Low leisure-based sitting time and being physically active were associated with reduced odds of death and diabetes in people with chronic obstructive pulmonary disease: a cohort study

Questions In people with chronic obstructive pulmonary disease (COPD), are activity phenotypes (based on physical activity and recreational screen time) associated with mortality and cardiometabolic risk factors? Design Cohort study. Participants People with COPD aged ≥ 40 years and who were current or ex-smokers were identified from the 2003 Scottish Health Survey. Outcome measures Data were collected regarding demographics, anthropometric measurements, medical history, physical activity, sedentary behaviour, health outcomes, and mortality. Analysis Participants were categorised into one of the following activity phenotypes: ‘couch potatoes’ were those who were insufficiently active with high leisure-based sitting time and/or no domestic physical activity; ‘light movers’ were insufficiently active with some domestic physical activity; ‘sedentary exercisers’ were sufficiently active with high leisure-based sitting time; and ‘busy bees’ were sufficiently active with low leisure-based sitting time. ‘Sufficiently active’ was defined as adhering to physical activity (PA) recommendations of ≥ 7.5 metabolic equivalent (MET) hours/week. ‘Low leisure-based sitting time’ was defined as ≤ 200 minutes of recreational screen time/day. Results The 584 participants had a mean age of 64 years (SD 12) and 52% were male. Over 5.5 years (SD 1.3) of follow-up, there were 81 all-cause deaths from 433 COPD participants with available data. Compared to the ‘couch potatoes’, there was a reduced risk of all-cause mortality in the ‘busy bees’ (Hazard Ratio 0.26, 95% CI 0.11 to 0.65) with a trend towards a reduction in mortality risk in the other phenotypes. The odds of diabetes were lower in the ‘busy bees’ compared to the ‘couch potatoes’ (OR 0.14, 95% CI 0.03 to 0.67). Conclusions Adhering to physical activity guidelines and keeping leisure-based sitting time low had a mortality benefit and lowered the odds of diabetes in people with COPD

Associations of total and type-specific physical activity with mortality in chronic obstructive pulmonary disease: a population-based cohort study

Background: Regular physical activity is recommended for all people with chronic obstructive pulmonary disease (COPD), but the dose of physical activity required to gain mortality benefit in this population is not yet known. This aim of this study was to examine the associations of total and type-specific physical activity with mortality risk in people with COPD. Methods: People with COPD aged ≥40 years were identified from the 1997 Health Survey for England and the 1998 and 2003 Scottish Health Survey cohorts. Self-reported total physical activity, moderate-vigorous intensity physical activity (MVPA), walking, domestic physical activity, and sport/exercise were assessed at baseline. Cox proportional hazards models were used to examine the associations between physical activity and mortality risk. Results: Two thousand three hundred ninety-eight participants with COPD were included in the analysis and followed up for a mean 8.5 (SD 3.9) years. For both total physical activity and MVPA, we observed doseresponse associations with all-cause and cardiovascular disease (CVD) mortality risk, and with respiratory mortality risk to a lesser extent. Compared to those who reported no physical activity, participants who met the physical activity guidelines demonstrated the greatest reductions in all-cause (HR 0.56, 95% CI 0.45–0.69), CVD (HR 0.48, 95% CI 0.32–0.71) and respiratory mortality risk (HR 0.40, 95% CI 0.24–0.67). Participants who reported a level of physical activity of at least half the dosage recommended by the guidelines also had a reduced risk of all-cause (HR 0.75, 95% CI 0.56–1.00) and CVD mortality (HR 0.48, 95% CI 0.26–0.88). Doseresponse associations with mortality risk were demonstrated for walking and sport/exercise, but not domestic physical activity. Conclusions: We found a dose-response association between physical activity and all-cause and CVD mortality risk in people with COPD, with protective effects appearing at levels considerably lower than the general physical activity recommendations. People with COPD may benefit from engagement in low levels of physical activity, particularly walking and structured exercise

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Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

An examination of physical activity and sedentary behaviour in people with chronic obstructive pulmonary disease

