarized descriptively. RESULTS: Five sources were identified. MSE measurement differed in relation to the description of the MSE (i.e., muscle-strengthening vs. strength training), examples of activities (e.g., sit-ups or push-ups vs. calisthenics vs. circuit training), and exercise frequency (i.e., days vs. times/week). Findings offer provisional evidence that some MSE may lower the hazards of recurrence and mortality. This association may vary by race, weight status, and menopausal status. CONCLUSIONS: In summary, limited available evidence suggests that MSE may lower the hazards of recurrence and mortality. More consistent measurement and analyses would help generate findings that are more readily comparable and applicable to inform clinical practice. Further research is needed to improve understanding of the strength and differences of these associations among underserved and underrepresented women.

Associations of steps per day and step intensity with the risk of cancer: Findings from the Women's Health Accelerometry Collaboration cohort.

OBJECTIVE: Accumulating more steps/day is associated with a lower risk of cancer mortality and composite cancer outcomes. However, less is known about the relationship of steps/day with the risk of multiple site-specific cancers. METHODS: This study included >22,000 women from the Women's Health Accelerometry Collaboration Cohort (2011-2022), comprised of women from the Women's Health Study and Women's Health Initiative Objective Physical Activity and Cardiovascular Health Study. Steps/day and step intensity were collected with accelerometry. Incident cancer cases and deaths were adjudicated. Stratified Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of the associations of steps/day and step intensity with incident breast, colon, endometrial, lung, and ovarian cancers, a composite of 13 physical activity-related cancers, total invasive cancer, and fatal cancer. RESULTS: On average, women were 73.4 years old, accumulated 4993 steps/day, and had 7.9 years of follow-up. There were small nonsignificant inverse associations with the risks of colon cancer (HR = 0.94, 95% CI: 0.83, 1.05), endometrial cancer (HR = 0.91, 95% CI: 0.82, 1.01), and fatal cancer (HR = 0.95 95% CI: 0.90, 1.00) per 1000 steps/day. More minutes at ≥40 steps/min and a faster peak 10- and 30-min step cadence were associated with a lower risk of endometrial cancer, but findings were attenuated after adjustment for body mass index and steps/day. CONCLUSIONS: Among women 62-97 years, there were small nonsignificant inverse associations of colon, endometrial, and fatal cancer with more steps/day. Epidemiologic studies with longer follow-up and updated assessments are needed to further explore these associations.

County-level Racial/Ethnic Residential Segregation and Physical Activity Behavior among US Adults.

The relationship between racial/ethnic residential segregation and physical activity (PA) remains unclear with both positive and negative associations between segregation and PA recently reported. We aimed to examine the relationship between county-level residential segregation and total daily PA and domain-specific PA and whether these associations varied by gender. Participants (N = 2625, mean age [SD] = 45.2 [15.4]) were recruited from the AmeriSpeak panel who completed up to two Activities Completed over Time in 24 Hours (ACT24) previous day recalls in 2019. PA outcomes were created for the following: (1) light PA (LPA), (2) moderate-to-vigorous PA (MVPA), (3) total active time, and (4) domain-specific PA, including leisure, work, household, transport, personal, and other activities. County-level residential segregation based on isolation. Weighted generalized linear models were used to examine the relationship between county-level segregation and each PA outcome, controlling for age, gender, race/ethnicity, income, employment, body mass index, county-level poverty, and census region. Overall, results showed no association between county-level residential segregation and LPA, MVPA, total active time, and domain-specific PA among NH Black and Hispanic populations. Among NH Black females, greater residential segregation was associated with more total hours/day of activity (ß = 3.54, 95% CI [0.23, 6.85]). Only NH Black females living in segregated neighborhoods had more total active time. Additionally, it is important to acknowledge that these relationships may vary among NH Black and Hispanic populations. Future studies should examine the interaction between segregation and a broader range of individual, contextual, and environmental factors in relation to PA and domain-specific PA.

Associations of device-measured physical activity and sedentary time with quality of life and fatigue in newly diagnosed breast cancer patients: Baseline results from the AMBER cohort study.

