Targeting the activated microenvironment with endosialin (CD248)-directed CAR-T cells ablates perivascular cells to impair tumor growth and metastasis.

BACKGROUND: Targeting of solid cancers with chimeric antigen receptor (CAR)-T cells is limited by the lack of suitable tumor-specific antigens and the immunosuppressive, desmoplastic tumor microenvironment that impedes CAR-T cell infiltration, activity and persistence. We hypothesized that targeting the endosialin (CD248) receptor, strongly expressed by tumor-associated pericytes and perivascular cancer-associated fibroblasts, would circumvent these challenges and offer an exciting antigen for CAR-T cell therapy due to the close proximity of target cells to the tumor vasculature, the limited endosialin expression in normal tissues and the lack of phenotype observed in endosialin knockout mice. METHODS: We generated endosialin-directed E3K CAR-T cells from three immunocompetent mouse strains, BALB/c, FVB/N and C57BL/6. E3K CAR-T cell composition (CD4+/CD8+ ratio), activity in vitro against endosialin+ and endosialin- cells, and expansion and activity in vivo in syngeneic tumor models as well as in tumor-naive healthy and wounded mice and tumor-bearing endosialin knockout mice was assessed. RESULTS: E3K CAR-T cells were active in vitro against both mouse and human endosialin+, but not endosialin-, cells. Adoptively transferred E3K CAR-T cells exhibited no activity in endosialin knockout mice, tumor-naive endosialin wildtype mice or in wound healing models, demonstrating an absence of off-target and on-target/off-tumor activity. By contrast, adoptive transfer of E3K CAR-T cells into BALB/c, FVB/N or C57BL/6 mice bearing syngeneic breast or lung cancer lines depleted target cells in the tumor stroma resulting in increased tumor necrosis, reduced tumor growth and a substantial impairment in metastatic outgrowth. CONCLUSIONS: Together these data highlight endosialin as a viable antigen for CAR-T cell therapy and that targeting stromal cells closely associated with the tumor vasculature avoids CAR-T cells having to navigate the harsh immunosuppressive tumor microenvironment. Further, the ability of E3K CAR-T cells to recognize and target both mouse and human endosialin+ cells makes a humanized and optimized E3K CAR a promising candidate for clinical development applicable to a broad range of solid tumor types.

Coengineering specificity, safety, and function into T cells for cancer immunotherapy.

Adoptive T-cell transfer (ACT) therapies, including of tumor infiltrating lymphocytes (TILs) and T cells gene-modified to express either a T cell receptor (TCR) or a chimeric antigen receptor (CAR), have demonstrated clinical efficacy for a proportion of patients and cancer-types. The field of ACT has been driven forward by the clinical success of CD19-CAR therapy against various advanced B-cell malignancies, including curative responses for some leukemia patients. However, relapse remains problematic, in particular for lymphoma. Moreover, for a variety of reasons, relative limited efficacy has been demonstrated for ACT of non-hematological solid tumors. Indeed, in addition to pre-infusion challenges including lymphocyte collection and manufacturing, ACT failure can be attributed to several biological processes post-transfer including, (i) inefficient tumor trafficking, infiltration, expansion and retention, (ii) chronic antigen exposure coupled with insufficient costimulation resulting in T-cell exhaustion, (iii) a range of barriers in the tumor microenvironment (TME) mediated by both tumor cells and suppressive immune infiltrate, (iv) tumor antigen heterogeneity and loss, or down-regulation of antigen presentation machinery, (v) gain of tumor intrinsic mechanisms of resistance such as to apoptosis, and (vi) various forms of toxicity and other adverse events in patients. Affinity-optimized TCRs can improve T-cell function and innovative CAR designs as well as gene-modification strategies can be used to coengineer specificity, safety, and function into T cells. Coengineering strategies can be designed not only to directly support the transferred T cells, but also to block suppressive barriers in the TME and harness endogenous innate and adaptive immunity. Here, we review a selection of the remarkable T-cell coengineering strategies, including of tools, receptors, and gene-cargo, that have been developed in recent years to augment tumor control by ACT, more and more of which are advancing to the clinic.