Insufficient levels of physical activity (PA), commonly referred to as ‘physical inactivity’, is a key risk factor for mortality and noncommunicable diseases such as cardiovascular disease (CVD), cancer, and diabetes [1]. PA is defined as any bodily movement produced by skeletal muscles that requires energy expenditure and encompasses exercise (planned, repetitive PA that aims to improve or maintain physical fitness), sport, and activities of daily living, work, leisure and transportation [2]. In the past two decades, there has been an increasing focus on the problem of physical inactivity in people with chronic obstructive pulmonary disease (COPD). COPD is a highly prevalent public health issue and will be the third leading cause of death worldwide by 2030 [3]. Physical inactivity is known to be more common in people with COPD compared with age-matched healthy individuals [4]. Reductions in PA occur early in the COPD disease trajectory and across all stages of disease severity, accompanied by deterioration in lung function and health status [5]. Despite consistent evidence of the detrimental health effects of physical inactivity, strategies to increase PA and subsequently improve health outcomes in people with COPD are not well established. Physical inactivity in daily life and decline in PA over time are both associated with a higher risk of mortality [6-8] and with a higher risk of COPD-related and exacerbation-related hospitalisations in people with COPD [6, 9, 10]. Although regular PA is recommended for all individuals with COPD [11], previous research has focused on exercise training in the context of pulmonary rehabilitation and there is a lack of high-quality evidence to guide the prescription of daily PA in this population. The dose and type of PA that confers long-terms health benefits, including longevity, has been examined in small clinical samples that are non-representative of the general COPD population. There is also considerable heterogeneity in the way that PA has been measured and classified, which makes it difficult to compare results across studies. Such limitations reduce the generalisability of the evidence base and subsequently, clinicians must rely on generic PA guidelines for older adults to inform PA recommendations in people with COPD. There are innate challenges in increasing PA in people with COPD. Disease-specific limitations such as dyspnoea, fatigue, reduced aerobic capacity, and use of oxygen therapy reduce the physical capability of people with COPD to engage in PA [12], particularly levels of moderate-to-vigorous intensity physical activity (MVPA), which are characterised by an energy expenditure of ≥3.0 metabolic equivalents (METs) [13]. Furthermore, a large number of studies have evaluated the effect of interventions such as exercise training and behaviour change approaches on PA, and there is limited evidence that either strategy can increase PA in people with COPD even when delivered as part of a comprehensive pulmonary rehabilitation program [14, 15]. Even in healthy individuals who meet current PA recommendations, MVPA comprises a relatively small proportion of total waking hours, with the majority of time spent in sedentary behaviour (SB) or light-intensity PA [16]. SB is defined as any waking behaviour characterised by an energy expenditure ≤1.5 METs [17], while in a sitting, reclining or lying posture, and includes activities such as television (TV) viewing, video game playing, computer use (collectively termed ‘screen time’), driving automobiles, and reading [18]. The reality that most of daily life is spent in SB has led to growing interest in the effects of SB on the risk of mortality and noncommunicable diseases over the last ten years. Although there is evidence to suggest that in the general population, 60-75 min/day of MVPA can eliminate the increased risk of mortality, CVD and cancer associated with SB [19, 20], such high levels of MVPA are unrealistic for most people with symptomatic COPD. There is also preliminary evidence that SB is associated with a higher risk of mortality [21, 22], cardiometabolic disease [23, 24] and hospitalisation [25] in the COPD population, and that targeting reductions in SB and increases in light-intensity PA may produce health benefits even if increases in MVPA are not realised [26, 27]. Laboratory-based controlled studies in populations other than COPD have shown that interrupting SB with light-intensity PA is sufficient to improve cardiometabolic risk biomarkers such as postprandial glucose and insulin responses [28-34], and to a lesser extent triglycerides and cholesterol [34, 35]. An alternative approach of reducing time in SB and increasing participation in light-intensity PA may therefore act as a feasible intermediate goal for people with COPD, and may lead better engagement with higher intensity PA in the future [36]. However, SB has not yet been characterised in people with COPD using thigh-worn accelerometry, which is able to directly quantify posture and capture the patterns in which SB is accumulated [37]. Strategies capable of reducing the time spent in SB in people with COPD are unknown. The series of studies contained in this thesis explored the characteristics of PA and SB in people with COPD, and the effects of changing the volume and patterns of PA and SB on health outcomes. Thus the aims of the body of work contained in the thesis were: 1) to examine the associations of total and type-specific PA with all-cause, CVD and respiratory mortality risk in people with COPD; 2) to quantify total SB, patterns of SB accumulation and PA in people with COPD; and the correlations of SB with clinically relevant outcomes; and 3) to determine, in people with stable COPD, whether a six-week behaviour change intervention was more effective than a sham intervention in reducing total SB and the accumulation of SB in prolonged bouts, and the feasibility of such an intervention with respect to uptake, retention, and compliance. To achieve these aims, this thesis contains a literature review (Chapter 1), three published research studies