BACKGROUND: This study examined associations of device-measured physical activity and sedentary time with quality of life (QOL) and fatigue in newly diagnosed breast cancer patients in the Alberta Moving Beyond Breast Cancer (AMBER) cohort study. METHODS: After diagnosis, 1409 participants completed the SF-36 version 2 and the Fatigue Scale, wore an ActiGraph device on their right hip to measure physical activity, and an activPAL device on their thigh to measure sedentary time (sitting/lying) and steps. ActiGraph data was analyzed using a hybrid machine learning method (R Sojourn package, Soj3x) and activPAL data were analyzed using activPAL algorithms (PAL Software version 8). Quantile regression was used to examine cross-sectional associations of QOL and fatigue with steps, physical activity, and sedentary hours at the 25th, 50th, and 75th percentiles of the QOL and fatigue distributions. RESULTS: Total daily moderate and vigorous physical activity (MVPA) hours was positively associated with better physical QOL at the 25th (ß = 2.14, p = <.001), 50th (ß = 1.98, p = <.001), and 75th percentiles (ß = 1.25, p = .003); better mental QOL at the 25th (ß = 1.73, p = .05) and 50th percentiles (ß = 1.07, p = .03); and less fatigue at the 25th (ß = 4.44, p < .001), 50th (ß = 3.08, p = <.001), and 75th percentiles (ß = 1.51, p = <.001). Similar patterns of associations were observed for daily steps. Total sedentary hours was associated with worse fatigue at the 25th (ß = -0.58, p = .05), 50th (ß = -0.39, p = .06), and 75th percentiles (ß = -0.24, p = .02). Sedentary hours were not associated with physical or mental QOL. CONCLUSIONS: MVPA and steps were associated with better physical and mental QOL and less fatigue in newly diagnosed breast cancer patients. Higher sedentary time was associated with greater fatigue symptoms.

Associations between health-related fitness and quality of life in newly diagnosed breast cancer patients.

PURPOSE: Newly diagnosed breast cancer patients face substantial stress and uncertainty that may undermine their quality of life (QoL). The purpose of the present study was to examine the associations between health-related fitness (HRF) and QoL in newly diagnosed breast cancer patients from the Alberta Moving Beyond Breast Cancer Study. METHODS: Newly diagnosed breast cancer patients with early-stage disease (n = 1458) were recruited between 2012 and 2019 in Edmonton and Calgary, Canada to complete baseline HRF and QoL assessments within 90 days of diagnosis. HRF assessments included cardiorespiratory fitness (VO2peak treadmill test), muscular fitness (upper and lower body strength and endurance tests), and body composition (dual x-ray absorptiometry). QoL was assessed by the Medical Outcomes Study Short Form 36 (SF-36) version 2. We used logistic regression analyses to examine the associations between quartiles of HRF and poor/fair QoL (bottom 20%) after adjusting for key covariates. RESULTS: In multivariable analysis, the least fit groups compared to the most fit groups for relative upper body strength (OR = 3.19; 95% CI = 1.98-5.14), lean mass percentage (OR = 2.31; 95% CI = 1.37-3.89), and relative VO2peak (OR = 2.08; 95% CI = 1.21-3.57) were independently at a significantly higher risk of poor/fair physical QoL. No meaningful associations were found for mental QoL. CONCLUSIONS: The three main components of HRF (muscular fitness, cardiorespiratory fitness, and body composition) were independently associated with physical QoL in newly diagnosed breast cancer patients. Exercise interventions designed to improve these components of HRF may optimize physical QoL and help newly diagnosed breast cancer patients better prepare for treatments and recovery.

Upper Limb Morbidity in Newly Diagnosed Individuals After Unilateral Surgery for Breast Cancer: Baseline Results from the AMBER Cohort Study.

