Publications by authors named "Rachel Davey"

153 Publications

Vitamin D receptor expression in mature osteoclasts reduces bone loss due to low dietary calcium intake in male mice.

J Steroid Biochem Mol Biol 2021 Feb 26;210:105857. Epub 2021 Feb 26.

Clinical and Health Sciences, Health and Biomedical Innovation, University of South Australia, SA, Australia. Electronic address:

Mature osteoclasts express the vitamin D receptor (VDR) and are able to respond to active vitamin D (1α, 25-dihydroxyvitamin D; 1,25(OH)D) by regulating cell maturation and activity. However, the in vivo consequences of vitamin D signalling directly within functionally mature osteoclasts is only partially understood. To investigate the in vivo role of VDR in mature osteoclasts, conditional deletion of the VDR under control of the cathepsin K promoter (Ctsk/Vdr), was assessed in 6 and 12-week-old mice, either under normal dietary conditions (NormCaP) or when fed a low calcium (0.03 %), low phosphorous (0.08 %) diet (LowCaP). Splenocytes from Ctsk/Vdr mice were co-cultured with MLO-Y4 osteocyte-like cells to assess the effect on osteoclastogenesis. Six-week-old Ctsk/Vdr mice demonstrated a 10 % decrease in vertebral bone volume (p < 0.05), which was associated with increased osteoclast size (p < 0.05) when compared to Vdr control mice. Control mice fed a LowCaP diet exhibited extensive trabecular bone loss associated with increased osteoclast surface, number and size (p < 0.0001). Interestingly, Ctsk/Vdr mice fed a LowCaP diet showed exacerbated loss of bone volume fraction (BV/TV%) and trabecular number (Tb.N), by a further 22 % and 21 %, respectively (p < 0.05), suggesting increased osteoclastic bone resorption activity with the loss of VDR in mature osteoclasts under these conditions. Co-culture of Ctsk/Vdr splenocytes with MLO-Y4 cells increased resulting osteoclast numbers 2.5-fold, which were greater in nuclei density and exhibited increased resorption of dentine compared to osteoclasts derived from Vdr splenocyte cultures. These data suggest that in addition to RANKL-mediated osteoclastogenesis, intact VDR signalling is required for the direct regulation of the differentiation and activity of osteoclasts in both in vivo and ex vivo settings.
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http://dx.doi.org/10.1016/j.jsbmb.2021.105857DOI Listing
February 2021

The calcitonin receptor regulates osteocyte lacunae acidity during lactation in mice.

J Endocrinol 2021 Apr;249(1):31-41

Department of Medicine, Austin Health, University of Melbourne, Heidelberg, Victoria, Australia.

The physiological role of calcitonin, and its receptor, the CTR (or Calcr), has long been debated. We previously provided the first evidence for a physiological role of the CTR to limit maternal bone loss during lactation in mice by a direct action on osteocytes to inhibit osteocytic osteolysis. We now extend these findings to show that CTR gene expression is upregulated two- to three-fold in whole bone of control mice at the end of pregnancy (E18) and lactation (P21) compared to virgin controls. This was associated with an increase in osteoclast activity evidenced by increases in osteoclast surface/bone surface and Dcstamp gene expression. To investigate the mechanism by which the CTR inhibits osteocytic osteolysis, in vivo acidification of the osteocyte lacunae during lactation (P14 days) was assessed using a pH indicator dye. A lower pH was observed in the osteocyte lacunae of lactating Global-CTRKOs compared to controls and was associated with an increase in the gene expression of ATPase H+ transporting V0 subunit D2 (Atp6v0d2) in whole bone of Global-CTRKOs at the end of lacation (P21). To determine whether the CTR is required for the replacement of mineral within the lacunae post-lactation, lacunar area was determined 3 weeks post-weaning. Comparison of the largest 20% of lacunae by area did not differ between Global-CTRKOs and controls post-lactation. These results provide evidence for CTR activation to inhibit osteocytic osteolysis during lactation being mediated by regulating the acidity of the lacunae microenvironment, whilst the CTR is dispensable for replacement of bone mineral within lacunae by osteocytes post-lactation.
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http://dx.doi.org/10.1530/JOE-20-0599DOI Listing
April 2021

Children's moderate-to-vigorous physical activity on weekdays versus weekend days: a multi-country analysis.

Int J Behav Nutr Phys Act 2021 02 10;18(1):28. Epub 2021 Feb 10.

MRC Epidemiology Unit & Centre for Diet and Activity Research, University of Cambridge, Cambridge, UK.

Purpose: The Structured Days Hypothesis (SDH) posits that children's behaviors associated with obesity - such as physical activity - are more favorable on days that contain more 'structure' (i.e., a pre-planned, segmented, and adult-supervised environment) such as school weekdays, compared to days with less structure, such as weekend days. The purpose of this study was to compare children's moderate-to-vigorous physical activity (MVPA) levels on weekdays versus weekend days using a large, multi-country, accelerometer-measured physical activity dataset.

Methods: Data were received from the International Children's Accelerometer Database (ICAD) July 2019. The ICAD inclusion criteria for a valid day of wear, only non-intervention data (e.g., baseline intervention data), children with at least 1 weekday and 1 weekend day, and ICAD studies with data collected exclusively during school months, were included for analyses. Mixed effects models accounting for the nested nature of the data (i.e., days within children) assessed MVPA minutes per day (min/day MVPA) differences between weekdays and weekend days by region/country, adjusted for age, sex, and total wear time. Separate meta-analytical models explored differences by age and country/region for sex and child weight-status.

Results/findings: Valid data from 15 studies representing 5794 children (61% female, 10.7 ± 2.1 yrs., 24% with overweight/obesity) and 35,263 days of valid accelerometer data from 5 distinct countries/regions were used. Boys and girls accumulated 12.6 min/day (95% CI: 9.0, 16.2) and 9.4 min/day (95% CI: 7.2, 11.6) more MVPA on weekdays versus weekend days, respectively. Children from mainland Europe had the largest differences (17.1 min/day more MVPA on weekdays versus weekend days, 95% CI: 15.3, 19.0) compared to the other countries/regions. Children who were classified as overweight/obese or normal weight/underweight accumulated 9.5 min/day (95% CI: 6.9, 12.2) and 10.9 min/day (95% CI: 8.3, 13.5) of additional MVPA on weekdays versus weekend days, respectively.