and one submitted manuscript (Chapters 2-5), and a discussion and clinical implications chapter (Chapter 6). The literature review provides an overview of COPD and discusses the literature on the characteristics, determinants and measurement of PA and SB, associations of PA and SB with health outcomes, and interventions to modify PA and SB in people with COPD. Chapter 2 contains a population-based cohort study that examined the dose-response associations between total PA and the risk of all-cause, CVD, and respiratory mortality within the context of current public health recommendations; and the dose-response associations between specific types of PA and the risk of all-cause, CVD (CVD), and respiratory mortality. Established thresholds were used to examine PA in MET-hours/week in order to provide clinicians with a meaningful reference standard to guide prescription of PA and enable future studies to make direct comparisons to the magnitude of mortality risk described in the sample. Two thousand three hundred ninety-eight participants with COPD were identified from the 1997 Health Survey for England and the 1998 and 2003 Scottish Health Survey cohorts. For both total physical activity and MVPA, dose-response associations were observed with all-cause and CVD mortality risk, and with respiratory mortality risk to a lesser extent. Compared to those who reported no PA, participants who met current PA recommendations demonstrated the greatest reductions in all-cause (hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.45–0.69) and CVD mortality risk (HR 0.48, 95% CI 0.32–0.71). Participants who reported adhering to at least half the recommended dosage of PA also had a reduced risk of all-cause (HR 0.75, 95% CI 0.56–1.00) and CVD mortality (HR 0.48, 95% CI 0.26–0.88). Dose-response associations with mortality risk were demonstrated for walking and sport/exercise, but not domestic PA. The results of this study demonstrate that people with COPD may still benefit from engagement in low levels of PA, particularly walking and structured exercise. The cross-sectional study in Chapter 3 utilised baseline data from the study in Chapter 4 to quantify total SB, patterns of SB accumulation and PA in people with COPD using thigh-worn accelerometry, and to examine the physiological and functional capacity correlates of SB. Of the 69 participants with COPD included in the study, who spent a mean (SD) 643 (105) min/day in SB and accumulated 374 (142) min/day of SB in prolonged bouts of ≥30 minutes, 39 participants (57%) spent ≥70% of their waking wear time in SB and were classified as ‘sedentary’. ‘Sedentary’ participants had a more unfavourable pattern of SB accumulation and spent less time in PA of any intensity. Time in SB expressed as a proportion of waking wear time was inversely correlated with light-intensity PA (r=-0.97, p<0.01), MVPA (r=-0.55, p<0.01) and exercise capacity (r=-0.33, p<0.01), but not with age, body mass index (BMI) or lung function. The results of this study indicated that people with COPD not only have high total SB but accumulate the majority of SB in prolonged bouts, and that any increase in light-intensity PA is likely to reduce SB in this population. Chapters 4 and 5 of this thesis present the methodology and findings, respectively, of a prospective, multi-centre randomised controlled trial that evaluated the effectiveness of a six-week behaviour intervention compared to a sham intervention in reducing total SB and the accumulation of SB in prolonged bouts in people with COPD, and the feasibility of such an intervention. Seventy people with stable COPD on the waitlist for pulmonary rehabilitation were randomised to either an Intervention Group that consisted of six once weekly sessions with a physiotherapist to reduce SB, or to a Sham Group that received six once weekly phone calls to monitor health status but no instructions on SB or PA. At six weeks, there were no between-group differences in total SB (mean difference 0.4%, 95% CI -3.9 to 4.7) or in usual bout duration (-1.2 min, 95% CI -6.9 to 4.5), which is defined as the duration of the sedentary bout corresponding to 50% of daily accumulated sedentary time and where higher values indicate the accumulation of SB in relatively fewer, more prolonged bouts. Although the behaviour change intervention resulted in small significant increases in purposeful stepping and non-significant increases in step count that exceeded the lower end of the minimal important difference (MID) of 600 steps/day [38], these increases in PA were insufficient to change overall time spent in light-intensity PA. Uptake and retention of, and compliance with, the behaviour intervention were 32%, 93% and 64%, respectively. This study demonstrated that a six-week behaviour change intervention did not reduce total SB nor the accumulation of SB in prolonged bouts compared to a sham intervention and may not be feasible in all people with stable COPD prior to pulmonary rehabilitation. A summary of the main findings of this thesis are presented in Chapter 6. Limitations, clinical implications and suggestions for future research are also discussed in this chapter. Overall, the series of studies in this thesis have demonstrated that in people with stable COPD: i) dose-response associations exist between PA and all-cause and CVD mortality risk, with protective effects appearing at levels considerably lower than current PA recommendations for the general population; ii) those identified as ‘sedentary’ using a cut-off of ≥70% waking wear time spent in SB also tend to accumulate SB in prolonged bouts and may benefit from pulmonary rehabilitation and additional interventions, such as PA counselling or behaviour change interventions, to reduce SB and increase PA levels; and iii) despite the strong inverse relationship observed between SB and light-intensity PA, a six-week behaviour change intervention was not effective in reducing SB nor reducing the accumulation of SB in prolonged bouts compared to a sham intervention, and may not be feasible prior to the commencement of pulmonary rehabilitation