PURPOSE: We aimed to examine potential associations between post-surgical upper limb morbidity and demographic, medical, surgical, and health-related fitness variables in newly diagnosed individuals with breast cancer. METHODS: Participants were recruited between 2012 and 2019. Objective measures of health-related fitness, body composition, shoulder range of motion, axillary web syndrome, and lymphedema were performed within 3 months of breast cancer surgery, and prior to or at the start of adjuvant cancer treatment. RESULTS: Upper limb morbidity was identified in 54% of participants and was associated with poorer upper limb function and higher pain. Multivariable logistic regression analysis identified mastectomy versus breast-conserving surgery (odds ratio [OR] 3.51, 95% confidence interval [CI] 2.65-4.65), axillary lymph node dissection versus sentinel lymph node dissection (OR 2.67, 95% CI 1.73-4.10), earlier versus later time from surgery (OR 1.58, 95% CI 1.15-2.18), and younger versus older age (OR 1.01, 95% CI 1.00-1.03) as significantly associated with a higher odds of upper limb morbidity, while mastectomy (OR 1.57, 95% CI 1.10-2.25), axillary lymph node dissection (OR 2.20, 95% CI 1.34-3.60), lower muscular endurance (OR 1.10, 95% CI 1.01-1.16) and higher percentage body fat (OR 1.04, 95% CI 1.00-1.07) were significantly associated with higher odds of moderate or greater morbidity severity. CONCLUSIONS: Upper limb morbidity is common in individuals after breast cancer surgery prior to adjuvant cancer treatment. Health-related fitness variables were associated with severity of upper limb morbidity. Findings may facilitate prospective surveillance of individuals at higher risk of developing upper limb morbidity.

Depression, happiness, and satisfaction with life in women newly diagnosed with breast cancer: Associations with device-measured physical activity and sedentary time.

BACKGROUND: Few studies have examined depression after a cancer diagnosis and before initiating adjuvant or neoadjuvant systemic treatments. In this study, we present baseline data on device-measured physical activity, sedentary behaviour, depression, happiness, and satisfaction with life in newly diagnosed breast cancer survivors. PURPOSE: To examine associations of accelerometer-assessed physical activity and sedentary time with depression symptoms and prevalence, happiness, and satisfaction with life. METHODS: Shortly after diagnosis, 1425 participants completed depression, happiness, and satisfaction with life measures and wore an ActiGraph® device on their hip to measure physical activity and the activPALTM inclinometer on their thigh for 7 days to measure sedentary time (sitting/lying) and steps (1384 completed both device measures). ActiGraph® data were analysed using a hybrid machine learning method (R Sojourn package, Soj3x), and activPALTM data using activPALTM algorithms (PAL Software version 8). We used linear and logistic regression to examine associations of physical activity and sedentary time with depression symptom severity (0-27) and depression prevalence, happiness (0-100), and satisfaction with life (0-35). For the logistic regression analysis, we compared participants with none-minimal depression (n = 895) to participants with some depression (that is, mild, moderate, moderately-severe, or severe depression [n = 530]). RESULTS: Participants reported a mean depression symptom severity score of 4.3 (SD = 4.1), a satisfaction with life score of 25.7 (SD = 7.2), and a happiness score of 70 (SD = 21.8). Higher moderate-to-vigorous physical activity (MVPA) was associated with reduced depression symptom severity scores (ß = -0.51, 95% CI: -0.87 to -0.14, p = 0.007). A 1 hour increase in MVPA was associated with a reduced odds of at least mild or worse depression by 24% (Odds Ratio [OR] = 0.76, 95% CI: 0.62-0.94, p = 0.012). Higher daily step counts were associated with lower depression symptom severity scores (ß = -0.16, 95% CI: -0.24 to -0.10, p < 0.001). Perceptions of happiness was associated with higher MVPA (ß = 2.17, 95% CI: 0.17-4.17, p = 0.033). Sedentary time was not associated with depression severity, but higher sedentary time was associated with lower perceptions of happiness (ß = -0.80, 95% CI: -1.48 to -0.11, p = 0.023). CONCLUSIONS: Higher physical activity was associated with fewer depression symptom severity scores and reduced odds of mild or worse depression in women newly diagnosed with breast cancer. Higher physical activity and daily step counts were also associated with stronger perceptions of happiness and satisfaction with life, respectively. Sedentary time was not associated with depression symptom severity or odds of having depression, but was associated with stronger perceptions of happiness.

