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During pulmonary rehabilitation (PR), patients receive individually tailored walking exercise training. The personalised nature of exercise prescription is a fundamental component of PR. Despite this, the measurement of physical activity (PA) has been limited to a ‘one size fits all’ approach and can be challenging to translate into clinically meaningful or real-world units, such as cadence. This discrepancy may partly explain the inconsistent evidence for the impact of PR on PA. It may also provide an opportunity to standardise PA assessment in the context of chronic respiratory disease (CRD) and PR, where field-based walking tests are routine measures. This technical note provides an example of how to develop personalised PA intensity thresholds, calibrated against an individual’s performance on the Incremental Shuttle Walking Test (ISWT; maximal) and Endurance Shuttle Walk Test (ESWT; sub-maximal). These are externally paced tests, with each level (speed) of the tests denoting a specific speed (intensity); ranging 1.8 km/h (ISWT Level 1) to 8.5 km/h (ISWT Level 12). From the ESWT, it becomes possible to evaluate adherence to each individual’s walking exercise prescription. Future research should explore this approach and its responsiveness to PR. It may be possible to extend this methodology with the inclusion of physiological parameters (e.g., heart rate, calorimetry, and oxygen consumption) to derive relative intensity markers (e.g. moderate-to-vigorous), accounting for individual differences in exercise capacity, under the same paradigm as PR exercise prescription.

IntroductionKnee osteoarthritis (KOA) is a leading cause of disability and is characterised by degenerative changes causing pain and loss of function. Neuromuscular electrical stimulation (NMES) has been shown to influence muscle size and strength in healthy subjects. A novel self-administered NMES device has been developed to help manage the symptoms of KOA. This study aims to investigate the effects of combining NMES of the calf and quadriceps on individuals with KOA.Methods and analysis193 individuals with KOA will be recruited to a single-centre, double-blind, randomised, sham-controlled trial at the Respiratory Biomedical Research Centre, Leicester, UK. Participants will be randomised (1:1) to follow an 8-week home-based intervention using a NMES device or sham device. The NMES device consists of footplate electrodes and two quadriceps electrodes. Footplate stimulation will be completed daily for 30 min and quadriceps stimulation for 20 min, five times a week (compliance is recorded in a self-reported participant diary). The primary outcome is the Western Ontario and McMaster Universities Arthritis Index pain domain, taken at 8 weeks follow-up. Secondary outcomes will explore quadriceps muscle strength, swelling, health-related quality of life, exercise capacity, anxiety and depression, sleep, physical activity and self-reported compliance. A powered subgroup analysis for compliance to the active device will be complete for the primary outcome. Participant focus groups will be completed following recruitment of half of the participants and after all participants have been recruited.Ethics and disseminationEthical approval has been obtained from the North-West Preston ethics committee (17/NW/0081). Participants are required to provide informed consent following review of the participant information sheet and discussion regarding study procedures with a member of the research team. The study results will be disseminated to the appropriate stakeholders through presentations, conferences and peer-reviewed journals. Results will be presented to participants following study completion at the Biomedical Research Centre—Respiratory, Glenfield Hospital, Leicester.Trial registration numberISRCTN registry,ISRCTN12112819(date registered 1 May 2019). IRAS registry 219 693. University Hospitals of Leicester registry 91 017. Protocol Version 8.

