Patterns of physical activity and sedentary behavior in child and adolescent cancer survivors assessed using wrist accelerometry: A cluster analysis approach.

Physical activity levels among childhood cancer survivors are typically quantified as a total amount using time spent in various intensities. Yet, most analyses do not consider the transitory nature of children's behaviors and a more detailed approach could provide complimentary information. We aimed to explore various behavior profiles of survivors' daily and hourly physical activity patterns. We measured 8-18-year-old survivors' activity levels over 7 days using wrist accelerometry and cluster analysis. Of the 37 participant datasets, survivors engaged in mean (SD) 36.3 (19.0) min/day of MVPA and 4.1 (1.9) hrs/day of sedentary activity. The cluster analysis revealed five daily movement patterns: 'most active' (prevalence 11%), 'active' (22%), 'moderately active + moderately sedentary' (35%), 'moderately active + high sedentary' (5%) and 'least active' (27%). Younger survivors and those with less time since treatment completion were more likely to be in the active clusters. Hourly behaviors were characterized by short bursts of MVPA and moderate bouts of sedentary activity. Our approach provides an insightful analysis into the nature and timing of childhood cancer survivors' movement behaviours. Our findings may assist in the development of targeted interventions to improve physical activity levels.

Evaluating the effect of upper-body morbidity on quality of life following primary breast cancer treatment: a systematic review and meta-analysis.

PURPOSE: Improvements in breast cancer management continue to increase survival and life expectancy after treatment. Yet the adverse effects of treatment may persist long term, threatening physical, psychological, and social wellbeing, leading to impaired quality of life (QOL). Upper-body morbidity (UBM) such as pain, lymphoedema, restricted shoulder range of motion (ROM), and impaired function are widely reported after breast cancer treatment, but evidence demonstrating its impact on QOL is inconsistent. Therefore, the aim of the study was to conduct a systematic review and meta-analysis evaluating the effect of UBM on QOL following primary breast cancer treatment. METHODS: The study was prospectively registered on PROSPERO (CRD42020203445). CINAHL, Embase, Emcare, PsycInfo, PubMed/Medline, and SPORTDiscus databases were searched for studies reporting QOL in individuals with and without UBM following primary breast cancer treatment. Primary analysis determined the standardised mean difference (SMD) in physical, psychological, and social wellbeing scores between UBM + /UBM - groups. Secondary analyses identified differences in QOL scores between groups, according to questionnaire. RESULTS: Fifty-eight studies were included, with 39 conducive to meta-analysis. Types of UBM included pain, lymphoedema, restricted shoulder ROM, impaired upper-body function, and upper-body symptoms. UBM + groups reported poorer physical (SMD = - 0.99; 95%CI = - 1.26, - 0.71; p < 0.00001), psychological (SMD = - 0.43; 95%CI = - 0.60, - 0.27; p < 0.00001), and social wellbeing (SMD = - 0.62; 95%CI = - 0.83, - 0.40; p < 0.00001) than UBM - groups. Secondary analyses according to questionnaire showed that UBM + groups rated their QOL poorer or at equal to, UBM - groups across all domains. CONCLUSIONS: Findings demonstrate the significant, negative impact of UBM on QOL, pervading physical, psychological, and social domains. IMPLICATIONS FOR CANCER SURVIVORS: Efforts to assess and minimise the multidimensional impact of UBM are warranted to mitigate impaired QOL after breast cancer.

The effect of exercise intensity on the inflammatory profile of cancer survivors: A randomised crossover study.

BACKGROUND: Systemic inflammation has been clearly linked to poorer health outcomes from cancer diagnosis through to survivorship. There is accumulating evidence that exercise can reduce inflammation. However, the optimal intensity of exercise to reduce systemic inflammation is unknown. AIMS: The aim of this randomised crossover study was to identify the difference between high- and low-intensity aerobic exercise on the inflammatory profile of cancer survivors after a single exercise session (acute) and a short training period (six sessions over 2 weeks). METHOD: Participants (n = 20) were randomised to either low- or high-intensity exercise. They underwent 2 weeks of stationary cycling at their assigned intensity and then underwent a 6-week washout period of no exercise before returning to complete 2 weeks of exercise at the remaining intensity. RESULTS: Twenty participants with a mean age of 56.4 (±9.4) years were enrolled and completed the intervention. There was no effect of exercise intensity after a single exercise session. After 2 weeks of training, there was a significant effect of intensity on chemokines CCL2 (mean difference ± SEM; 13.2 pg/mL ± 5.0, p = .04) and CXCL12 (150.3 pg/mL ± 51.8, p = .02), where CCL2 was decreased after low-intensity exercise and CXCL12 decreased after high-intensity exercise. DISCUSSION: Our data suggest that while exercise intensity may impact different cell types in the circulation, both low- and high-intensity exercise can positively modulate inflammatory markers. CONCLUSION: The potential to scale up low-intensity exercise over time is likely to be more broadly applicable and achievable for cancer survivor cohorts while still eliciting beneficial effects on systemic inflammation.