A lentiviral vector for the production of T cells with an inducible transgene and a constitutively expressed tumour-targeting receptor.

Vectors that facilitate the engineering of T cells that can better harness endogenous immunity and overcome suppressive barriers in the tumour microenvironment would help improve the safety and efficacy of T-cell therapies for more patients. Here we report the design, production and applicability, in T-cell engineering, of a lentiviral vector leveraging an antisense configuration and comprising a promoter driving the constitutive expression of a tumour-directed receptor and a second promoter enabling the efficient activation-inducible expression of a genetic payload. The vector allows for the delivery of a variety of genes to human T cells, as we show for interleukin-2 and a microRNA-based short hairpin RNA for the knockdown of the gene coding for haematopoietic progenitor kinase 1, a negative regulator of T-cell-receptor signalling. We also show that a gene encoded under an activation-inducible promoter is specifically expressed by tumour-redirected T cells on encountering a target antigen in the tumour microenvironment. The single two-gene-encoding vector can be produced at high titres under an optimized protocol adaptable to good manufacturing practices.

Position of the Society for Nutrition Education and Behavior: Nutrition Educator Competencies for Promoting Healthy Individuals, Communities, and Food Systems: Rationale and Application.

It is the position of the Society for Nutrition Education and Behavior that to improve the health of individuals, communities, and food systems, it is essential that nutrition educators meet each of 6 content competencies (basic food and nutrition knowledge, nutrition across the life cycle, food science, physical activity, food and nutrition policy, and agricultural production and food systems) and 4 process competencies (behavior and education theory; nutrition education program design, implementation and evaluation; written, oral, and social media communication; and nutrition education research methods). These competencies reflect the breadth of the nutrition education field and are grounded in peer-reviewed research. The rationale and evidence base for these competencies are presented. They are designed for educational institutions to plan curricula and programs; public, private, and nonprofit organizations for training; individuals for professional development; and policymakers and advocates to inform strong, comprehensive nutrition education policy.

Trajectories of physical activity from midlife to old age and associations with subsequent cardiovascular disease and all-cause mortality.

INTRODUCTION: It is well established that physical activity (PA) protects against mortality and morbidity, but how long-term patterns of PA are associated with mortality and cardiovascular disease (CVD) remains unclear. METHODS: 3231 men recruited to the British Regional Heart Study, a prospective cohort study, reported usual PA levels at baseline in 1978-1980 (aged 40-59 years) and at 12-year, 16-year and 20-year follow ups. Twenty-year trajectories of PA, spanning from 1978/1980 to 2000, were identified using group-based trajectory modelling. Men were subsequently followed up until 30 June 2016 for mortality through National Health Service central registers and for non-fatal CVD events through primary and secondary care records. Data analyses were conducted in 2019. RESULTS: Three PA trajectories were identified: low/decreasing (22.7%), light/stable (51.0%) and moderate/increasing (26.3%). Over a median follow-up of 16.4 years, there were 1735 deaths. Compared with the low/decreasing group, membership of the light/stable (HR 0.83, 95% CI 0.74 to 0.94) and moderate/increasing (HR 0.76, 95% CI 0.66 to 0.88) groups was associated with a lower risk of all-cause mortality. Similar associations were observed for CVD mortality, major coronary heart disease and all CVD events. Associations were only partially explained by a range of confounders. Sensitivity analyses suggested that survival benefits were largely driven by most recent/current PA. CONCLUSIONS: A dose-response relationship was observed, with higher levels of PA from midlife to old age associated with additional benefits. However, even fairly modest and sustained PA was protective and may be more achievable for the most inactive.

Physical frailty in older men: prospective associations with diet quality and patterns.