Social-cognitive, demographic, clinical, and health-related correlates of physical activity and sedentary behaviour in newly diagnosed women with breast cancer.

PURPOSE: Identifying correlates of physical activity and sedentary behaviour allows for the identification of factors that may be targeted in future behaviour change interventions. This study sought to determine the social-cognitive, demographic, clinical, and health-related correlates of physical activity and sedentary behaviour in individuals recently diagnosed with breast cancer. METHODS: Data were collected from 1381 participants within 90 days of diagnosis in the Alberta Moving Beyond Breast Cancer (AMBER) Cohort Study. Physical activity and sedentary behaviour were measured with ActiGraph GT3X+® and activPALTM devices, respectively, for seven consecutive days. Correlates were collected via a self-reported questionnaire, medical record extraction, or measured by staff. RESULTS: Multivariable models were fitted for sedentary behaviour, light physical activity, and moderate-to-vigorous physical activity. Greater sedentary behaviour was associated with higher body fat percentage (BF%) (ß=0.044; p<0.001) and being single (ß=0.542; p<0.002). Lower light physical activity was associated with higher BF% (ß=-0.044; p<0.001), higher body mass index (ß=-0.039; p<0.001), greater disease barrier influence (ß=-0.006; p<0.001), a HER2-positive diagnosis (ß=-0.278; p=0.001), and being single (ß=-0.385; p= 0.001). Lower moderate-to-vigorous physical activity was associated with higher BF% (ß =-0.011; p=0.001), greater disease barrier influence (ß=-0.002; p<0.001), and being of Asian (ß=-0.189; p=0.002) or Indian/South American (ß=-0.189; p=0.002) descent. Greater moderate-to-vigorous physical activity was associated with having greater intentions (ß=0.049; p=0.033) and planning (ß=0.026; p=0.015) towards physical activity. CONCLUSION: Tailoring interventions to increase physical activity for individuals recently diagnosed with breast cancer may improve long-term outcomes across the breast cancer continuum.

The Alberta moving beyond breast cancer (AMBER) cohort study: baseline description of the full cohort.

PURPOSE: The Alberta Moving Beyond Breast Cancer (AMBER) Study is an ongoing prospective cohort study investigating how direct measures of physical activity (PA), sedentary behavior (SB), and health-related fitness (HRF) are associated with survival after breast cancer. METHODS: Women in Alberta with newly diagnosed stage I (≥ T1c) to IIIc breast cancer were recruited between 2012 and 2019. Baseline assessments were completed within 90 days of surgery. Measurements included accelerometers to measure PA and SB; a graded treadmill test with gas exchange analysis to measure cardiorespiratory fitness (VO2peak); upper and lower body muscular strength and endurance; dual-X-ray absorptiometry to measure body composition; and questionnaires to measure self-reported PA and SB. RESULTS: At baseline, the 1528 participants' mean age was 56 ± 11 years, 59% were post-menopausal, 62% had overweight/obesity, and 55% were diagnosed with stage II or III disease. Based on device measurements, study participants spent 8.9 ± 1.7 h/day sedentary, 4.4 ± 1.2 h/day in light-intensity activity, 0.9 ± 0.5 h/day in moderate-intensity activity, and 0.2 ± 0.2 h/day in vigorous-intensity activity. For those participants who reached VO2peak, the average aerobic fitness level was 26.6 ± 6 ml/kg/min. Average body fat was 43 ± 7.1%. CONCLUSION: We have established a unique cohort of breast cancer survivors with a wealth of data on PA, SB, and HRF obtained through both direct and self-reported measurements. Study participants are being followed for at least ten years to assess all outcomes after breast cancer. These data will inform clinical and public health guidelines on PA, SB, and HRF for improving breast cancer outcomes.

Body Composition and Metabolomics in the Alberta Physical Activity and Breast Cancer Prevention Trial.