Irradiation-Induced Dysbiosis: The Compounding Effect of High-Fat Diet on Metabolic and Immune Functions in Mice.

The negative impact of irradiation or diet on the metabolic and immune profiles of cancer survivors have been previously demonstrated. The gut microbiota plays a critical role in regulating these functions and is highly sensitive to cancer therapies. The aim of this study was to investigate the effect of irradiation and diet on the gut microbiota and metabolic or immune functions. We exposed C57Bl/6J mice to a single dose of 6 Gy radiation and after 5 weeks, fed them a chow or high-fat diet (HFD) for 12 weeks. We characterised their faecal microbiota, metabolic (whole body and adipose tissue) functions, and systemic (multiplex cytokine, chemokine assay, and immune cell profiling) and adipose tissue inflammatory profiles (immune cell profiling). At the end of the study, we observed a compounding effect of irradiation and diet on the metabolic and immune profiles of adipose tissue, with exposed mice fed a HFD displaying a greater inflammatory signature and impaired metabolism. Mice fed a HFD also showed altered microbiota, irrespective of irradiation status. An altered diet may exacerbate the detrimental effects of irradiation on both the metabolic and inflammatory profiles. This could have implications for the diagnosis and prevention of metabolic complications in cancer survivors exposed to radiation.

Ballet after breast cancer: investigating the feasibility and acceptability of a novel 16-week classical ballet intervention for breast cancer survivors.

PURPOSE: The "Ballet after breast cancer" study sought to investigate the feasibility and acceptability of a 16-week classical ballet intervention for breast cancer survivors, delivered face-to-face and/or online. METHODS: Breast cancer survivors were recruited to take part in 2 × 1-h ballet classes per week for 16 weeks. Primary outcomes of feasibility and acceptability were assessed according to rates of enrolment and attendance and participant feedback via questionnaire. Secondary outcomes included quality of life (QOL), upper-body disability, shoulder range of motion (ROM), muscular strength, aerobic capacity, and physical activity levels. Associations between rate of attendance and changes in secondary measures were explored. RESULTS: Thirty-one participants (62% of eligible individuals) enrolled in the program. Twenty-nine women commenced the intervention [53.3 ± 10.8 years (Mean ± SD)], attending 77.6% [67.6, 87.5] (Mean [95% CI]) of sessions. Based on these rates of enrolment and attendance, and participant feedback, the program was deemed feasible and acceptable to participants. Significant improvements in shoulder ROM and reductions in sedentary behaviour were achieved. Participants also reported improvements in physical capacity and psychological, social, and cognitive wellbeing. CONCLUSIONS: The "Ballet after breast cancer" program, delivered face-to-face and/or online, was feasible and acceptable to breast cancer survivors. Improvements in shoulder ROM achieved doing ballet were pertinent given the adverse effects of upper-body morbidity on breast cancer survivor QOL. Improvements in physical activity behaviour and perceived benefits to wellbeing also support the use of ballet to mitigate QOL impairment after treatment. IMPLICATIONS FOR CANCER SURVIVORS: The physical demands and the fun, creative, and social characteristics of ballet promote improvement across multiple domains of health and wellbeing. Ballet shows promise as an activity to improve QOL and increase long-term engagement in health-promoting physical activity after breast cancer.

A Digital Educational Intervention With Wearable Activity Trackers to Support Health Behaviors Among Childhood Cancer Survivors: Pilot Feasibility and Acceptability Study.