BACKGROUND: increasing numbers of older adults are living with frailty and its adverse consequences. We investigated relationships between diet quality or patterns and incident physical frailty in older British men and whether any associations were influenced by inflammation. METHODS: prospective study of 945 men from the British Regional Heart Study aged 70-92 years with no prevalent frailty. Incident frailty was assessed by questionnaire after 3 years of follow-up. Frailty was defined as having at least three of: low grip strength, low physical activity, slow walking speed, unintentional weight loss and feeling of low energy, all based on self-report. The Healthy Diet Indicator (HDI) based on WHO dietary guidelines and the Elderly Dietary Index (EDI) based on a Mediterranean-style dietary intake were computed from questionnaire data and three dietary patterns were identified using principal components analysis: prudent, high fat/low fibre and high sugar. RESULTS: men in the highest EDI category and those who followed a prudent diet were less likely to become frail [top vs bottom category odds ratio (OR) (95% CI) 0.49 (0.30, 0.82) and 0.53 (0.30, 0.92) respectively] after adjustment for potential confounders including BMI and prevalent cardiovascular disease. No significant association was seen for the HDI. By contrast those who had a high fat low fibre diet pattern were more likely to become frail [OR (95% CI) 2.54 (1.46, 4.40)]. These associations were not mediated by C-reactive protein (marker of inflammation). CONCLUSIONS: the findings suggest adherence to a Mediterranean-style diet is associated with reduced risk of developing frailty in older people.

Objectively measured physical activity, sedentary behaviour and all-cause mortality in older men: does volume of activity matter more than pattern of accumulation?

OBJECTIVES: To understand how device-measured sedentary behaviour and physical activity are related to all-cause mortality in older men, an age group with high levels of inactivity and sedentary behaviour. METHODS: Prospective population-based cohort study of men recruited from 24 UK General Practices in 1978-1980. In 2010-2012, 3137 surviving men were invited to a follow-up, 1655 (aged 71-92 years) agreed. Nurses measured height and weight, men completed health and demographic questionnaires and wore an ActiGraph GT3x accelerometer. All-cause mortality was collected through National Health Service central registers up to 1 June 2016. RESULTS: After median 5.0 years' follow-up, 194 deaths occurred in 1181 men without pre-existing cardiovascular disease. For each additional 30 min in sedentary behaviour, or light physical activity (LIPA), or 10 min in moderate to vigorous physical activity (MVPA), HRs for mortality were 1.17 (95% CI 1.10 to 1.25), 0.83 (95% CI 0.77 to 0.90) and 0.90 (95% CI 0.84 to 0.96), respectively. Adjustments for confounders did not meaningfully change estimates. Only LIPA remained significant on mutual adjustment for all intensities. The HR for accumulating 150 min MVPA/week in sporadic minutes (achieved by 66% of men) was 0.59 (95% CI 0.43 to 0.81) and 0.58 (95% CI 0.33 to 1.00) for accumulating 150 min MVPA/week in bouts lasting ≥10 min (achieved by 16% of men). Sedentary breaks were not associated with mortality. CONCLUSIONS: In older men, all activities (of light intensity upwards) were beneficial and accumulation of activity in bouts ≥10 min did not appear important beyond total volume of activity. Findings can inform physical activity guidelines for older adults.

Healthier diet quality and dietary patterns are associated with lower risk of mobility limitation in older men.

PURPOSE: To investigate associations between diet quality, dietary patterns and mobility limitation 15 years later in a population-based sample of older British men. METHODS: We used longitudinal data from 1234 men from the British Regional Heart Study, mean age 66 years at baseline. Mobility limitation was defined as difficulty going up- or downstairs or walking 400 yards as a result of a long-term health problem. Dietary intake was measured using a food frequency questionnaire data from which the Healthy Diet Indicator (HDI), the Elderly Dietary Index (EDI), and three a posteriori dietary patterns were derived. The a posteriori dietary patterns were identified using principal components analysis: (1) high fat/low fibre, (2) prudent and (3) high sugar. RESULTS: Men with greater adherence to the EDI or HDI were less likely to have mobility limitation at follow-up, top vs bottom category odds ratio for the EDI OR 0.50, 95% CI 0.34, 0.75, and for the HDI OR 0.55, 95% CI 0.35, 0.85, after adjusting for age, social class, region of residence, smoking, alcohol consumption and energy intake. Men with a higher score for the high-fat/low-fibre pattern at baseline were more likely to have mobility limitation at follow-up, top vs bottom quartile odds ratio OR 3.28 95% CI 2.05, 5.24. These associations were little changed by adjusting for BMI and physical activity. CONCLUSION: Our study provides evidence that healthier eating patterns could contribute to prevention or delay of mobility limitation in older British men.