Conclusions: Children from multiple countries/regions accumulated significantly more MVPA on weekdays versus weekend days during school months. This finding aligns with the SDH and warrants future intervention studies to prioritize less-structured days, such as weekend days, and to consider providing opportunities for all children to access additional opportunities to be active.
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http://dx.doi.org/10.1186/s12966-021-01095-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877033PMC
February 2021

A smartphone app for sedentary behaviour change in cardiac rehabilitation and the effect on hospital admissions: the ToDo-CR randomised controlled trial study protocol.

BMJ Open 2020 12 15;10(12):e040479. Epub 2020 Dec 15.

Health Research Institute, Faculty of Health, University of Canberra, Canberra, Australian Capital Territory, Australia.

Introduction: Cardiac rehabilitation (CR) is recommended for secondary prevention of cardiovascular disease and reducing the risk of repeat cardiac events. Physical activity is a core component of CR; however, studies show that participants remain largely sedentary. Sedentary behaviour is an independent risk factor for all-cause mortality. Strategies to encourage sedentary behaviour change are needed. This study will explore the effectiveness and costs of a smartphone application (Vire) and an individualised online behaviour change program (ToDo-CR) in reducing sedentary behaviour, all-cause hospital admissions and emergency department visits over 12 months after commencing CR.

Methods And Analysis: A multicentre, assessor-blind parallel randomised controlled trial will be conducted with 144 participants (18+ years). Participants will be recruited from three phase-II CR centres. They will be assessed on admission to CR and randomly assigned (1:1) to one of two groups: CR plus the ToDo-CR 6-month programme or usual care CR. Both groups will be re-assessed at 6 months and 12 months for the primary outcome of all-cause hospital admissions and presentations to the emergency department. Accelerometer-measured changes in sedentary behaviour and physical activity will also be assessed. Logistic regression models will be used for the primary outcome of hospital admissions and emergency department visits. Methods for repeated measures analysis will be used for all other outcomes. A cost-effectiveness analysis will be conducted to evaluate the effects of the intervention on the rates of hospital admissions and emergency department visits within the 12 months post commencing CR.

Ethics And Dissemination: This study received ethical approval from the Australian Capital Territory Health (2019.ETH.00162), Calvary Public Hospital Bruce (20-2019) and the University of Canberra (HREC-2325) Human Research Ethics Committees (HREC). Results will be disseminated through peer-reviewed academic journals. Results will be made available to participants on request.

Trial Registration Number: ACTRN12619001223123.
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http://dx.doi.org/10.1136/bmjopen-2020-040479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745513PMC
December 2020

Can physical activity measurement alone improve objectively-measured physical activity in primary care?: A systematic review and meta-analysis.

Prev Med Rep 2020 Dec 21;20:101230. Epub 2020 Oct 21.

School of Public Health & Social Work and Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Australia.

There is evidence that simply measuring physical activity alone can increase self-reported physical activity behaviour. The aim of this review was to describe changes in objectively-measured physical activity within control groups in primary care physical activity intervention studies. Five electronic databases (PubMed, MEDLINE, SPORTDiscus, PsychINFO and CINAHL) were searched from inception to February 2019. Physical activity controlled intervention studies objectively measuring physical activity in primary care with adults were included and -analyses were completed. Thirty studies were eligible and 22 studies were included in the -analysis. No statistically significant change in steps.day, counts.day and counts.minute were found in the -analyses within control groups. Moderate-to-vigorous physical activity minutes.day significantly decreased (-3.97; 95% CI -6.31 to -1.64; P < 0.001). Sub-analyses revealed there was a trend for steps.day to increase in participants < 50 years old (504; 95% CI -20 to 1029; P = 0.06). Noteworthy increases (≥10%) in objectively-measured physical activity within control groups were found in 17% of studies. Noteworthy increases were reported in studies with younger participants, one-third of the pedometer studies, one-third of studies with participants at risk of chronic disease and in studies with a shorter duration between measurements. No control group improvements were found in participants with chronic disease. Overall, no significant improvements in objectively-measured physical activity were found within control groups in primary care. Further investigation of noteworthy increases in control group physical activity levels is indicated, particularly in certain sub-groups of participants as this may effect physical activity research and interventions in these populations.
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http://dx.doi.org/10.1016/j.pmedr.2020.101230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607506PMC
December 2020

Paracrine signalling by cardiac calcitonin controls atrial fibrogenesis and arrhythmia.

Nature 2020 11 4;587(7834):460-465. Epub 2020 Nov 4.

Division of Cardiovascular Medicine, Radcliffe Department of Medicine, British Heart Foundation Centre of Research Excellence, University of Oxford, John Radcliffe Hospital, Oxford, UK.

Atrial fibrillation, the most common cardiac arrhythmia, is an important contributor to mortality and morbidity, and particularly to the risk of stroke in humans. Atrial-tissue fibrosis is a central pathophysiological feature of atrial fibrillation that also hampers its treatment; the underlying molecular mechanisms are poorly understood and warrant investigation given the inadequacy of present therapies. Here we show that calcitonin, a hormone product of the thyroid gland involved in bone metabolism, is also produced by atrial cardiomyocytes in substantial quantities and acts as a paracrine signal that affects neighbouring collagen-producing fibroblasts to control their proliferation and secretion of extracellular matrix proteins. Global disruption of calcitonin receptor signalling in mice causes atrial fibrosis and increases susceptibility to atrial fibrillation. In mice in which liver kinase B1 is knocked down specifically in the atria, atrial-specific knockdown of calcitonin promotes atrial fibrosis and increases and prolongs spontaneous episodes of atrial fibrillation, whereas atrial-specific overexpression of calcitonin prevents both atrial fibrosis and fibrillation. Human patients with persistent atrial fibrillation show sixfold lower levels of myocardial calcitonin compared to control individuals with normal heart rhythm, with loss of calcitonin receptors in the fibroblast membrane. Although transcriptome analysis of human atrial fibroblasts reveals little change after exposure to calcitonin, proteomic analysis shows extensive alterations in extracellular matrix proteins and pathways related to fibrogenesis, infection and immune responses, and transcriptional regulation. Strategies to restore disrupted myocardial calcitonin signalling thus may offer therapeutic avenues for patients with atrial fibrillation.
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http://dx.doi.org/10.1038/s41586-020-2890-8DOI Listing
November 2020

A Behavioral Change Smartphone App and Program (ToDo-CR) to Decrease Sedentary Behavior in Cardiac Rehabilitation Participants: Prospective Feasibility Cohort Study.