BACKGROUND: Childhood cancer survivors are at increased risk of cardiometabolic complications that are exacerbated by poor health behaviors. Critically, many survivors do not meet physical activity guidelines. OBJECTIVE: The primary aim was to evaluate the feasibility and acceptability of iBounce, a digital health intervention for educating and engaging survivors in physical activity. Our secondary aims were to assess the change in survivors' physical activity levels and behaviors, aerobic fitness, and health-related quality of life (HRQoL) after participating in the iBounce program. METHODS: We recruited survivors aged 8 to 13 years who were ≥12 months post cancer treatment completion. The app-based program involved 10 educational modules, goal setting, and home-based physical activities monitored using an activity tracker. We assessed objective physical activity levels and behaviors using cluster analysis, aerobic fitness, and HRQoL at baseline and after the intervention (week 12). Parents were trained to reassess aerobic fitness at home at follow-up (week 24). RESULTS: In total, 30 participants opted in, of whom 27 (90%) completed baseline assessments, and 23 (77%) commenced iBounce. Our opt-in rate was 59% (30/51), and most (19/23, 83%) of the survivors completed the intervention. More than half (13/23, 57%) of the survivors completed all 10 modules (median 10, IQR 4-10). We achieved a high retention rate (19/27, 70%) and activity tracker compliance (15/19, 79%), and there were no intervention-related adverse events. Survivors reported high satisfaction with iBounce (median enjoyment score 75%; ease-of-use score 86%), but lower satisfaction with the activity tracker (median enjoyment score 60%). Parents reported the program activities to be acceptable (median score 70%), and their overall satisfaction was 60%, potentially because of technological difficulties that resulted in the program becoming disjointed. We did not observe any significant changes in physical activity levels or HRQoL at week 12. Our subgroup analysis for changes in physical activity behaviors in participants (n=11) revealed five cluster groups: most active, active, moderately active, occasionally active, and least active. Of these 11 survivors, 3 (27%) moved to a more active cluster group, highlighting their engagement in more frequent and sustained bouts of moderate-to-vigorous physical activity; 6 (56%) stayed in the same cluster; and 2 (18%) moved to a less active cluster. The survivors' mean aerobic fitness percentiles increased after completing iBounce (change +17, 95% CI 1.7-32.1; P=.03) but not at follow-up (P=.39). CONCLUSIONS: We demonstrated iBounce to be feasible for delivery and acceptable among survivors, despite some technical difficulties. The distance-delivered format provides an opportunity to engage survivors in physical activity at home and may address barriers to care, particularly for regional or remote families. We will use these pilot findings to evaluate an updated version of iBounce. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12621000259842; https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=ACTRN12621000259842.

Parent perceptions of their child's and their own physical activity after treatment for childhood cancer.

PURPOSE: Parents are important facilitators of physical activity for children, yet little is known about the perceptions of parents of childhood cancer survivors. We investigated parent perceptions of their own and their child's physical activity levels after cancer treatment and examined associations with clinical, demographic, and psychosocial factors. METHODS: We conducted a cross-sectional survey among 125 parents and 125 survivors. Parents reported on the perceived importance of their child being physically active and concerns regarding exercising after cancer treatment. RESULTS: Parents and survivors self-reported median (range) of 127.5 (0-1260) and 220 (0-1470) min/week of moderate-to-vigorous physical activity. Most parents (n = 109, 98%) believed that physical activity was highly important for their child. Some parents (n = 19, 17%) reported concerns, most commonly regarding exercise safety (n = 7, 22%). Parents were more likely to perceive that their child should increase physical activity if their child was an adolescent and had high body fat percentage. CONCLUSIONS: Physical activity levels varied widely among survivors, reflecting factors including parents' lifestyles, limited understanding of exercise benefits and perceptions of risk. Given survivors' insufficient physical activity levels and sedentary behaviour among families, embedding physical activity promotion into health systems and follow-up support could benefit the entire family unit.

The effect of exercise intensity on exercise-induced hypoalgesia in cancer survivors: A randomized crossover trial.