BackgroundChronic obstructive pulmonary disease (COPD) patients exhibit lower peak oxygen uptake (V′O2peak), altered muscle metabolism and impaired exercise tolerance compared with age-matched controls. Whether these traits reflect muscle-level deconditioning (impacted by ventilatory constraints) and/or dysfunction in mitochondrial ATP production capacity is debated. By studying aerobic exercise training (AET) at a matched relative intensity and subsequent exercise withdrawal period we aimed to elucidate the whole-body and muscle mitochondrial responsiveness of healthy young (HY), healthy older (HO) and COPD volunteers to whole-body exercise.MethodsHY (n=10), HO (n=10) and COPD (n=20) volunteers were studied before and after 8 weeks of AET (65% V′O2peak) and after 4 weeks of exercise withdrawal. V′O2peak, muscle maximal mitochondrial ATP production rate (MAPR), mitochondrial content, mitochondrial DNA (mtDNA) copy number and abundance of 59 targeted fuel metabolism mRNAs were determined at all time-points.ResultsMuscle MAPR (normalised for mitochondrial content) was not different for any substrate combination in HO, HY and COPD at baseline, but mtDNA copy number relative to a nuclear-encoded housekeeping gene (mean±sd) was greater in HY (804±67) than in HO (631±69; p=0.041). AET increased V′O2peak in HO (17%; p=0.002) and HY (21%; pConclusionsIntrinsic mitochondrial function was not impaired by ageing or COPD in the untrained state. Whole-body and muscle mitochondrial responses to AET were robust in HY, evident in HO, but deficient in COPD. All groups showed robust muscle mRNA responses. Higher relative exercise intensities during whole-body training may be needed to maximise whole-body and muscle mitochondrial adaptation in COPD.

Background: Voluntary resistance exercise (RE) training increases muscle mass and strength in patients with chronic obstructive pulmonary disease (COPD). Nonvolitional transcutaneous neuromuscular electrical stimulation (NMES) may be an alternative strategy for reducing ambulatory muscle weakness in patients unable to perform RE training, but little comparative data are available. This study, therefore, investigated changes in muscle mRNA abundance of a number of gene targets in response to a single bout of NMES compared with RE. Methods: Twenty-six patients with stable COPD (15 male; FEV1, 43±18% predicted; age, 64±8 years; fat free mass index, 16.6±1.8 kg/m2) undertook 30 minutes of quadriceps NMES (50 Hz, current at the limit of tolerance) or 5×30 maximal voluntary isokinetic knee extensions. Vastus lateralis muscle biopsies were obtained at rest immediately before and 24 hours after intervention. Expression of 384 targeted mRNA transcripts was assessed by real time TaqMan PCR. Significant change in expression from baseline was determined using the ΔΔCT method with a false discovery rate (FDR) of

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Impaired muscle function contributes to exercise intolerance in COPD, but it is unclear if the muscle level adaptive response to exercise training in COPD is blunted. We therefore aimed to determine temporal muscle mRNA responses to aerobic exercise training (AET) and subsequent training cessation in COPD and healthy controls (HC) & examined associations with ΔVO2PEAK during training. 19 patients with COPD (6 male; mean ±SD 70±6yrs; FEV1%pred 57±16; VO2PEAK 24.4±7.4ml/min/kg lean mass) & 10 HC (5 male; 71±5yrs; FEV1%pred 113±21; VO2PEAK 29.7±4) had vastus lateralis biopsies (fasted resting) at baseline; after 1,4 & 8wk of cycle AET (30min, 3/wk, 65% peak power); and 4wk after training cessation. 94 exercise-responsive mRNAs were quantified in muscle by RT-PCR and analysed using Ingenuity Pathway Analysis (IPA, Qiagen) to detect biological functions significantly changed from baseline. IPA identified altered biological functions after 1,4 & 8wk of training and after 4wk training cessation in HC and COPD (Fig). The magnitude and pattern of mRNA responses were similar in COPD and HC, & persisted 4wk after training cessation. VO2PEAK increased 18% in HC (p Changes in mRNA expression were dissociated from whole-body ΔVO2PEAK in COPD. These data support the contention that the responsiveness of skeletal muscle to AET in COPD is not blunted, at least at the level of mRNA expression.