JMIR Form Res 2020 Nov 3;4(11):e17359. Epub 2020 Nov 3.

Health Research Institute, University of Canberra, Bruce, Australia.

Background: Cardiac rehabilitation participants are encouraged to meet physical activity guidelines to reduce the risk of repeat cardiac events. However, previous studies have found that physical activity levels are low and sedentary behavior is high, both during and after cardiac rehabilitation. There is potential for smartphone apps to be effective in reducing sedentary behavior, although among the few studies that have investigated smartphone apps in cardiac rehabilitation, none targeted sedentary behavior.

Objective: This study aims to evaluate the feasibility of a behavioral smartphone app (Vire) and a web-based behavior change program (ToDo-CR) to decrease sedentary behavior in cardiac rehabilitation participants.

Methods: Using a single-center, pre-post design, participants were recruited by nursing staff on admission to cardiac rehabilitation. All eligible participants installed the Vire app, were given a Fitbit Flex, and received the 6-week ToDo-CR program while attending cardiac rehabilitation. The ToDo-CR program uses personalized analytics to interpret important behavioral aspects (physical activity, variety, and social opportunity) and real-time information for generating and suggesting context-specific actionable microbehavioral alternatives (Do's). Do's were delivered via the app, with participants receiving 14 to 19 Do's during the 6-week intervention period. Outcome measures were collected at 0, 6, and 16 weeks. The assessors were not blinded. Feasibility outcomes included recruitment and follow-up rates, resource requirements, app usability (Unified Theory of Acceptance and Use of Technology 2 [UTAUT2] questionnaire), and objectively measured daily minutes of sedentary behavior (ActiGraph) for sample size estimation. Secondary outcomes included functional aerobic capacity (6-min walk test), quality of life (MacNew Heart Disease Health-Related Quality of Life Questionnaire), anxiety and depression (Hospital Anxiety and Depression Scale questionnaire), BMI, waist circumference, waist-to-hip ratio, and blood pressure.

Results: Between January and May 2019, 20 participants were recruited consecutively. One-third of people who commenced cardiac rehabilitation were eligible to participate. Other than declining to take part in the study (15/40, 38%), not having a smartphone was a major reason for exclusion (11/40, 28%). Those excluded without a smartphone were significantly older than participants with a smartphone (mean difference 20 [SD 5] years; P<.001). Participants were, on average, aged 54 (SD 13) years, mostly male (17/20, 85%), and working (12/20, 67%). At 6 weeks, 95% (19/20) of participants were assessed, and 60% (12/20) of participants were assessed at 16 weeks. Participants were relatively satisfied with the usability of the app (UTAUT2 questionnaire). Overall, participants spent 11 to 12 hours per day sitting. There was a medium effect size (Cohen d=0.54) for the reduction in sedentary behavior (minutes per day) over 16 weeks.

Conclusions: The use of a behavioral smartphone app to decrease sitting time appears to be feasible in cardiac rehabilitation. A larger randomized controlled trial is warranted to determine the effectiveness of the app.
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http://dx.doi.org/10.2196/17359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7671837PMC
November 2020

Implementation pilot of a novel electronic bedside nursing chart: a mixed-methods case study.

Aust Health Rev 2020 Sep;44(5):672-676

Centre for Quality and Patient Safety Research - Monash Health Partnership, School of Nursing and Midwifery, Deakin University, 221 Burwood Highway, Burwood, Vic. 3125, Australia; and Corresponding author. Email:

The aim of this study was to investigate the implementation of a novel electronic bedside nursing chart in an acute hospital setting. The case study used multiple data sources captured within a real-life clinical ward context. Quantitative findings included significant reductions in nurse-reported missed care (P<0.05) and increased mean time spent at the bedside (from 21 to 28min h-1; P<0.0001); reductions in patient-reported missed care and nurses' walking distances were not significant. Qualitative themes included: (1) inconsistent expectations (perceptions about potential vs actual functionality and benefits of the technology); (2) decisional conflict between managers and end-user nurses (discordance between governance decisions and clinical operations; 30% of beds were closed and six of the eight trained nurse 'super-users' were moved from the pilot ward); and (3) workflow effects (ergonomic set-up of the digital interface). This study highlights the complex challenges of implementing and examining the effects of technology to support nursing care. Shared understanding of the technology goals and project scope in relation to nursing care and flexible and adaptive project and contingency planning are fundamental considerations. Complexity, unpredictability and uncertainty of 'usual business' are common confounders in acute hospital settings.
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http://dx.doi.org/10.1071/AH18231DOI Listing
September 2020

Do physical activity and sedentary time mediate the association of the perceived environment with BMI? The IPEN adult study.

Health Place 2020 07 22;64:102366. Epub 2020 Jun 22.

Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Australia; Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA.

The study's main aim was to examine whether adults' accelerometer-based physical activity and sedentary time mediated the associations of neighbourhood physical environmental perceptions with body mass index (BMI) and weight status across 10 high- and middle-income countries. Data from the IPEN Adult study, an observational multi-country study (n = 5712) were used. Results showed that sedentary time was a non-significant or inconsistent mediator in all models. MVPA mediated the associations of street connectivity, land use mix-diversity, infrastructure/safety for walking and aesthetics with BMI in single models. In the multiple model, MVPA only fully mediated the relation between land use mix-diversity and BMI. This finding was replicated in the models with weight status as outcome. MVPA partially mediated associations of composite environmental variables with weight status. So, although MVPA mediated some associations, future comprehensive studies are needed to determine other mechanisms that could explain the relation between the physical environment and weight outcomes. Food intake, food accessibility and the home environment may be important variables to consider. Based on the consistency of results across study sites, global advocacy for policies supporting more walkable neighbourhoods should seek to optimize land-use-mix when designing and re-designing cities or towns.
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http://dx.doi.org/10.1016/j.healthplace.2020.102366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447836PMC
July 2020

"Everything is provided free, but they are still hesitant to access healthcare services": why does the indigenous community in Attapadi, Kerala continue to experience poor access to healthcare?

Int J Equity Health 2020 06 26;19(1):105. Epub 2020 Jun 26.

Health Research Institute, University of Canberra, ACT, Canberra, 2617, Australia.