Twenty-Year Trajectories of Physical Activity Types from Midlife to Old Age.

PURPOSE: Correlates of physical activity (PA) vary according to type. However, predictors of long-term patterns of PA types into old age are unknown. This study aimed to identify 20-yr trajectories of PA types into old age and their predictors. METHODS: Seven thousand seven hundred thirty-five men (age, 40-59 yr) recruited from UK towns in 1978 to 1980 were followed up after 12, 16, and 20 yr. Men reported participation in sport/exercise, recreational activity and walking, health status, lifestyle behaviors and socio-demographic characteristics. Group-based trajectory modeling identified the trajectories of PA types and associations with time-stable and time-varying covariates. RESULTS: Men with ≥3 measures of sport/exercise (n = 5116), recreational activity (n = 5085) and walking (n = 5106) respectively were included in analyses. Three trajectory groups were identified for sport/exercise, four for recreational activity and three for walking. Poor health, obesity and smoking were associated with reduced odds of following a more favorable trajectory for all PA types. A range of socioeconomic, regional and lifestyle factors were also associated with PA trajectories but the magnitude and direction were specific to PA type. For example, men with manual occupations were less likely to follow a favorable sport/exercise trajectory but more likely to follow an increasing walking trajectory compared to men with nonmanual occupations. Retirement was associated with increased PA but this was largely due to increased sport/exercise participation. CONCLUSIONS: Physical activity trajectories from middle to old age vary by activity type. The predictors of these trajectories and effects of major life events, such as retirement, are also specific to the type of PA.

Does total volume of physical activity matter more than pattern for onset of CVD? A prospective cohort study of older British men.

AIMS: With increasing age, physical inactivity and sedentary behaviour levels increase, as does cardiovascular disease (CVD) incidence. We investigate how device-measured sedentary behaviour and physical activity (PA) are related to CVD onset in men aged 70+; whether the total volume of activity is more important than pattern. METHODS AND RESULTS: Prospective population-based cohort study of men recruited from 24 UK General Practices in 1978-80. In 2010-12, 3137 survivors were invited to complete questionnaires and wear an Actigraph GT3x accelerometer for 7 days. PA intensity was categorised as sedentary, light and moderate to vigorous (MVPA). Men were followed up for Myocardial Infarction, stroke and heart failure (ICD9 410-414, 430-438 and 428) morbidity and mortality from 2010 to 12 to June 2016. Hazard Ratios (HRs) for incident Cardiovascular Disease (CVD) were estimated. 1528/3137 (49%) men had sufficient accelerometer data. 254 men with pre-existing CVD were excluded. Participants' mean age was 78.4 (range 71-92) years. After median 4.9 years follow-up, 122 first CVD events occurred in 1181 men (22.7/1000 person-years) with complete data. For each additional 30 min in sedentary behaviour, light PA,10 min in MVPA, or 1000 steps/day, HRs for CVD were 1.09(95%CI 1.00, 1.19), 0.94(0.85, 1.04), 0.88(0.81, 0.96) and 0.86(0.78 to 0.95) respectively, adjusted for measurement-related factors, socio-demographics, health behaviours and disability. HRs for accumulating 150 min/week MVPA in bouts ≥1 min and bouts ≥10 min were 0.47(0.32 to 0.69), and 0.49(0.25, 0.98). CONCLUSIONS: In older men, high volume of steps or MVPA rather than MVPA bouts was associated with reduced CVD risk.

Tracking of sport and exercise types from midlife to old age: a 20-year cohort study of British men.