Pain is experienced by people with cancer during treatment and in survivorship. Exercise can have an acute hypoalgesic effect (exercise-induced hypoalgesia; EIH) in healthy individuals and some chronic pain states. However, EIH, and the moderating effect of exercise intensity, has not been investigated in cancer survivors. This study examined the effect of low- and high-intensity aerobic exercise on EIH in cancer survivors after a single exercise session as well as a brief period of exercise training (2-weeks, three exercise sessions per week). Participants (N = 19) were randomized to low- (30%-40% Heart Rate Reserve (HRR) or high- (60%-70% HRR) intensity stationary cycling for 15-20 min. Pressure pain thresholds (PPT) were assessed over the rectus femoris and biceps brachii before and after a single exercise session and again after a short training period at the assigned intensity. Then, following a 6-week washout period, the intervention was repeated at the other intensity. After the first exercise session, high-intensity exercise resulted in greater EIH over the rectus femoris than low intensity (mean difference ± SE: -0.51 kg/cm2  ± 0.15, Cohen's d = 0.78, p = 0.004). After a 2-week training period, we found no difference in EIH between intensities (0.01 kg/cm2  ± 0.25, d = 0.00 p = 0.99), with comparable moderate effect sizes for both low- and high-intensity exercise, indicative of EIH. No EIH was observed over the biceps brachii of the arm at either low or high intensity. Low-intensity exercise training may be a feasible option to increase pain thresholds in cancer survivors.

Accuracy of perceived physical activity and fitness levels among childhood cancer survivors.

BACKGROUND: Childhood cancer survivors do not engage in sufficient physical activity and have low fitness levels. Perceived physical activity and fitness levels may influence survivors' engagement in health behaviours. We aimed to investigate survivors' perceptions of physical activity and fitness levels and identify how accurate their perceptions were. We further explored survivors' attitudes toward physical activity, including perceived importance and desire to increase activity levels. PROCEDURE: We recruited 116 childhood cancer survivors (8-18 years) and assessed their perceived physical activity levels using a questionnaire and the Godin's Leisure Score Index. Accuracy of their perceptions was established by comparing their perceived physical activity levels with the recommended guidelines. Survivors reported their perceived fitness levels using the International Fitness Scale. We compared survivors' perceptions with their performance on the 6-minute walk test using weighted Cohen's kappa to determine interrater agreement between perceived and objectively measured fitness. RESULTS: Most survivors did not meet the physical activity guidelines (<420 min/week). One-third incorrectly perceived whether their self-reported physical activity levels were appropriate (84% underestimated, while 16% overestimated). Survivors had average fitness and were inaccurate at perceiving their fitness level. Survivors highly valued the importance of being able to do physical activity, and 89% reported a desire to increase their physical activity. CONCLUSIONS: Our results reveal that many survivors are not accurate when perceiving their physical activity and fitness levels. Emphasising the need for objective fitness assessments, and patient education in clinical practice may support survivors to accurately perceive their physical activity and fitness levels, thus improving health behaviours.

The Use of Activity Trackers in Interventions for Childhood Cancer Patients and Survivors: A Systematic Review.

Activity trackers have emerged as promising devices used to motivate and/or objectively monitor physical activity (PA) levels. It is unknown how activity trackers have been used in interventions for children and adolescents affected by cancer. This review aimed to investigate the effectiveness of wearable activity trackers to monitor and/or improve PA levels and health outcomes in pediatric oncology. Based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses, we conducted an electronic search of four databases (Cumulative Index to Nursing and Allied Health Literature [CINAHL], Medline, Embase, and SportDiscus) between January 2000 and March 2020. The review included PA interventions that used an activity tracker with children (≤18 years) diagnosed with cancer. We excluded studies including adult participants (>18 at time of study participation) and cross-sectional or case-report studies. Twelve studies examining 517 children and adolescent patients and survivors of pediatric cancer (age range: 4-18 years) were included. Intervention delivery ranged from 2 weeks to 12 months. Two of 12 studies reported increases in PA and 6 showed improvements in health outcomes, including aerobic fitness and negative mood. PA interventions using activity trackers within pediatric oncology are highly diverse in study design, study population, and intervention features. Preliminary data suggest that interventions using wearable activity trackers may have a positive impact on health outcomes in children and adolescents affected by cancer. Future research is needed to establish optimal intervention approaches to using activity trackers to increase PA in children affected by cancer.

Ionizing radiation-induced circulatory and metabolic diseases.

Risks to health are the prime consideration in all human situations of ionizing radiation exposure and therefore of relevance to radiation protection in all occupational, medical, and public exposure situations. Over the past few decades, advances in therapeutic strategies have led to significant improvements in cancer survival rates. However, a wide range of long-term complications have been reported in cancer survivors, in particular circulatory diseases and their major risk factors, metabolic diseases. However, at lower levels of exposure, the evidence is less clear. Under real-life exposure scenarios, including radiotherapy, radiation effects in the whole organism will be determined mainly by the response of normal tissues receiving relatively low doses, and will be mediated and moderated by systemic effects. Therefore, there is an urgent need for further research on the impact of low-dose radiation. In this article, we review radiation-associated risks of circulatory and metabolic diseases in clinical, occupational or environmental exposure situations, addressing epidemiological, biological, risk modelling, and systems biology aspects, highlight the gaps in knowledge and discuss future directions to address these gaps.