Background: Inequity in access to healthcare services is a constant concern. While advances in healthcare have progressed in the last several decades, thereby significantly improving the prevention and treatment of disease, these benefits have not been shared equally. Excluded communities such as Indigenous communities typically face a lack of access to healthcare services that others do not. This study seeks to understand why the indigenous communities in Attapadi continue to experience poor access to healthcare in spite of both financial protection and adequate coverage of health services.

Methods: Ethnographic fieldwork was carried out among the various stakeholders living in Attapadi. A total of 47 in-depth interviews and 6 focus group discussions were conducted amongst the indigenous community, the healthcare providers and key informants. The data was coded utilising a reflexive and inductive approach leading to the development of the key categories and themes.

Results: The health system provided a comprehensive financial protection package in addition to a host of healthcare facilities for the indigenous communities to avail services. In spite of this, they resisted attempts by the health system to improve their access. The failure to provide culturally respectful care, the discrimination of the community at healthcare facilities, the centralisation of the delivery of services as well as the lack of power on the part of the indigenous community to negotiate with the health system for services that were less disruptive for their lives were identified as the barriers to improving healthcare access. The existing power differentials between the community and the health system stakeholders also ensured that meaningful involvement of the community in the local health system did not occur.

Conclusion: Improving access to health care for indigenous communities would require UHC interventions to be culturally safe, locally relevant and promote active involvement of the community at all stages of the intervention. Continuing structural power imbalances that affect access to resources and prevent meaningful involvement of indigenous communities also need to be addressed.
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http://dx.doi.org/10.1186/s12939-020-01216-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7320563PMC
June 2020

Comparison of device-based physical activity and sedentary behaviour following percutaneous coronary intervention in a cohort from Sweden and Australia: a harmonised, exploratory study.

BMC Sports Sci Med Rehabil 2020 9;12:17. Epub 2020 May 9.

3Department of Health, Medicine and Caring Sciences, Unit of Physiotherapy, Linköping University, Linköping, Sweden.

Background: Few studies have measured device-based physical activity and sedentary behaviour following a percutaneous coronary intervention (PCI), with no studies comparing these behaviours between countries using the same methods. The aim of the study was to compare device-based physical activity and sedentary behaviour, using a harmonised approach, following a PCI on-entry into centre-based cardiac rehabilitation in two countries.

Methods: A cross-sectional study was conducted at two outpatient cardiac rehabilitation centres in Australia and Sweden. Participants were adults following a PCI and commencing cardiac rehabilitation (Australia  = 50, Sweden  = 133). Prior to discharge from hospital, Australian participants received brief physical activity advice (< 5 mins), while Swedish participants received physical activity counselling for 30 min. A triaxial accelerometer (Actigraph GT3X/ActiSleep) was used to objectively assess physical activity (light (LPA), moderate-to-vigorous (MVPA)) and sedentary behaviour. Outcomes included daily minutes of physical activity and sedentary behaviour, and the proportion and distribution of time spent in each behaviour.

Results: There was no difference in age, gender or relationship status between countries. Swedish (S) participants commenced cardiac rehabilitation later than Australian (A) participants (days post-PCI A 16 vs S 22,  < 0.001). Proportionally, Swedish participants were significantly more physically active and less sedentary than Australian participants (LPA A 27% vs S 30%,  < 0.05; MVPA A 5% vs S 7%,  < 0.01; sedentary behaviour A 68% vs S 63%,  < 0.001). When adjusting for wear-time, Australian participants were doing less MVPA minutes (A 42 vs S 64,  < 0.001) and more sedentary behaviour minutes (A 573 vs S 571,  < 0.001) per day. Both Swedish and Australian participants spent a large part of the day sedentary, accumulating 9.5 h per day in sedentary behaviour.

Conclusion: Swedish PCI participants when commencing cardiac rehabilitation are more physically active than Australian participants. Potential explanatory factors are differences in post-PCI in-hospital physical activity education between countries and pre-existing physical activity levels. Despite this, sedentary behaviour is high in both countries. Internationally, interventions to address sedentary behaviour are indicated post-PCI, in both the acute setting and cardiac rehabilitation, in addition to traditional physical activity and cardiac rehabilitation recommendations.

Trial Registrations: Australia: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12615000995572. Registered 22 September 2015, Sweden: World Health Organization Trial Registration Data Set: NCT02895451.
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http://dx.doi.org/10.1186/s13102-020-00164-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210676PMC
May 2020

Androgens stimulate erythropoiesis through the DNA-binding activity of the androgen receptor in non-hematopoietic cells.

Eur J Haematol 2020 Sep 15;105(3):247-254. Epub 2020 May 15.

Central Clinical School, Australian Centre for Blood Diseases, Monash University, Melbourne, Vic., Australia.

Background: Androgens function through DNA and non-DNA binding-dependent signalling of the androgen receptor (AR). How androgens promote erythropoiesis is not fully understood.

Design And Methods: To identify the androgen signalling pathway, we treated male mice lacking the second zinc finger of the DNA-binding domain of the AR (AR ) with non-aromatizable 5α-dihydrotestosterone (5α-DHT) or aromatizable testosterone. To distinguish direct hematopoietic and non-hematopoietic mechanisms, we performed bone marrow reconstitution experiments.

Results: In wild-type mice, 5α-DHT had greater erythroid activity than testosterone, which can be aromatized to estradiol. The erythroid response in wild-type mice following 5α-DHT treatment was associated with increased serum erythropoietin (EPO) and its downstream target erythroferrone, and hepcidin suppression. 5α-DHT had no erythroid activity in AR mice, proving the importance of DNA binding by the AR. Paradoxically, testosterone, but not 5α-DHT, suppressed EPO levels in AR mice, suggesting testosterone following aromatization may oppose the erythroid-stimulating effects of androgens. Female wild-type mice reconstituted with AR bone marrow cells remained responsive to 5α-DHT. In contrast, AR mice reconstituted with female wild-type bone marrow cells showed no response to 5α-DHT.

Conclusion: Erythroid promoting effects of androgens are mediated through DNA binding-dependent actions of the AR in non-hematopoietic cells, including stimulating EPO expression.
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http://dx.doi.org/10.1111/ejh.13431DOI Listing
September 2020

Built Environment, Physical Activity, and Obesity: Findings from the International Physical Activity and Environment Network (IPEN) Adult Study.