BACKGROUND: Previous physical activity (PA) tracking studies have examined the stability of overall PA and/or PA types, but few have investigated how specific types of sport/exercise track over the life course. The aim of this study was to determine how specific sports/exercises in midlife track and predict future sport/exercise and PA in men transitioning to old age. METHODS: Seven thousand seven hundred thirty-five men (aged 40-59 years) recruited in 1978-80 were followed up after 12, 16 and 20 years. At each wave men self-reported participation in sport/exercise. Frequent sport/exercise participants (> 1/month) reported the types of sport/exercise they engaged in. Men also reported total PA, health status, lifestyle behaviours and socio-demographic characteristics. Stability of each sport/exercise was assessed using kappa statistics and intraclass correlation coefficients. Logistic regression estimated the odds of participating in sport/exercise and being active at 20-year follow up according to specific types of sport/exercise in midlife. RESULTS: Three thousand three hundred eighty-four men with complete data at all waves were included in analyses. Tracking of specific sports/exercises ranged from fair to substantial, with golf being the most common and most stable. Bowls was the most frequently adopted. Odds of participating in sport/exercise and being active in old age varied according to sport/exercise types in midlife. Golf and bowls in midlife were the strongest predictors of sport/exercise participation in old age. Golf, cricket and running/jogging in midlife were among the strongest predictors of being active in old age. Compared to participating in just one sport/exercise in midlife, sampling multiple sports/exercises was more strongly associated with sport/exercise participation and being active in old age. CONCLUSION: The stability of sport/exercise participation from midlife to old age varies by type. Specific sports/exercises in midlife may be more likely to predict future PA than others. However, participating in a range of sports/exercises may be optimal for preserving PA into old age.

Association Between 20-Year Trajectories of Nonoccupational Physical Activity From Midlife to Old Age and Biomarkers of Cardiovascular Disease: A 20-Year Longitudinal Study of British Men.

The trajectories of physical activity (PA) from midlife into old age and their associations with established and novel cardiovascular disease (CVD) risk factors in later life remain unclear. This study examined associations between 20-year nonoccupational PA trajectories and a range of CVD biomarkers at ages 60-79 years. We used data from a sample of 3,331 men (mean baseline age = 50.2 ± 5.8 years) recruited in 1978-1980, with follow-up after 12, 16, and 20 years, reporting habitual nonoccupational PA at each wave. At the 20-year follow-up, surviving men attended a physical examination and provided a fasting blood sample. Group-based trajectory modeling was used to identify trajectories. Adjusted regression analyses examined the association between trajectory-group membership and several cardiometabolic, cardiac, and inflammatory markers at follow-up. Three distinct 20-year trajectories were identified: low/decreasing (21.3%), light/stable (51.8%), and moderate/increasing (27.0%). Compared with the low/decreasing group, membership in the light/stable and moderate/increasing trajectory groups was associated with a more favorable cardiometabolic profile and lower levels of inflammation and endothelial dysfunction. Although following a moderate-increasing PA trajectory was most favorable, more modest but sustained doses of PA into old age may be sufficient to lower CVD risk.

Objectively measured physical activity and cardiac biomarkers: A cross sectional population based study in older men.

BACKGROUND: N-terminal pro-brain natriuretic peptide (NT-proBNP) and high sensitivity Troponin T (hsTnT) are markers of cardiac injury used in diagnosis of heart failure and myocardial infarction respectively, and associated with increased risk of cardiovascular disease. Since physical activity is protective against cardiovascular disease and heart failure, we investigated whether higher levels of physical activity, and less sedentary behaviour were associated with lower NT-proBNP and hsTnT. METHODS AND RESULTS: Cross sectional study of 1130 men, age 70-91years, from the British Regional Heart Study, measured in 2010-2012. Fasting blood samples were analysed for NT-proBNP and hsTnT. Physical activity and sedentary behaviour were measured using ActiGraph GT3X accelerometers. Relationships between activity and NT-proBNP or hsTnT were non-linear; biomarker levels were lower with higher total activity, steps, moderate/vigorous activity and light activity only at low to moderate levels of activity. For example, for each additional 10min of moderate/vigorous activity, NT-proBNP was lower by 35.7% (95% CI -47.9, -23.6) and hsTnT by 8.4% (95% CI -11.1, -5.6), in men who undertook <25 or 50min of moderate/vigorous activity per day respectively. Biomarker levels increased linearly with increasing sedentary behaviour, but not independently of moderate/vigorous activity. CONCLUSION: Associations between biomarkers and moderate/vigorous activity (and between hsTnT and light activity) were independent of sedentary behaviour, suggesting activity is driving the relationships. In these older men with concomitantly low levels of physical activity, activity may be more important in protecting against cardiac health deterioration in less active individuals, although reverse causality might be operating.