Barriers and enablers to physical activity and aerobic fitness deficits among childhood cancer survivors.

BACKGROUND: Physical activity and aerobic fitness are modifiable risk factors for cardiovascular disease (CVD) after childhood cancer. How survivors engage in physical activity remains unclear, potentially increasing CVD risk. We assessed survivors' physical activity levels, barriers and enablers, fitness, and identified predictors of fitness and physical activity stage of change. METHODS: Childhood cancer survivors (CCS; 8-18 years old) ≥1 year post-treatment were assessed for aerobic fitness (6-min walk test), used to extrapolate VO2max , and body composition (InBody 570). Survivors self-reported physical activity to determine stage of change (Patient-Centered Assessment and Counselling for Exercise). Physical activity and fitness were compared with guidelines and CVD-risk cut-points (VO2max  < 42 mL/kg/min: males; VO2max  < 35 mL/kg/min: females). Multiple regression and mediator-moderator analysis were used to identify fitness predictors and stage of change. RESULTS: One hundred two survivors (12.8 ± 3.3 years) participated (46% acute lymphoblastic leukaemia). Forty percent of males (VO2max  = 43.3 ± 6.3 mL/kg/min) and 28% of females (VO2max  = 36.5 ± 5.9 mL/kg/min) were in the CVD-risk category, while 25% met physical activity guidelines. Most prevalent physical activity barriers were fatigue (52%), preferring television instead of exercise (38%), and lacking time (34%). Predictive factors for reduced fitness included being older, female, higher waist-to-height ratio, higher screen time, and moderated by lower physical activity (r2  = 0.91, P < .001). Survivors with higher physical activity stage of change were male, lower body fat percentage, lower screen time, and lived with both parents (r = 0.42, P = .003). CONCLUSION: Aerobic fitness and physical activity of CCS is low compared with population norms, potentially increasing CVD risk. Addressing physical activity barriers and enablers, including reducing screen time, could promote regular physical activity, reducing CVD risk.

The 6-minute walk test is a good predictor of cardiorespiratory fitness in childhood cancer survivors when access to comprehensive testing is limited.

Cardiovascular disease is up to 10 times more likely among childhood cancer survivors compared to siblings. Low cardiorespiratory fitness is a modifiable risk-factor for cardiovascular diseases. Yet, cardiorespiratory fitness is not routinely screened in pediatric oncology, and healthy VO2max cut-points are unavailable. We aimed to predict cardiorespiratory fitness by developing a simple algorithm and establish cut-points identifying survivors' cardiovascular fitness health-risk zones. We recruited 262 childhood cancer survivors (8-18 years old, ≥1-year posttreatment). Participants completed gold-standard cardiorespiratory fitness assessment (Cardiopulmonary Exercise Test [CPET; VO2max ]) and 6-minute walk test (6MWT). Associations with VO2max were included in a linear regression algorithm to predict VO2max , which was then cross-validated. We used Bland-Altman's limits of agreement and Receiver Operating Characteristic curves using FITNESSGRAM's "Healthy Fitness Zones" to identify cut-points for adequate cardiorespiratory fitness. A total of 199 participants (aged 13.7 ± 2.7 years, 8.5 ± 3.5 years posttreatment) were included. We found a strong positive correlation between VO2max and 6MWT distance (r = 0.61, r2 = 0.37, p < 0.001). Our regression algorithm included 6MWT distance, waist-to-height ratio, age and sex to predict VO2max (r = 0.79, r2 = 0.62, p < 0.001). Forty percentages of predicted VO2max values were within ±3 ml/kg/min of measured VO2max . The cut-point for FITNESSGRAM's "health-risk" fitness zone was 39.8 ml/kg/min (males: AUC = 0.88), and 33.5 ml/kg/min (females: AUC = 0.82). We present an algorithm to reasonably predict cardiorespiratory fitness for childhood cancer survivors, using inexpensive measures. This algorithm has useful clinical application, particularly when CPET is unavailable. Our algorithm has the potential to assist clinicians to identify survivors below the cut-points with increased cardiovascular disease-risk, to monitor and refer for tailored interventions with exercise specialists.