Annu Rev Public Health 2020 04;41:119-139

Centre for Urban Transitions, Swinburne University of Technology, Hawthorn, Victoria 3122, Australia.

Creating more physical activity-supportive built environments is recommended by the World Health Organization for controlling noncommunicable diseases. The IPEN (International Physical Activity and Environment Network) Adult Study was undertaken to provide international evidence on associations of built environments with physical activity and weight status in 12 countries on 5 continents ( > 14,000). This article presents reanalyzed data from eight primary papers to identify patterns of findings across studies. Neighborhood environment attributes, whether measured objectively or by self-report, were strongly related to all physical activity outcomes (accelerometer-assessed total physical activity, reported walking for transport and leisure) and meaningfully related to overweight/obesity. Multivariable indexes of built environment variables were more strongly related to most outcomes than were single-environment variables. Designing activity-supportive built environments should be a higher international health priority. Results provide evidence in support of global initiatives to increase physical activity and control noncommunicable diseases while achieving sustainable development goals.
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http://dx.doi.org/10.1146/annurev-publhealth-040218-043657DOI Listing
April 2020

Sex-specific adipose tissue imprinting of regulatory T cells.

Nature 2020 03 26;579(7800):581-585. Epub 2020 Feb 26.

Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia.

Adipose tissue is an energy store and a dynamic endocrine organ. In particular, visceral adipose tissue (VAT) is critical for the regulation of systemic metabolism. Impaired VAT function-for example, in obesity-is associated with insulin resistance and type 2 diabetes. Regulatory T (T) cells that express the transcription factor FOXP3 are critical for limiting immune responses and suppressing tissue inflammation, including in the VAT. Here we uncover pronounced sexual dimorphism in T cells in the VAT. Male VAT was enriched for T cells compared with female VAT, and T cells from male VAT were markedly different from their female counterparts in phenotype, transcriptional landscape and chromatin accessibility. Heightened inflammation in the male VAT facilitated the recruitment of T cells via the CCL2-CCR2 axis. Androgen regulated the differentiation of a unique IL-33-producing stromal cell population specific to the male VAT, which paralleled the local expansion of T cells. Sex hormones also regulated VAT inflammation, which shaped the transcriptional landscape of VAT-resident T cells in a BLIMP1 transcription factor-dependent manner. Overall, we find that sex-specific differences in T cells from VAT are determined by the tissue niche in a sex-hormone-dependent manner to limit adipose tissue inflammation.
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http://dx.doi.org/10.1038/s41586-020-2040-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241647PMC
March 2020

Validity of the Past-day Adults' Sedentary Time Questionnaire in a Cardiac Rehabilitation Population.

J Cardiopulm Rehabil Prev 2020 09;40(5):325-329

Department of Physiotherapy (Dr Freene), and Centre for Research & Action in Public Health, Health Research Institute (Dr Davey), University of Canberra, Bruce, ACT, Australia; Departments of Cardiology (Ms McManus and Dr Tan) and Exercise Physiology (Ms Mair), Canberra Hospital and Health Services, Garran, ACT, Australia; and School of Public Health, The University of Queensland, Herston, Queensland, Australia (Dr Clark).

Purpose: Self-report measures of sedentary behavior are easier to use in a clinical setting; yet, no self-report measures of sedentary behavior appear to be validated in cardiac rehabilitation over time. The aim of this study was to assess the validity of the Past-day Adults' Sedentary Time (PAST) questionnaire in a cardiac rehabilitation population over 12 mo.

Methods: Seventy-two cardiac rehabilitation participants were recruited to a prospective cohort study. Participants wore an ActiGraph ActiSleep accelerometer (sedentary time <100 counts/min) for 7 consecutive days and completed the self-administered PAST questionnaire at baseline, 6 wk, and 6 and 12 mo. Total daily sedentary time from both methods were compared using Bland-Altman plots and Spearman rank-order correlations.

Results: Agreement between the 2 measures of sedentary time improved over 12 mo. At 6 and 12 mo, there was a good level of agreement between measures (mean difference between accelerometer and PAST 57 and -0.7 min, respectively), although the dispersion of the differences was wide (95% limits of agreement -428 to 541 and -500 to 498 min, respectively). There were weak correlations between the PAST questionnaire and average accelerometer measured sedentary time at all time points (α = -0.249 to 0.188).

Conclusions: Following repeated assessments, the PAST questionnaire may be useful to determine sedentary time in cardiac rehabilitation participants at a group level, with participants appearing to more accurately recall their time spent in sedentary behavior. Further research is indicated to assess the validity of sedentary behavior questionnaires in cardiac rehabilitation, with a combination of objective and self-reported measures currently recommended.
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http://dx.doi.org/10.1097/HCR.0000000000000488DOI Listing
September 2020

Do associations of sex, age and education with transport and leisure-time physical activity differ across 17 cities in 12 countries?

Int J Behav Nutr Phys Act 2019 12 3;16(1):121. Epub 2019 Dec 3.

Mary Mackillop Institute for Health Research, Australian Catholic University, Melbourne, Victoria, Australia.

Background: Leisure-time and transport activity domains are studied most often because they are considered more amenable to intervention, but to date evidence on these domains is limited. The aim of the present study was to examine patterns of socio-demographic correlates of adults' leisure-time and transport physical activity and how these associations varied across 17 cities in 12 countries.

Methods: Participants (N = 13,745) aged 18-66 years in the IPEN Adult study and with complete data on socio-demographic and self-reported physical activity characteristics were included. Participants reported frequency and duration of leisure-time and transport activities in the last 7 days using the self-administered International Physical Activity Questionnaire-Long Form. Six physical activity outcomes were examined in relation with age, education, and sex, and analyses explored variations by city and curvilinear associations.

Results: Sex had the most consistent results, with five of six physical activity outcomes showing females were less active than males. Age had the most complex associations with self-report transport and leisure-time physical activity. Compared to older people, younger adults were less likely to engage in transport physical activity, but among those who did, younger people were likely to engage in more active minutes. Curvilinear associations were found between age and all three leisure-time physical activity outcomes, with the youngest and the oldest being more active. Positive associations with education were found for leisure-time physical activity only. There were significant interactions of city with sex and education for multiple physical activity outcomes.