BACKGROUND: Obesity is correlated with many biomarkers, but the extent to which these correlate with underlying body composition is poorly understood. OBJECTIVES: Our objectives were to 1) describe/compare distinct contributions of fat/lean mass with BMI-metabolite correlations and 2) identify novel metabolite biomarkers of fat/lean mass. METHODS: The Alberta Physical Activity and Breast Cancer Prevention Trial was a 2-center randomized trial of healthy, inactive, postmenopausal women (n = 304). BMI (in kg/m2) was calculated using weight and height, whereas DXA estimated fat/lean mass. Ultra-performance liquid chromatography and mass spectrometry measured relative concentrations of serum metabolite concentrations. We estimated partial Pearson correlations between 1052 metabolites and BMI, adjusting for age, smoking, and site. Fat mass index (FMI; kg/m2) and lean mass index (LMI; kg/m2) correlations were estimated similarly, with mutual adjustment to evaluate independent effects. RESULTS: Using a Bonferroni-corrected α level <4.75 × 10-5,  we observed 53 BMI-correlated metabolites (|r| = 0.24-0.42). Of those, 21 were robustly correlated with FMI (|r| > 0.20), 25 modestly (0.10 ≤ |r| ≤ 0.20), and 7 virtually null (|r| < 0.10). Ten of 53 were more strongly correlated with LMI than with FMI. Examining non-BMI-correlated metabolites, 6 robustly correlated with FMI (|r| = 0.24-0.31) and 2 with LMI (r = 0.25-0.26). For these, correlations for fat and lean mass were in opposing directions compared with BMI-correlated metabolites, in which correlations were mostly in the same direction. CONCLUSIONS: Our results demonstrate how a thorough evaluation of the components of fat and lean mass, along with BMI, provides a more accurate assessment of the associations between body composition and metabolites than BMI alone. Such an assessment makes evident that some metabolites correlated with BMI predominantly reflect lean mass rather than fat, and some metabolites related to body composition are not correlated with BMI. Correctly characterizing these relations is important for an accurate understanding of how and why obesity is associated with disease.

Rest-activity profiles among U.S. adults in a nationally representative sample: a functional principal component analysis.

BACKGROUND: The 24-h rest and activity behaviors (i.e., physical activity, sedentary behaviors and sleep) are fundamental human behaviors essential to health and well-being. Functional principal component analysis (fPCA) is a flexible approach for characterizing rest-activity rhythms and does not rely on a priori assumptions about the activity shape. The objective of our study is to apply fPCA to a nationally representative sample of American adults to characterize variations in the 24-h rest-activity pattern, determine how the pattern differs according to demographic, socioeconomic and work characteristics, and examine its associations with general health status. METHODS: The current analysis used data from adults 25 or older in the National Health and Nutrition Examination Survey (NHANES, 2011-2014). Using 7-day 24-h actigraphy recordings, we applied fPCA to derive profiles for overall, weekday and weekend rest-activity patterns. We examined the association between each rest-activity profile in relation to age, gender, race/ethnicity, education, income and working status using multiple linear regression. We also used multiple logistic regression to determine the relationship between each rest-activity profile and the likelihood of reporting poor or fair health. RESULTS: We identified four distinct profiles (i.e., high amplitude, early rise, prolonged activity window, biphasic pattern) that together accounted for 86.8% of total variation in the study sample. We identified numerous associations between each rest-activity profile and multiple sociodemographic characteristics. We also found evidence suggesting the associations differed between weekdays and weekends. Finally, we reported that the rest-activity profiles were associated with self-rated health. CONCLUSIONS: Our study provided evidence suggesting that rest-activity patterns in human populations are shaped by multiple demographic, socioeconomic and work factors, and are correlated with health status.

Lifetime high occupational physical activity and total and cause-specific mortality among 320 000 adults in the NIH-AARP study: a cohort study.