Irradiation impairs mitochondrial function and skeletal muscle oxidative capacity: significance for metabolic complications in cancer survivors.

BACKGROUND: Metabolic complications are highly prevalent in cancer survivors treated with irradiation but the underlying mechanisms remain unknown. METHODS: Chow or high fat-fed C57Bl/6J mice were irradiated (6Gy) before investigating the impact on whole-body or skeletal muscle metabolism and profiling their lipidomic signature. Using a transgenic mouse model (Tg:Pax7-nGFP), we isolated muscle progenitor cells (satellite cells) and characterised their metabolic functions. We recruited childhood cancer survivors, grouped them based on the use of total body irradiation during their treatment and established their lipidomic profile. RESULTS: In mice, irradiation delayed body weight gain and impaired fat pads and muscle weights. These changes were associated with impaired whole-body fat oxidation in chow-fed mice and altered ex vivo skeletal muscle fatty acid oxidation, potentially due to a reduction in oxidative fibres and reduced mitochondrial enzyme activity. Irradiation led to fasting hyperglycaemia and impaired glucose uptake in isolated skeletal muscles. Cultured satellite cells from irradiated mice showed decreased fatty acid oxidation and reduced glucose uptake, recapitulating the host metabolic phenotype. Irradiation resulted in a remodelling of lipid species in skeletal muscles, with the extensor digitorum longus muscle being particularly affected. A large number of lipid species were reduced, with several of these species showing a positive correlation with mitochondrial enzymes activity. In cancer survivors exposed to irradiation, we found a similar decrease in systemic levels of most lipid species, and lipid species that increased were positively correlated with insulin resistance (HOMA-IR). CONCLUSION: Irradiation leads to long-term alterations in body composition, and lipid and carbohydrate metabolism in skeletal muscle, and affects muscle progenitor cells. Such changes result in persistent impairment of metabolic functions, providing a new mechanism for the increased prevalence of metabolic diseases reported in irradiated individuals. In this context, changes in the lipidomic signature in response to irradiation could be of diagnostic value.

Epigenetic Reprogramming of Immune Cells in Women With PCOS Impact Genes Controlling Reproductive Function.

CONTEXT: Polycystic ovary syndrome (PCOS) is a chronic disease affecting reproductive function and whole-body metabolism. Although the etiology is unclear, emerging evidence indicates that the epigenetics may be a contributing factor. OBJECTIVE: To determine the role of global and genome-wide epigenetic modifications in specific immune cells in PCOS compared with controls and whether these could be related to clinical features of PCOS. DESIGN: Cross-sectional study. PARTICIPANTS: Women with (n = 17) or without PCOS (n = 17). SETTING: Recruited from the general community. MAIN OUTCOME MEASURES: Isolated peripheral blood mononuclear cells were analyzed using multicolor flow cytometry methods to determine global DNA methylation levels in a cell-specific fashion. Transcriptomic and genome-wide DNA methylation analyses were performed on T helper cells using RNA sequencing and reduced representation bisulfite sequencing. RESULTS: Women with PCOS had lower global DNA methylation in monocytes (P = 0.006) and in T helper (P = 0.004), T cytotoxic (P = 0.004), and B cells (P = 0.03). Specific genome-wide DNA methylation analysis of T helper cells from women with PCOS identified 5581 differentially methylated CpG sites. Functional gene ontology enrichment analysis showed that genes located at the proximity of differentially methylated CpG sites belong to pathways related to reproductive function and immune cell function. However, these genes were not altered at the transcriptomic level. CONCLUSIONS: It was shown that PCOS is associated with global and gene-specific DNA methylation remodeling in a cell type-specific manner. Further investigation is warranted to determine whether epigenetic reprogramming of immune cells is important in determining the different phenotypes of PCOS.

Inflammatory and immunometabolic consequences of gut dysfunction in HIV: Parallels with IBD and implications for reservoir persistence and non-AIDS comorbidities.