Associations of total and type-specific physical activity with mortality in chronic obstructive pulmonary disease: a population-based cohort study

Abstract Background Regular physical activity is recommended for all people with chronic obstructive pulmonary disease (COPD), but the dose of physical activity required to gain mortality benefit in this population is not yet known. This aim of this study was to examine the associations of total and type-specific physical activity with mortality risk in people with COPD. Methods People with COPD aged ≥40 years were identified from the 1997 Health Survey for England and the 1998 and 2003 Scottish Health Survey cohorts. Self-reported total physical activity, moderate-vigorous intensity physical activity (MVPA), walking, domestic physical activity, and sport/exercise were assessed at baseline. Cox proportional hazards models were used to examine the associations between physical activity and mortality risk. Results Two thousand three hundred ninety-eight participants with COPD were included in the analysis and followed up for a mean 8.5 (SD 3.9) years. For both total physical activity and MVPA, we observed dose-response associations with all-cause and cardiovascular disease (CVD) mortality risk, and with respiratory mortality risk to a lesser extent. Compared to those who reported no physical activity, participants who met the physical activity guidelines demonstrated the greatest reductions in all-cause (HR 0.56, 95% CI 0.45–0.69), CVD (HR 0.48, 95% CI 0.32–0.71) and respiratory mortality risk (HR 0.40, 95% CI 0.24–0.67). Participants who reported a level of physical activity of at least half the dosage recommended by the guidelines also had a reduced risk of all-cause (HR 0.75, 95% CI 0.56–1.00) and CVD mortality (HR 0.48, 95% CI 0.26–0.88). Dose-response associations with mortality risk were demonstrated for walking and sport/exercise, but not domestic physical activity. Conclusions We found a dose-response association between physical activity and all-cause and CVD mortality risk in people with COPD, with protective effects appearing at levels considerably lower than the general physical activity recommendations. People with COPD may benefit from engagement in low levels of physical activity, particularly walking and structured exercise