Conclusions: Although socio-demographic correlates of physical activity are widely studied, the present results provide new information. City-specific findings suggest there will be value in conducting more detailed case studies. The curvilinear associations of age with leisure-time physical activity as well as significant interactions of leisure-time activity with sex and education should be further investigated. The findings of lower leisure-time physical activity among females as well as people with low education suggest that greater and continued efforts in physical activity policies and programs tailored to these high-risk groups are needed internationally.
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http://dx.doi.org/10.1186/s12966-019-0894-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6888920PMC
December 2019

Associations of built environment and proximity of food outlets with weight status: Analysis from 14 cities in 10 countries.

Prev Med 2019 12 22;129:105874. Epub 2019 Oct 22.

Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Australia; Family Medicine and Public Health, University of California San Diego, USA. Electronic address:

The study aimed to examine associations of neighborhood built environments and proximity of food outlets (BE measures) with body weight status using pooled data from an international study (IPEN Adult). Objective BE measures were calculated using geographic information systems for 10,008 participants (4463 male, 45%) aged 16-66 years in 14 cities. Participants self-reported proximity to three types of food outlets. Outcomes were body mass index (BMI) and overweight/obesity status. Male and female weight status associations with BE measures were estimated by generalized additive mixed models. Proportion (95% CI) of overweight (BMI 25 to <30) ranged from 16.6% (13.1, 19.8) to 41.1% (37.3, 44.7), and obesity (BMI ≥ 30) from 2.9% (1.3, 4.4) to 31.3% (27.7, 34.7), with Hong Kong being the lowest and Cuernavaca, Mexico highest for both proportions. Results differed by sex. Greater street intersection density, public transport density and perceived proximity to restaurants (males) were associated with lower odds of overweight/obesity (BMI ≥ 25). Proximity to public transport stops (females) was associated with higher odds of overweight/obesity. Composite BE measures were more strongly related to BMI and overweight/obesity status than single variables among men but not women. One standard deviation improvement in the composite measures of BE was associated with small reductions of 0.1-0.5% in BMI but meaningful reductions of 2.5-5.3% in the odds of overweight/obesity. Effects were linear and generalizable across cities. Neighborhoods designed to support public transport, with food outlets within walking distance, may contribute to global obesity control.
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http://dx.doi.org/10.1016/j.ypmed.2019.105874DOI Listing
December 2019

Objectively measured access to recreational destinations and leisure-time physical activity: Associations and demographic moderators in a six-country study.

Health Place 2019 09 7;59:102196. Epub 2019 Sep 7.

Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Australia; Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA.

Within the growing body of research linking neighbourhood environmental attributes with physical activity, associations between recreational destinations and non-walking leisure-time physical activity (LTPA) are rarely studied, and to date, not across multiple cities. We examined six potential associations of objectively-measured access to private recreational facilities (e.g., fitness centres, swimming pools) and parks with adults' non-walking LTPA (e.g., swimming, cycling, tennis), using data gathered with consistent methods from adults living in international cities with a range of environment attributes. The potential effects of socio-demographic moderators and between-city variations were also examined. Data from 6725 adults from 10 cities (6 countries) were gathered. Adults were more likely to engage in non-walking LTPA if they had a greater number of private recreational facilities within 0.5 or 1 km of the home, particularly in women, and if they lived closer to a park. The amount of non-zero LTPA was only associated (positively) with the number of recreational facilities within 1 km. Relationships between amount of LTPA and park proximity appear complex, with likely contextual and cultural differences. Improving access to private recreational facilities could promote non-walking LTPA, especially in women.
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http://dx.doi.org/10.1016/j.healthplace.2019.102196DOI Listing
September 2019

High sedentary behaviour and low physical activity levels at 12 months after cardiac rehabilitation: A prospective cohort study.

Ann Phys Rehabil Med 2020 Jan 26;63(1):53-58. Epub 2019 Aug 26.

Health Research Institute, University of Canberra, Bruce, ACT, Australia; Centre for Research & Action in Public Health, Health Research Institute, University of Canberra, Bruce, ACT, Australia. Electronic address:

Background: International cardiac rehabilitation guidelines recommend that participants meet public health physical activity guidelines. Few studies have objectively measured how much time cardiac rehabilitation participants spend in physical activity and sedentary behaviour, particularly over the long term.

Objective: The aim of this study was to objectively assess physical activity and sedentary behaviour of cardiac rehabilitation participants over 12 months and determine whether they met the public health physical activity and sedentary behaviour guidelines.

Methods: Cardiac rehabilitation participants with coronary heart disease were recruited in a prospective cohort study (n=72). Participants wore an ActiGraph ActiSleep accelerometer for 7 consecutive days at baseline, 6 weeks, and 6 and 12 months to assess daily minutes of moderate-to-vigorous physical activity and sedentary behaviour (<100 counts/min). Other outcomes collected were self-reported physical activity and sedentary behaviour, body mass index, waist-to-hip ratio, lipid profile, blood glucose level, quality of life, exercise capacity, anxiety and depression.

Results: By intent-to-treat analysis, during the 6-week cardiac rehabilitation program, participants increased their light physical activity (P<0.01), which was maintained up to 12 months. Moderate-to-vigorous physical activity and sedentary behaviour did not change during the 6-week cardiac rehabilitation program but did improve over 6 months (sedentary behaviour decreased [P<0.001], moderate-to-vigorous physical activity increased [P<0.05]), which was maintained up to 1 year. Completion of moderate-to-vigorous physical activity in 10-min bouts did not change over 12 months, nor did the proportion of participants meeting physical activity guidelines (15-21%). Sedentary behaviour remained high throughout (11 hr/day).

Conclusion: Most cardiac rehabilitation participants did not meet the physical activity guidelines during and after a 6-week program up to 12 months. Reducing sedentary behaviour may be a more achievable first-line strategy for cardiac patients, moving participants along the energy expenditure continuum, aiming to increase their physical activity levels over the medium to long term.

Trial Registration: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12615000995572, http://www.ANZCTR.org.au/ACTRN12615000995572.aspx.
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http://dx.doi.org/10.1016/j.rehab.2019.07.008DOI Listing
January 2020

Correction to: A closer look at the relationship among accelerometer-based physical activity metrics: ICAD pooled data.

Int J Behav Nutr Phys Act 2019 08 8;16(1):62. Epub 2019 Aug 8.

Department of Health and Human Physiology, University of Iowa, Iowa City, IA, USA.