Trajectories of self-reported physical activity and predictors during the transition to old age: a 20-year cohort study of British men.

BACKGROUND: Maintenance of physical activity (PA) during later life is associated with optimal health; however, the long-term trajectories of PA into old age and their predictors have not been extensively researched using latent class methods. This study aimed to identify trajectories of self-reported PA and their predictors in men transitioning from midlife to old age. METHODS: 7735 men (aged 40-59 years) recruited in 1978-80 were followed up after 12, 16 and 20 years, reporting PA, health status, lifestyle behaviours and socio-demographic characteristics. Group-based trajectory modelling identified the trajectories of PA and associations with time-stable and time-varying covariates. We considered a range of sociodemographic and health and lifestyle factors as potential covariates. RESULTS: 4952 men (mean baseline age 49.1 ± 5.6 years) providing PA data at ≥3 time points were included in analyses. Three distinct 20-year trajectories were identified: low decreasing (24.6%, n = 1218), light stable (51.1%, n = 2530) and moderate increasing (24.3%, n = 1204). Being older, having a manual occupation, having never married or had children, residing in the midlands or North of England, suffering from a range of health conditions, being a smoker/ex-smoker and never consuming breakfast cereal or alcohol were independently associated with reduced odds of belonging to the moderate increasing trajectory group compared to the low decreasing group. Of the time-varying covariates considered, leaving employment was associated with a decrease in PA in the low decreasing group (ß -0.306, p < 0.001) but an increase in the light stable (ß 0.324, p < 0.001) and moderate increasing groups (ß 0.847, p < 0.001). Developing cardiovascular-related conditions was associated with a decrease in PA in the low decreasing (ß -0.408, p < 0.001) and light stable groups (ß -0.118, p < 0.001) but no association was observed in the moderate increasing group (ß -0.060, p = 0.313). CONCLUSIONS: Three distinct trajectories of PA were identified in men transitioning from midlife to old age, of which nearly a quarter had persistently low levels of PA. Promotion efforts may need to focus attention prior to middle age and consider a number of sociodemographic, health and lifestyle factors to sustain PA into old age. The effects of retirement and development of cardiovascular disease may vary according to PA trajectories.

Medical students' perceived educational needs to prevent and treat childhood obesity.

BACKGROUND: Medical schools are challenged to incorporate more prevention-based education into curricula, offering an opportunity to revisit approaches to nutrition education. The objective of this study was to explore United States (US) medical students' understanding of childhood obesity, specifically barriers to childhood obesity prevention and treatment and students' perceived educational deficits. METHODS: The research team conducted phone interviews with 78 3rd- and 4th-year medical students, representing 25 different medical schools across the US. Using a semi-structured interview guide, researchers asked students to describe the etiology of childhood obesity and reflect on where they acquired knowledge of the etiology and what additional resources they would need to treat obese children. Using a phenomenological approach to analysis, researchers identified five dominant emergent themes. RESULTS: Student-perceived barriers to childhood obesity prevention and treatment in clinical care included student-centered (e.g., lack of knowledge), patient-centered (e.g., lack of access), and healthcare system-centered barriers (e.g., limited time). Students requested more applicable nutrition information and counseling skills relevant to preventing and treating childhood obesity; however, they tended to identify others (e.g., parents, schools), rather than themselves, when asked to describe how childhood obesity should be prevented or treated. DISCUSSION: To provide students with an understanding of their role in preventing and treating childhood obesity, US medical schools need to provide students with childhood obesity-specific and general nutrition education. To build their self-efficacy in nutrition counseling, schools can use a combination of observation and practice led by skilled physicians and other healthcare providers. Increasing students' self-efficacy through training may help them overcome perceived barriers to childhood obesity prevention and treatment.

Objectively measured physical activity and kidney function in older men; a cross-sectional population-based study.