A behaviour change intervention to reduce sedentary time in people with chronic obstructive pulmonary disease: protocol for a randomised controlled trial

Introduction: Replacing sedentary behaviour with light intensity physical activity (ie, activities classified as less than three metabolic equivalents, such as slow-paced walking) may be a more realistic strategy for reducing cardiometabolic risk in people with chronic obstructive pulmonary disease than only aiming to increase levels of moderate-vigorous intensity physical activity. Behaviour change interventions to reduce sedentary behaviour in people with chronic obstructive pulmonary disease have not yet been developed or tested. Research questions: Is a 6-week behaviour change intervention effective and feasible in reducing sedentary time in people with chronic obstructive pulmonary disease? Design: This study will be a multi-centre, randomised, controlled trial with concealed allocation, assessor blinding, and intention-to-treat analysis, comparing a 6-week behaviour change intervention aimed at reducing sedentary time with a sham intervention in people with chronic obstructive pulmonary disease. Participants and setting: Seventy participants will be recruited from the waiting lists for pulmonary rehabilitation programs at Royal Prince Alfred Hospital and Prince of Wales Hospital, Sydney, Australia. Intervention: The behaviour change intervention aims to reduce sedentary time through a process of guided goal setting with participants to achieve two target behaviours: (1) replace sitting and lying down with light-intensity physical activity where possible, and (2) stand up and move for 2 minutes after 30 minutes of continuous sedentary time. Three face-to-face sessions and three phone sessions will be held with a physiotherapist over the 6-week intervention period. The ‘capability’, ‘opportunity’, ‘motivation’ and ‘behaviour’ (COM-B) model will be applied to each participant to determine which components of behaviour (capability, opportunity or motivation) need to change in order to reduce sedentary time. Based on this ‘behavioural diagnosis’, the Behaviour Change Wheel will be used to systematically select appropriate behaviour change techniques to assist participants in achieving their weekly goals. Behaviour change techniques will include providing information about the health consequences of sedentary behaviour, self-monitoring and review of weekly goals, problem-solving of barriers to achieving weekly goals, and providing feedback on sedentary time using the Jawbone UP3 activity monitor. Control: The sham intervention will consist of weekly phone calls for 6 weeks, to enquire whether the participants’ health status has changed over the intervention period (eg, hospitalised for an acute exacerbation). No instructions regarding physical activity or exercise will be given. Measurements: Outcomes will be assessed at baseline, at the end of the 6-week intervention period, and at the 3-month follow-up. Primary outcome measures will be: (1) total sedentary time, including the pattern of accumulation of sedentary time, assessed by the activPAL3 activity monitor, and (2) feasibility of the intervention assessed by uptake and retention of participants, participant compliance, self-reported achievement of weekly goals, and adverse events. Secondary outcome measures will include functional exercise capacity, health-related quality of life, domain-specific and behaviour-specific sedentary time, patient activation, and anxiety and depression. Semi-structured interviews will be conducted with participants who receive the behaviour change intervention to explore acceptability and satisfaction with the different components of the intervention. Analysis: Analysis of covariance (ANCOVA) will be used to calculate between-group comparisons of total sedentary time and the number of bouts of sedentary time > 30 minutes after adjusting baseline values. Uncertainty about the size of the mean between-group differences will be quantified with 95% CI. Within-group comparisons will be examined using paired t-tests and described as mean differences with 95% CIs. Secondary outcome measures will be analysed similarly. The feasibility measures will be analysed descriptively. Semi-structured interviews will be conducted until data saturation is achieved and there are no new emerging themes. De-identified interview transcripts will be coded independently by two researchers and analysed alongside data collection using the COM-B model as a thematic framework. Discussion/significance: If behaviour change interventions are found to be an effective and feasible method for reducing sedentary time, such interventions may be used to reduce cardiometabolic risk in people with chronic obstructive pulmonary disease. An approach that emphasises participation in light-intensity physical activity may increase the confidence and willingness of people with chronic obstructive pulmonary disease to engage in more intense physical activity, and may serve as an intermediate goal to increase uptake of pulmonary rehabilitation

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