The gastrointestinal mucosa is critical for maintaining the integrity and functions of the gut. Disruption of this barrier is a hallmark and a risk factor for many intestinal and chronic inflammatory diseases. Inflammatory bowel disease (IBD) and HIV infection are characterized by microbial translocation and systemic inflammation. Despite the clinical overlaps between HIV and IBD, significant differences exist such as the severity of gut damage and mechanisms of immune cell homeostasis. Studies have supported the role of metabolic activation of immune cells in promoting chronic inflammation in HIV and IBD. This inflammatory response persists in HIV+ persons even after long-term virologic suppression by antiretroviral therapy (ART). Here, we review gut dysfunction and microbiota changes during HIV infection and IBD, and discuss how this may induce metabolic reprogramming of monocytes, macrophages and T cells to impact disease outcomes. Drawing from parallels with IBD, we highlight how factors such as lipopolysaccharides, residual viral replication, and extracellular vesicles activate biochemical pathways that regulate immunometabolic processes essential for HIV persistence and non-AIDS metabolic comorbidities. This review highlights new mechanisms and support for the use of immunometabolic-based therapeutics towards HIV remission/cure, and treatment of metabolic diseases.

How physically active do Australian and New Zealander childhood cancer survivors perceive themselves? A report from the ANZCHOG survivorship study.

PURPOSE: Childhood cancer survivors are at risk of treatment late-effects. Physical activity represents a necessary complementary therapy and modifiable risk-factor across all ages for many cardio-metabolic late-effects. This study assessed perceived physical activity in Australian and New Zealander childhood cancer survivors. METHODS: We recruited parents of survivors aged <16 years, and adult survivors of childhood cancer aged ≥16 years, ≥5 years since diagnosis, with age-matched controls for comparison. We compared perceived moderate-vigorous physical activity between survivors and controls, using regression to identify associations with physical activity. RESULTS: We recruited 914 participants (570 childhood cancer survivors and 344 age-matched controls). Parents of survivors perceived more moderate-vigorous physical activity than child controls (248 ± 218, 95% Confidence Interval (CI) = 218-280 vs 185 ± 214 min/week, 95% CI = 144-225, p = 0.036), with no perceived difference between adult survivors and controls (125 ± 152, 95% CI = 108-140 vs 160 ± 201 min/week, 95% CI = 132-187, p = 0.477). Twenty-seven percent of child survivors (vs. 14.5% controls) and 30% of adult survivors (vs. 39.4% controls) met recommendations. Adult survivors who received radiotherapy (OR = 0.585, 95% CI = 0.343-0.995, p = 0.048) or not completed university (OR = 1.808, 95% CI = 1.071-3.053, p = 0.027) were less likely to meet recommendations. CONCLUSIONS: Over two-thirds of Australian and New Zealander childhood cancer survivors across all ages are perceived to not meet physical activity recommendations. Adult survivors who had radiotherapy or did not complete university appeared at-risk for low physical activity. PRACTICAL IMPLICATIONS: Physical activity is important for everyone, but critical among childhood cancer survivors due to increased late cardio-metabolic risks. Monitoring survivors' perceived but also objectively measured physical activity as complementary to routine care is warranted, to provide education and motivate survivors to take control of their health.

The effectiveness of high intensity intermittent training on metabolic, reproductive and mental health in women with polycystic ovary syndrome: study protocol for the iHIT- randomised controlled trial.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a reproductive-metabolic condition. Insulin resistance is a hallmark of PCOS and is related to increased hyperandrogenism that drives inherent metabolic, reproductive and psychological features of the syndrome. Insulin resistance in women with PCOS is managed by weight loss, lifestyle interventions (i.e. exercise, diet) and insulin-sensitising medications. This manuscript describes the protocol of our study evaluating the effectiveness of high intensity intermittent training (HIIT) or moderate intensity exercise on cardiometabolic, reproductive and mental health in overweight women with PCOS. METHODS/DESIGN: We will employ a three arm, parallel-group, randomised controlled trial recruiting 60 women diagnosed with PCOS, aged between 18 and 45 years and with a body mass index (BMI) greater than 25 kg/m2. Following screening and baseline testing, women will be randomised by simple randomisation procedure using computer generated sequence allocation to undergo one of two 12-week supervised interventions: either HIIT or moderate intensity exercise (standard supervised exercise), or to standard care [Con] (unsupervised lifestyle advice) at a 1:1:1 allocation ratio. The primary outcome for this trial is to measure the improvements in metabolic health; specifically changes in insulin sensitivity in response to different exercise intensities. Baseline and post-intervention testing include anthropometric measurements, cardiorespiratory fitness testing, reproductive hormone profiles (anti-müllerian hormone and steroid profiles), metabolic health, health-related quality of life and mental health questionnaires and objective and subjective lifestyle monitoring. Reporting of the study will follow the CONSORT statement. DISCUSSION: This trial aims to demonstrate the comparative efficacy and maintenance of different exercise intensities to advance the understanding of PCOS management and provide insight into the optimal exercise intensity for improved cardiometabolic outcomes. Secondary outcomes will include the impact of different exercise protocols on reproductive hormone profiles, mental health and health-related quality of life. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12615000242527 . Registered on 17 March 2015.