Background: kidney function declines in older adults and physical activity levels are low. We investigated whether higher levels of physical activity and lower levels of sedentary behaviour were associated with lower odds of low kidney function in older men. Methods: cross-sectional study of 1,352 men from the British Regional Heart Study, mean (standard deviation) age 78.5 (4.6) year. Physical activity and sedentary behaviour were measured using Actigraph GT3X accelerometers. Kidney function was measured by estimated Glomerular filtration rate (eGFR) using the chronic kidney disease-EPI creatinine-cystatin equation. Associations between physical (in)activity and kidney function were investigated using regression models. Results: higher levels of physical activity and lower levels of sedentary behaviour were associated with reduced odds ratios (ORs) for lower eGFR (<45 versus ≥45 ml/min per 1.73 m2) after adjustment for covariates. Each additional 1,000 steps, 30 min of light physical activity and 10 min of moderate/vigorous physical activity per day were associated with a lower odds (95% confidence interval (CI)) of a low eGFR; OR 0.81 (0.73, 0.91), OR 0.87 (0.78, 0.97) and OR 0.84 (0.76, 0.92), respectively. Each additional 30 min of sedentary behaviour per day was associated with a higher odds of a low eGFR (1.16 95% CI 1.06, 1.27). Associations between moderate/vigorous physical activity and lower kidney function persisted after adjustment for light physical activity or sedentary behaviour. Conclusion: physical activity is associated with kidney function in older men and could be of public health importance in this group who are at increased risk of poor kidney function and low physical activity. More evidence is needed on whether the association is causal.

Physical Activity, Sedentary Behavior, and Inflammatory and Hemostatic Markers in Men.

PURPOSE: This study aimed to determine whether higher levels of physical activity (PA) and less sedentary behavior (SB) are associated with less inflammation, indicated by inflammatory and hemostatic biomarkers, in older men. METHODS: A cross-sectional study of 1139 men, from the British Regional Heart Study (mean ± SD age = 78 ± 5 yr), and longitudinal analyses of 490 men with two PA measures 1 yr apart were used in this study. Single fasting venous blood samples were analyzed for several biomarkers. PA and SB were measured using ActiGraph GT3X accelerometers. Total time and time spent in bouts of moderate to vigorous PA (MVPA), light PA, and SB were derived. Linear regression analyses were used to investigate associations. RESULTS: Cross-sectionally, higher total PA, daily steps, and MVPA were all associated with lower levels of interleukin 6 (IL-6), C-reactive protein (CRP), tissue plasminogen activator (tPA), von Willebrand factor (vWF), and D-dimer, whereas higher levels of SB were associated with higher levels of IL-6, CRP, and tPA. Each additional 10 min of MVPA was associated with a 3.2% lower IL-6 (95% confidence interval [CI] = -4.5% to -1.8%), 5.6% lower CRP (95% CI = -7.8 to -3.3), 2.2% lower tPA (95% CI = -3.0 to -1.4), 1.2% lower vWF (95% CI = -2.1 to -0.3), and 1.8% lower D-dimer (95% CI = -2.9 to -0.7), and for CRP, vWF, and D-dimer independently of SB. Associations between SB and IL-6 or tPA were independent of MVPA. Longer bouts of PA or SB were not more strongly associated with outcomes than shorter bouts. Longitudinal analyses were inconsistent with these findings, possibly because of power limitations. CONCLUSION: Although PA (particularly MVPA) was generally associated with inflammatory and hemostatic biomarkers, we found no evidence that longer bouts were more important than shorter bouts.

Association of Maximum Temperature With Sedentary Time in Older British Men.

BACKGROUND: Sedentary behavior is very common in older adults and a risk factor for mortality. Understanding determinants of sedentary behavior may help in defining strategies aimed to reduce the time spent sedentary. The degree of difference in sedentary time attributable to varying temperatures has not been yet estimated in older men. METHODS: Men aged 71 to 91 years participating in an established UK population-based cohort study were invited to wear an Actigraph GT3X accelerometer for 1 week in 2010-12. Outcome was sedentary time (<1.5 Metabolic Equivalent of Task) in minutes per day. Associations between daily outdoor maximum temperature and accelerometer-measured sedentary time were estimated using multilevel models. RESULTS: 43% (1361/3137) of invited men participated in the study and provided adequate data. Men spent on average 615 minutes in sedentary time per day (72% of the total accelerometer-wear time). After adjusting for covariates, men spent 26 minutes more per day (P < .001) in sedentary time when temperatures were in the lowest (-3.5; 9.2°C) versus highest quintile (19.1; 29.5°C). CONCLUSIONS: Sedentary time in older adults is highest at lowest temperatures, typically recorded in winter. Findings are relevant for guidelines: interventions may consider targeting older men in winter providing recommendations for minimizing sedentariness on daily basis.