Following publication of the original article [1], the author reported that the name of the collaborator group was missing from the author group.
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http://dx.doi.org/10.1186/s12966-019-0828-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686467PMC
August 2019

Modification of lactoferrin by peroxynitrite reduces its antibacterial activity and changes protein structure.

Proteins 2020 01 23;88(1):166-174. Epub 2019 Jul 23.

Department of Chemistry and Biochemistry, University of Denver, Denver, Colorado.

Lactoferrin (LF) is a multifunctional protein that plays important physiological roles as one of the most concentrated proteins in many human and other mammalian fluids and tissues. In particular, LF provides antibacterial properties to human milk, saliva, and tear fluid. LF also protects against stress-induced lipid peroxidation at inflammation sites through its iron-binding ability. Previous studies have shown that LF can be efficiently nitrated via biologically relevant mediators such as peroxynitrite (ONOO ), which are also present at high intracellular concentrations during inflammation and nitrosative stress. Here, we examine changes in antibacterial properties and structure of LF following ONOO treatment. The reaction induces nitration of tyrosine and tryptophan residues, which are commonly used as biomarker molecules for several diseases. Treatment with ONOO at a 10/1 M ratio of ONOO to tyrosine inhibited all antibacterial activity exhibited by native LF. Secondary structural changes in LF were assessed using circular dichroism spectroscopy. Nitration products with and without the addition of Fe show significant reduction in alpha-helical properties, suggesting partial protein unfolding. Iron-binding capacity of LF was also reduced after treatment with ONOO , suggesting a decreased ability of LF to protect against cellular damage. LC-MS/MS spectrometry was used to identify LF peptide fragments nitrated by ONOO , including tyrosine residue Y92 located in the iron-binding region. These results suggest that posttranslational modification of LF by ONOO could be an important pathway to exacerbate infection, for example, in inflamed tissues and to reduce the ability of LF to act as an immune responder and decrease oxidative damage.
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http://dx.doi.org/10.1002/prot.25782DOI Listing
January 2020

Control group changes in objectively measured physical activity in primary care: protocol for a systematic review and meta-analysis.

Syst Rev 2019 06 18;8(1):144. Epub 2019 Jun 18.

School of Public Health & Social Work and Institute of Health and Biomedical Innovation, Queensland University of Technology, Victoria Park Road, Kelvin Grove, 4059, Australia.

Background: There is some evidence that simply measuring physical activity alone can increase self-reported physical activity behaviour. Objective measures of physical activity in intervention studies have increased substantially over the last decade. Yet, there is no synthesised evidence of observed changes in the control group physical activity in trials that have used objective physical activity measurement approaches. Understanding factors associated with control group increases (or decreases) in physical activity may have implications for planning physical activity research and in clinical settings where objective measures of physical activity may be used. The aim of this systematic review is to describe changes in objectively measured physical activity that have occurred within control groups in primary care physical activity intervention studies and, if possible, identify factors that are potentially associated with these changes.

Methods: The PRISMA-P reporting guidelines for systematic review protocols will be followed. Five electronic databases (PubMed, MEDLINE, SPORTDiscuss, PsychINFO, CINAHL) will be searched to identify physical activity controlled (randomised, cluster, quasi-experimental) studies conducted with adults in primary care. Search terms will be based on previous systematic reviews, and only peer-reviewed articles published in English will be considered. The main outcome measure is the change in objectively measured physical activity within the control group. Risk of bias will be assessed using the Cochrane Collaboration tool and the Risk Of Bias in Non-randomised Studies-of Interventions tool. Meta-analyses will be conducted where possible among studies with sufficient homogeneity.

Discussion: This systematic review and meta-analysis will determine the extent to which physical activity measurement alone is associated with changes in objectively measured physical activity levels in control groups in primary care. Findings from this study will inform future physical activity intervention research and practice. If measuring physical activity alone is associated with increases in physical activity levels that may be considered beneficial for health, this could indicate that measurement alone may be a low cost, efficient and effective method to increase a proprotion of the population's physical activity levels.

Systematic Review Registration: PROSPERO CRD42018104896.
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http://dx.doi.org/10.1186/s13643-019-1060-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6582473PMC
June 2019

International Comparison of the Levels and Potential Correlates of Objectively Measured Sedentary Time and Physical Activity among Three-to-Four-Year-Old Children.

Int J Environ Res Public Health 2019 05 31;16(11). Epub 2019 May 31.

Population Health Sciences, Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Clifton, Bristol BS8 2BN, UK.

Physical activity (PA) patterns track from childhood through to adulthood. The study aimed to determine the levels and correlates of sedentary time (ST), total PA (TPA), and moderate-to-vigorous PA (MVPA) in preschool-aged children. We conducted cross-sectional analyses of 1052 children aged three-to-four-years-old from six studies included in the International Children's Accelerometry Database. Multilevel linear regression models adjusting for age, gender, season, minutes of wear time, and study clustering effects were used to estimate associations between age, gender, country, season, ethnicity, parental education, day of the week, time of sunrise, time of sunset, and hours of daylight and the daily minutes spent in ST, TPA, and MVPA. Across the UK, Switzerland, Belgium, and the USA, children in our analysis sample spent 490 min in ST per day and 30.0% and 21.2% of children did not engage in recommended daily TPA (≥180 min) and MVPA (≥60 min) guidelines. There was evidence for an association between all 10 potential correlates analyzed and at least one of the outcome variables; average daily minutes spent in ST, TPA and/or MVPA. These correlates can inform the design of public health interventions internationally to decrease ST and increase PA in preschoolers.
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http://dx.doi.org/10.3390/ijerph16111929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6603940PMC
May 2019

Frequency of a very brief intervention by physiotherapists to increase physical activity levels in adults: a pilot randomised controlled trial.

BMC Sports Sci Med Rehabil 2019 22;11. Epub 2019 May 22.

3School of Public Health & Social Work and Institute of Health and Biomedical Innovation, Queensland University of Technology, Victoria Park Road, Kelvin Grove, 4059 Australia.

Background: There is evidence that brief physical activity interventions by health professionals can increase physical activity levels. In addition, there is some evidence that simply measuring physical activity alone can increase physical activity behaviour. However, preliminary work is required to determine the effects of potential measurement frequency. The aim of this pilot study was to examine whether frequency of physical activity measurement, with very brief advice from a physiotherapist, influenced objectively measured physical activity in insufficiently active adults.