OBJECTIVES: We examined the associations of history and duration in high occupational physical activity (OPA) with long-term total and cause-specific mortality. METHODS: The sample included 322 126 participants (135 254 women) from the National Institutes of Health-AARP Diet and Health Study, established in 1995-1996. History and duration in high OPA were reported by participants. All-cause, cardiovascular, cancer and other cause mortality records available through 31 December 2011. RESULTS: The prevalence of high OPA was 52.1% in men and 16.1% in women. During 13.6 years (SD, 3.3) of follow-up, 73 563 participants (25 219 women) died. In age-adjusted models, the risk of death was higher among men (HR 1.14, 95% CI 1.12 to 1.16) and women (HR 1.22, 95% CI 1.18 to 1.26) with a history of high OPA. However, these associations were substantially attenuated in women (HR 1.04, 95% CI 1.00 to 1.07, an 81.8% attenuation) and eliminated in men (HR 1.02, 95% CI 0.99 to 1.04, 85.7% attenuation) after multivariable adjustments. Similar important attenuation results were found when examining duration in high OPA, as well as using cause-specific deaths as the outcomes. Educational attainment and smoking patterns were the main contributors in the excess mortality among people working in highly physically active jobs in both men and women. CONCLUSION: Participating in high OPA was not consistently associated with a higher mortality risk, after adjustments for education and smoking factors. Workers in high OPA should be aware that they might not be getting all well-known health benefits of being physically active if they are only very active at work.

Independent and joint associations of weightlifting and aerobic activity with all-cause, cardiovascular disease and cancer mortality in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial.

OBJECTIVES: Both aerobic moderate to vigorous physical activity (MVPA) and muscle-strengthening exercise (MSE) are recommended, but the mortality benefits of weightlifting, a specific type of MSE, are limited. METHODS: In the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, we used Cox proportional hazards regression to calculate hazard ratios (HRs) and 95% CIs for the associations between weightlifting and mortality, adjusting for demographics, lifestyle and behavioural risk factors. The sample included 99 713 adults who completed the follow-up questionnaire that assessed weightlifting who were subsequently followed up through 2016 to determine mortality (median 9, IQR 7.6-10.6 years). RESULTS: Mean age at the follow-up questionnaire was 71.3 (IQR 66-76) years, 52.6% female, with mean body mass index of 27.8 (SD 4.9) kg/m2. Weightlifting was associated with a 9% lower risk of all-cause mortality (HR=0.91 (95% CI 0.88 to 0.94)) and CVD mortality (0.91 (95% CI 0.86 to 0.97)) after adjusting for MVPA. Joint models revealed that adults who met aerobic MVPA recommendations but did not weightlift had a 32% lower all-cause mortality risk (HR=0.68 (95% CI 0.65 to 0.70)), while those who also reported weightlifting 1-2 times/week had a 41% lower risk (HR=0.59 (95% CI 0.54 to 0.64)), both compared with adults reporting no aerobic MVPA or weightlifting. Without adjustment for MVPA, weightlifting was associated with lower cancer mortality (HR=0.85 (95% CI 0.80 to 0.91)). CONCLUSION: Weightlifting and MVPA were associated with a lower risk of all-cause and CVD mortality, but not cancer mortality. Adults who met recommended amounts of both types of exercise appeared to gain additional benefit.

Gastroesophageal reflux disease: A risk factor for laryngeal squamous cell carcinoma and esophageal squamous cell carcinoma in the NIH-AARP Diet and Health Study cohort.