Preadipocytes from obese humans with type 2 diabetes are epigenetically reprogrammed at genes controlling adipose tissue function.

BACKGROUND: Deterioration of the adipogenic potential of preadipocytes may contribute to adipose tissue dysfunction in obesity and type 2 diabetes (T2D). Here, we hypothesized that extracellular factors in obesity epigenetically reprogram adipogenesis potential and metabolic function of preadipocytes. METHODS: The transcriptomic profile of visceral adipose tissue preadipocytes collected from Lean, Obese and Obese with T2D was assessed throughout in vitro differentiation using RNA sequencing. Reduced Representation Bisulfite Sequencing was used to establish the genome-wide DNA methylation profile of human preadipocytes and 3T3-L1 preadipocytes treated by the inflammatory cytokine Tumour Necrosis Factor-α (TNF-α) or palmitate. RESULTS: While preadipocytes from all obese subjects (Obese+Obese T2D), compared to those of Lean, were transcriptionally different in response to differentiation in culture, preadipocytes from Obese T2D showed impaired insulin signalling and a further transcriptomic shift towards altered adipocyte function. Cultures with a lower expression magnitude of adipogenic genes throughout differentiation (PLIN1, CIDEC, FABP4, ADIPOQ, LPL, PDK4, APOE, LIPE, FABP3, LEP, RBP4 and CD36) were associated with DNA methylation remodelling at genes controlling insulin sensitivity and adipocytokine signalling pathways. Prior incubation of 3T3-L1 preadipocytes with TNF-α or palmitate markedly altered insulin responsiveness and metabolic function in the differentiated adipocytes, and remodelled DNA methylation and gene expression at specific genes, notably related to PPAR signalling. CONCLUSIONS: Our findings that preadipocytes retain the memory of the donor in culture and can be reprogrammed by extracellular factors support a mechanism by which adipocyte precursors are epigenetically reprogrammed in vivo. Epigenetic reprogramming of preadipocytes represents a mechanism by which metabolic function of visceral adipose tissue may be affected in the long term by past exposure to obesity- or T2D-specific factors.

Genes controlling the activation of natural killer lymphocytes are epigenetically remodeled in intestinal cells from germ-free mice.

Remodeling of the gut microbiota is implicated in various metabolic and inflammatory diseases of the gastrointestinal tract. We hypothesized that the gut microbiota affects the DNA methylation profile of intestinal epithelial cells (IECs) which could, in turn, alter intestinal function. In this study, we used mass spectrometry and methylated DNA capture to respectively investigate global and genome-wide DNA methylation of intestinal epithelial cells from germ-free (GF) and conventionally raised mice. In colonic IECs from GF mice, DNA was markedly hypermethylated. This was associated with a dramatic loss of ten-eleven-translocation activity, a lower DNA methyltransferase activity and lower circulating levels of the 1-carbon metabolite, folate. At the gene level, we found an enrichment for differentially methylated regions proximal to genes regulating the cytotoxicity of NK cells (false-discovery rate < 8.9E-6), notably genes regulating the cross-talk between NK cells and target cells, such as members of the NK group 2 member D ligand superfamily Raet. This distinct epigenetic signature was associated with a marked decrease in Raet1 expression and a loss of CD56+/CD45+ cells in the intestine of GF mice. Thus, our results indicate that altered activity of methylation-modifying enzymes in GF mice influences the IEC epigenome and modulates the crosstalk between IECs and NK cells. Epigenetic reprogramming of IECs may modulate intestinal function in diseases associated with altered gut microbiota.-Poupeau, A., Garde, C., Sulek, K., Citirikkaya, K., Treebak, J. T., Arumugam, M., Simar, D., Olofsson, L. E., Bäckhed, F., Barrès, R. Genes controlling the activation of natural killer lymphocytes are epigenetically remodeled in intestinal cells from germ-free mice.