Introduction: Reduced mitochondrial ATP production capacity is likely to contribute to exercise limitation in COPD. It is unknown whether this is attributable to a COPD-specific impairment in intrinsic mitochondrial function(Mito func ),a reduction in mitochondrial mass(Mito mass ),a reduction in mitochondrial number(Mito numb ) or a combination. Method and Results: 20 COPD [6 male, age 70 (1) years, FEV 1 56 (4)%] and 10 healthy controls(HC),[5 male, age 71 (2) years,FEV 1 113(6)%)] completed maximal cardio-pulmonary exercise testing (CPET) to determine peak oxygen consumption (VO 2 ), and a resting micro-biopsy of the Vastus Lateralis muscle. Intrinsic Mito func was assessed bio-luminometrically in isolated mitochondria as the maximal rate of ATP production (MAPR;using glutamate and succinate as substrates) and normalisation using maximal citrate synthase (CS) activity, Mito mass was CS activity/muscle total protein content and mtDNA relative copy number was an index of Mito numb . Conclusion: Intrinsic mito func was not lower in COPD patients compared to HC volunteers and mito numb were similar between groups. However, mito mass and peak VO 2 were lower in COPD. Mitochondrial function is therefore not impaired in skeletal muscle of COPD patients, but they are deconditioned. This points to the utility of endurance exercise training as a therapeutic intervention.

Background: PES may be an effective strategy for increasing muscle mass and strength in COPD patients. We investigated the acute genomic response of quadriceps muscle to a single bout of PES or RE in stable COPD patients. Method: 26 COPD patients [15 male; mean(SD) FEV 1 % pred, 42.9(17.9)%; age, 63.9(7.9) yrs; fat free mass index, 16.6(1.8)kg/m 2 ] underwent 30min of quadriceps PES (50Hz, 300μs pulse duration, 15s/5s duty cycle) or 5x30 maximal isokinetic knee extensions at 180°/s. Resting vastus lateralis muscle biopsies were performed immediately before and 24hr after PES or RE. Microfluidic low density microarray cards were used to assess the expression of 384 targeted transcripts by RT-PCR. Significant change in expression from baseline was determined using the ΔΔC T method with a False Discovery Rate (FDR) of Results: PES and RE altered mRNA abundance of 18 and 68 genes respectively (FDR

Introduction: Skeletal muscle dysfunction, in particularly the quadriceps, is a prognostic marker in COPD and a therapeutic target. There are numerous methods of inducing quadriceps muscle change and measuring this response. This study aimed to assess the responsiveness following a NMES training intervention. We hypothesised that single leg NMES would induce changes in quadriceps, and that different measurement modalities would vary in sensitivity to change. Methods: Participants underwent 6 weeks of single leg quadriceps NMES. Measures of muscle mass, size and function were collected pre and post intervention, including thigh lean mass using DEXA (Tdexa), isometric quadriceps strength (QMVC), 2D ultrasound (US) quadriceps cross sectional area (US2D csa), quadriceps muscle thickness using US (USqt) and a novel method measuring quadriceps volume using 3D US (US3D vol). Results: 16 COPD patients (8 male), mean (SD);age 65 (9),FEV1 49.9% (22.0) completed the study. Significant changes were seen between trained and untrained limb for QMVC, US2D csa, USqt and US3D vol. A non-significant trend in increased thigh mass was noted following 6 weeks of NMES (Figure 1). Discussion: 6 weeks of NMES increases strength and size of the quadriceps. Muscle specific measures (using US) were more sensitive to change than whole thigh regional mass (using DEXA).