Cross-sectional associations of objectively measured physical activity and sedentary time with sarcopenia and sarcopenic obesity in older men.

This study investigated associations between objectively measured physical activity (PA) with sarcopenia and sarcopenic obesity in older British men. Participants were men aged 70-92years (n=1286) recruited from UK Primary Care Centres. Outcomes included (i) sarcopenia, defined as low muscle mass (lowest two fifths of the mid-upper arm muscle circumference distribution) accompanied by low muscular strength (hand grip strength <30kg) or low physical performance (gait speed≤0.8m/s); (ii) severe sarcopenia, required all three conditions; (iii) sarcopenic obesity defined as sarcopenia or severe sarcopenia and a waist circumference of >102cm. Independent variables included time spent in PA intensities measured by GT3x accelerometers, worn during one week in 2010-12. Multinomial regression models were used for cross-sectional analyses relating PA and sarcopenia. In total, 14.2% (n=183) of men had sarcopenia and a further 5.4% (n=70) had severe sarcopenia. 25.3% of sarcopenic or severely sarcopenic men were obese. Each extra 30min per day of moderate-to-vigorous PA (MVPA) was associated with a reduced risk of severe sarcopenia (relative risk [RR] 0.53, 95% confidence interval [CI] 0.30, 0.93) and sarcopenic obesity (RR 0.47 [95% CI 0.27, 0.84]). Light PA (LPA) and sedentary breaks were marginally associated with a reduced risk of sarcopenic obesity. Sedentary time was marginally associated with an increased risk of sarcopenic obesity independent of MVPA (RR 1.18 [95% CI 0.99, 1.40]). MVPA may reduce the risk of severe sarcopenia and sarcopenic obesity among older men. Reducing sedentary time and increasing LPA and sedentary breaks may also protect against sarcopenic obesity.

Objectively measured physical activity, sedentary time and subclinical vascular disease: Cross-sectional study in older British men.

Low physical activity (PA) and high levels of sedentary time (ST) are associated with higher cardiovascular disease (CVD) risk among older people. However, their independent contribution and importance of duration of PA and ST bouts remain unclear. We investigated associations between objectively measured PA, ST and non-invasive vascular measures, markers of CVD risk. Cross-sectional study of 1216 men from the British Regional Heart Study, mean age 78.5years, measured in 2010-2012. Carotid intima thickness (CIMT), distensibility coefficient (DC) and plaque presence were measured using ultrasound; pulse wave velocity (cfPWV) and augmentation index (AIx) using a Vicorder. PA and ST were measured using hip-worn ActiGraph GT3X accelerometers. After adjusting for covariates, each additional 1000 steps per day was associated with a 0.038m/s lower cfPWV (95% CI=-0.076, 0.0003), 0.095 10(-3) kPa(-1) higher DC (95% CI=0.006, 0.185), 0.26% lower AIx (95% CI=-0.40, -0.12) and a 0.005mm lower CIMT (95% CI=-0.008, -0.001). Moderate and vigorous PA (MVPA) was associated with lower AIx and CIMT, light PA (LPA) with lower cfPWV and CIMT and ST with higher cfPWV, AIx and CIMT and lower DC. LPA and ST were highly correlated (r=-0.62). The independence of MVPA and ST or MVPA and LPA was inconsistent across vascular measures. Bout lengths for both PA and ST were not associated with vascular measures. In our cross-sectional study of older men, all PA regardless of intensity or bout duration was beneficially associated with vascular measures, as was lower ST. LPA was particularly relevant for cfPWV and CIMT.