BACKGROUND: Prior studies have suggested that gastroesophageal reflux disease (GERD) may be associated with risk of squamous cancers of the larynx and esophagus; however, most of these studies have had methodological limitations or insufficient control for potential confounders. METHODS: We prospectively examined the association between GERD and esophageal adenocarcinoma (EADC), esophageal squamous cell carcinoma (ESCC), and laryngeal squamous cell carcinoma (LSCC) in 490,605 participants of the NIH-AARP Diet and Health Study cohort who were 50-71 years of age at baseline. Exposure to risk factors were obtained from the baseline questionnaire. GERD diagnosis was extracted among eligible participants via linkage to Medicare diagnoses codes and then multiply imputed for non-Medicare-eligible participants. Hazard ratios (HRs) and 95% CIs of GERD were computed using Cox regression. RESULTS: From 1995 to 2011, we accrued 931 cases of EADC, 876 cases of LSCC, and 301 cases of ESCC in this cohort and estimated multivariable-adjusted HRs of 2.23 (95% CI, 1.72-2.90), 1.91 (95% CI, 1.24-2.94), and 1.99 (95% CI, 1.39-2.84) for EADC, LSCC, and ESCC, respectively. The associations were independent of sex, smoking status, alcohol intake, and follow-up time periods. We estimated that among the general population in the United States, 22.04% of people aged 50-71 years suffered from GERD. Using risk factor distributions for the United States from national survey data, 16.92% of LSCC cases and 17.32% of ESCC cases among individuals aged 50-71 years were estimated to be associated with GERD. CONCLUSION: GERD is a common gastrointestinal disorder, but future prospective studies are needed to replicate our findings. If replicated, they may inform clinical surveillance of GERD patients and suggest new avenues for prevention of these malignancies.

Population Attributable Risks of Subtypes of Esophageal and Gastric Cancers in the United States.

INTRODUCTION: To help target preventive strategies, we estimated US population attributable risks (PARs) of demographic and potentially modifiable risk factors for esophageal squamous cell carcinoma (ESCC), esophageal adenocarcinoma (EAC), gastric cardia adenocarcinoma (GCA), and gastric noncardia adenocarcinoma (GNCA). METHODS: We prospectively examined the associations for risk factors and these cancers in 490,605 people in the National Institutes of Health-the American Association of Retired Persons Diet and Health cohort Diet and Health Study cohort from 1995 to 2011. Exposures were obtained from the baseline questionnaire. Diagnoses of gastroesophageal reflux disease were extracted for a subset of eligible National Institutes of Health-the American Association of Retired Persons Diet and Health cohort subjects through linkage to Medicare and then multiply imputed for non-Medicare-eligible subjects. Hazard ratios were calculated using multivariable-adjusted Cox proportional hazards regression. Adjusted population attributable risks were calculated for the US population aged 50-71 years by combining the hazard ratios with the estimated joint distribution of risk factor prevalence from the 2015 National Health Interview Survey. RESULTS: Smoking remained the most important risk factor for ESCC and was estimated to cause more than 1/3 of EAC and GCA and 1/10 of GNCA. Obesity and gastroesophageal reflux disease were associated with more than 1/2 of EAC and 1/3 of GCA. Compared with each lowest-risk level category, common risk factors were estimated to be associated with 73.7% of ESCC (95% confidence interval [CI]: 62.1%-85.4%), 70.3% of EAC (95% CI: 64.4%-76.2%), 69.3% of GCA (95% CI: 61.0%-77.7%), and 33.6% of GNCA (95% CI: 21.7%-45.5%). DISCUSSION: These factors accounted for a large proportion of esophageal and gastric cancers in the United States, highlighting opportunities for education and intervention to reduce the burden of these highly fatal cancers.

Bayesian modeling reveals metabolite-dependent ultrasensitivity in the cyanobacterial circadian clock.

Mathematical models can enable a predictive understanding of mechanism in cell biology by quantitatively describing complex networks of interactions, but such models are often poorly constrained by available data. Owing to its relative biochemical simplicity, the core circadian oscillator in Synechococcus elongatus has become a prototypical system for studying how collective dynamics emerge from molecular interactions. The oscillator consists of only three proteins, KaiA, KaiB, and KaiC, and near-24-h cycles of KaiC phosphorylation can be reconstituted in vitro. Here, we formulate a molecularly detailed but mechanistically naive model of the KaiA-KaiC subsystem and fit it directly to experimental data within a Bayesian parameter estimation framework. Analysis of the fits consistently reveals an ultrasensitive response for KaiC phosphorylation as a function of KaiA concentration, which we confirm experimentally. This ultrasensitivity primarily results from the differential affinity of KaiA for competing nucleotide-bound states of KaiC. We argue that the ultrasensitive stimulus-response relation likely plays an important role in metabolic compensation by suppressing premature phosphorylation at nighttime.