Introduction Deconditioning is a key cause of exercise intolerance in COPD patients. Exercise training provides an effective method of improving aerobic exercise performance in this group. There is poor understanding on the trajectory of changes made in exercise performance between COPD and Healthy controls (HC), during aerobic training and more importantly limited data exists on the rates of detraining between the groups. Methods This study measures sub-maximal and maximal performance in response to an aerobic training programme and to a period of detraining. COPD and HC undertook 8 weeks of supervised cycling exercise training three times a week. There consequently followed a 4 week period of detraining, and resumption of pre cycling habitual activity (not engaging in regular exercise). A symptom limited incremental cycle (ramp protocol) and constant work rate (sub-maximal/endurance) cardiopulmonary exercise tests (CPET) were performed at baseline, after 4 and 8 weeks of training and after detraining. Cycling training intensity and CPET endurance work were equivalent to 65% of the Work (in Watts (W)) at VO2 Peak during the baseline CPET ramp test. Training intensity was re-set if there was any improvement during the 4-week CPET ramp test. Results 10 COPD patients (MRC 3, 2 males, age 74 years, FEV1 63.5% predicted) and 7 HC (MRC 1, 4 males, age 71 years, FEV1 111% predicted) completed the study. COPD group had lower starting training workloads (59.5 vs 121 Watts, p HC showed a significant increase in Peak VO2 uptake in the ramp but COPD patients only showed an increasing trend. There were however increases in the time achieved during sub-maximal testing in both groups during the 8 week training period. However during detraining, there was relative preservation in the HC but a significant reduction in endurance time in the COPD group. (All values median, unless stated) Conclusion/discussion Exercising training at moderate intensities showed no changes in maximal performance in COPD groups, compared to HC. However gains in sub-maximal performance were seen in both groups. Training induced gains in sub-maximal performance may be better preserved in HC during detraining, when compared to the COPD groups.

Introduction and objectives Impaired skeletal muscle function is an important systemic manifestation of COPD which can be improved by exercise training. Non-volitional training using neuromuscular electrical stimulation (NMES) may be an effective training technique in situations where voluntary exercise may be difficult or impractical (e.g. peri-exacerbation or severe ventilatory limitation). Exercise is known to result in both intramuscular and systemic inflammation. However, the cellular response to NMES, which directly depolarises the motor units, is unclear. We investigated the impact of acute and repeated bouts of unilateral NMES in COPD patients. Methods 16 patients underwent 6 weeks of unilateral NMES 5 times a week for 30 min at 50 Hz at Glenfield Hospital, Leicester. Mean (SD) age was 65 (9) years, FEV 1 : 50 (22)% predicted, BMI 26.5 (5.2) Kg/m 2 ). Isometric quadriceps strength, regional muscle mass (DEXA) and quadriceps thickness (ultrasound) were recorded at baseline and at the end of the intervention. Vastus lateralis muscle biopsies were obtained from both the trained and untrained limbs at baseline, 24 h after the first bout of NMES and at 6 weeks. Venous blood was taken at the same time. Biopsies were analysed for neutrophil (neutrophil elastase) and macrophage (CD163) density using immunohistochemistry. ELISA measurements of inflammatory cytokines (IL-6 and TNFα) were performed on blood samples. Results Quadriceps strength increased by 7.6% (p = 0.024), thigh mass by 2.8% (p = 0.185), and quadriceps thickness by 11% (p = 0.002). Muscle biopsies for 11 patients were analysed. Neutrophil density 24 h after a single bout of unilateral NMES significantly increased in both the trained and untrained limb, with larger increase in the stimulated muscle (Table 1). Neutrophil density returned to baseline in the trained limb following training. No changes were seen in muscle macrophage density, serum IL-6 or serum TNFα. Conclusion A single bout of unilateral NMES provokes an intramuscular neutrophilic inflammatory response in both the trained and untrained limb, which are not mediated by changes in circulating IL-6 or TNFα. Neutrophil infiltration returned to baseline in the stimulated leg following training.

Finding an effective rehabilitative modality that does not evoke severe dyspnoea is indeed of great interest to clinicians. The DICES trial aims to identify the optimal training modality by studying the efficacy of high-frequency neuromuscular electrical stimulation (NMES), and low-frequency NMES or strength training in severely dyspnoeic individuals with COPD with quadriceps muscle weakness at baseline. We have some queries regarding the data analysis employed by Sillen et al .1 A power calculation is described in the online supplement which is based …