Methods: Using concealed allocation and blinded assessments, eligible participants ( = 40) were randomised to a lower-measurement-frequency (baseline and 18-weeks) or higher-measurement-frequency group (baseline, 6, 12 and 18-weeks). The primary outcome was daily minutes of moderate-to-vigorous physical activity (accelerometry). Secondary outcomes included functional aerobic capacity (STEP tool), quality-of-life (AQoL-6D), body mass index, waist circumference, waist-to-hip ratio and blood pressure.

Results: Between-group comparisons were not significant in intention-to-treat analyses. However, there was a trend for the higher-measurement-frequency group to complete more daily minutes of moderate-to-vigorous physical activity at 18-weeks (mean difference 19.6 vs - 11.9 mins/week,  = 0.084), with a medium effect size (Cohen's  = 0.58). This was significant in per-protocol analysis ( = 0.049, Cohen's  = 0.77). Within-group comparisons indicated both groups increased their aerobic fitness ( ≤ 0.01), but only the higher-measurement-frequency group decreased their waist circumference (mean decrease 2.3 cm, 95%CI 0.3-4.3,  = 0.024), diastolic blood pressure (mean decrease 3.4 mmHg, 95%CI 0.03-6.8,  = 0.048) and improved their quality-of-life for independent living (mean increase 3.3, 95%CI 0.2-6.4,  = 0.031).

Conclusion: Very brief physical activity interventions by physiotherapists may be an efficient approach to increase physical activity in community-dwelling adults. A larger trial is warranted.

Trial Registration: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12616000566437, http://www.ANZCTR.org.au/ACTRN12616000566437.aspx, registered 2 May 2016.
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http://dx.doi.org/10.1186/s13102-019-0118-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6530136PMC
May 2019

A closer look at the relationship among accelerometer-based physical activity metrics: ICAD pooled data.

Int J Behav Nutr Phys Act 2019 04 29;16(1):40. Epub 2019 Apr 29.

Department of Health and Human Physiology, University of Iowa, Iowa City, IA, USA.

Background: Accelerometers are widely used to assess child physical activity (PA) levels. Using the accelerometer data, several PA metrics can be estimated. Knowledge about the relationships between these different metrics can improve our understanding of children's PA behavioral patterns. It also has significant implications for comparing PA metrics across studies and fitting a statistical model to examine their health effects. The aim of this study was to examine the relationships among the metrics derived from accelerometers in children.

Methods: Accelerometer data from 24,316 children aged 5 to 18 years were extracted from the International Children's Accelerometer Database (ICAD) 2.0. Correlation coefficients between wear time, sedentary behavior (SB), light-intensity PA (LPA), moderate-intensity PA (MPA), vigorous-intensity PA (VPA), moderate- and vigorous-intensity PA (MVPA), and total activity counts (TAC) were calculated.

Results: TAC was approximately 22X10 counts higher (p < 0.01) with longer wear time (13 to 18 h/day) as compared to shorter wear time (8 to < 13 h/day), while MVPA was similar across the wear time categories. MVPA was very highly correlated with TAC (r = .91; 99% CI = .91 to .91). Wear time-adjusted correlation between SB and LPA was also very high (r = -.96; 99% CI = -.96, - 95). VPA was moderately correlated with MPA (r = .58; 99% CI = .57, .59).

Conclusions: TAC is mostly explained by MVPA, while it could be more dependent on wear time, compared to MVPA. MVPA appears to be comparable across different wear durations and studies when wear time is ≥8 h/day. Due to the moderate to high correlation between some PA metrics, potential collinearity should be addressed when including multiple PA metrics together in statistical modeling.
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http://dx.doi.org/10.1186/s12966-019-0801-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6489360PMC
April 2019

Infographic:The effects of residential relocation on walking, physical activity and travel behaviour.

Br J Sports Med 2019 Dec 29;53(23):1486-1487. Epub 2019 Mar 29.

Prevention Research Collaboration, Sydney School of Public Health, University of Sydney, Camperdown, New South Wales, Australia.

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http://dx.doi.org/10.1136/bjsports-2018-100398DOI Listing
December 2019

The androgen receptor in the hypothalamus positively regulates hind-limb muscle mass and voluntary physical activity in adult male mice.

J Steroid Biochem Mol Biol 2019 05 8;189:187-194. Epub 2019 Mar 8.

Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, 3084, Australia. Electronic address:

We have previously shown that expression of the androgen receptor (AR) in neurons within the brain positively regulates hind-limb muscle mass and physical activity in male mice. To further investigate the region of the brain responsible for mediating these effects of testosterone and to determine whether they are only important for muscle mass accrual during development or whether they are also important for the maintenance of muscle mass in the adult, we deleted the AR specifically in the hypothalamus of adult male mice (Hyp-ARKOs). Hyp-ARKO mice were generated by bilateral stereotaxic microinjection of an adeno-associated virus (AAV) expressing GFP and iCre recombinase under the control of the e-synapsin promoter into the hypothalamus of 10-week-old exon 3-AR floxed male mice. AR mRNA was deleted by 45% in the hypothalamus of Hyp-ARKOs at 5 weeks post-AAV-eSyn-iCre injection. This led to an increase in the mass of the androgen-dependent organs, seminal vesicles and kidneys, by 30% (P < 0.01) and 10% (P < 0.05) respectively, and an increase in serum luteinizing hormone (LH) by 2 fold (P < 0.05). Whilst the mean value for serum testosterone was higher in the Hyp-ARKOs, this did not reach statistical significance. Despite a phenotype consistent with increased androgen bioactivity in Hyp-ARKOs, which would be expected to increase muscle mass, the mass of the hind-limb muscles, gastrocnemius (Gast) (P = 0.001), extensor digitorum longus (EDL) (P < 0.001) and soleus (Sol) (P < 0.01) were paradoxically decreased by 12-19% compared to controls. Voluntary physical activity was reduced by 65% (P < 0.05) in Hyp-ARKO male mice and was associated with a reduction in gene expression of Drd1a and Maob (P ≤ 0.05) in the hypothalamus, suggesting involvement of the brain dopaminergic system. These data provide compelling evidence that androgen signalling via the AR in the hypothalamus acts to positively regulate the maintenance of hind-limb muscle mass and voluntary activity in adult male mice, independent of AR signalling in peripheral tissues.
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http://dx.doi.org/10.1016/j.jsbmb.2019.02.018DOI Listing
May 2019