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RationaleDietary nitrate supplementation improves skeletal muscle oxygen utilisation and vascular endothelial function. We hypothesised that these effects might be sufficient to improve exercise performance in patients with COPD and hypoxia severe enough to require supplemental oxygen.MethodsWe conducted a single-centre, double-blind, placebo-controlled, cross-over study, enrolling adults with COPD who were established users of long-term oxygen therapy. Participants performed an endurance shuttle walk test, using their prescribed oxygen, 3 hours after consuming either 140 mL of nitrate-rich beetroot juice (BRJ) (12.9 mmol nitrate) or placebo (nitrate-depleted BRJ). Treatment order was allocated (1:1) by computer-generated block randomisation.MeasurementsThe primary outcome was endurance shuttle walk test time. The secondary outcomes included area under the curve to isotime for fingertip oxygen saturation and heart rate parameters during the test, blood pressure, and endothelial function assessed using flow-mediated dilatation. Plasma nitrate and nitrite levels as well as FENO were also measured.Main results20 participants were recruited and all completed the study. Nitrate-rich BRJ supplementation prolonged exercise endurance time in all participants as compared with placebo: median (IQR) 194.6 (147.5–411.7) s vs 159.1 (121.9–298.5) s, estimated treatment effect 62 (33–106) s (p<0.0001). Supplementation also improved endothelial function: NR-BRJ group +4.1% (−1.1% to 14.8%) vs placebo BRJ group −5.0% (−10.6% to –0.6%) (p=0.0003).ConclusionAcute dietary nitrate supplementation increases exercise endurance in patients with COPD who require supplemental oxygen. Trial registration number ISRCTN14888729.

Background A polymorphism (rs35705950) 3 kb upstream of MUC5B, the gene encoding Mucin 5 subtype B, has been shown to be associated with familial and sporadic idiopathic pulmonary fibrosis (IPF). We set out to verify whether this variant is also a risk factor for fibrotic lung disease in other settings and to confirm the published findings in a UK Caucasian IPF population. Methods Caucasian UK healthy controls (n=416) and patients with IPF (n=110), sarcoidosis (n=180) and systemic sclerosis (SSc) (n=440) were genotyped to test for association. The SSc and sarcoidosis cohorts were subdivided according to the presence or absence of fibrotic lung disease. To assess correlation with disease progression, time to decline in forced vital capacity and/or lung carbon monoxide transfer factor was used in the IPF and SSc groups, while a persistent decline at 4 years since baseline was evaluated in patients with sarcoidosis. Results A significant association of the MUC5B promoter single nucleotide polymorphism with IPF (p=2.04×10–17; OR 4.90, 95% CI 3.42 to 7.03) was confirmed in this UK population. The MUC5B variant was not a risk factor for lung fibrosis in patients with SSc or sarcoidosis and did not predict more rapidly progressive lung disease in any of the groups. Rather, a trend for a longer time to decline in forced vital capacity was observed in patients with IPF. Conclusions We confirm the MUC5B variant association with IPF. We did not observe an association with lung fibrosis in the context of SSc or sarcoidosis, potentially highlighting fundamental differences in genetic susceptibility, although the limited subgroup numbers do not allow a definitive exclusion of an association.

BackgroundOscillatory positive expiratory pressure (OPEP) devices are intended to facilitate sputum clearance and reduce cough, but there is limited evidence for their effectiveness in COPD, or to guide patient selection. We aimed to assess the impact of OPEP therapy on quality of life and objective measures of cough and sleep disturbance in patients with COPD with regular sputum production.MethodsWe enrolled stable patients with COPD, who reported sputum production every day or most days, into an assessor-blind, parallel-group, randomised controlled trial comparing 3 months of using an Acapella device against usual care (including use of the active cycle of breathing technique). The primary outcome was cough-related quality of life measured using the Leicester Cough Questionnaire (LCQ). Secondary outcomes included fatigue (Functional Assessment of Chronic Illness Therapy, FACIT score) and generic quality of life (EuroQol-5 Dimensions, EQ-5D). In a substudy (n=45), objective monitoring of cough and disturbance/movement during sleep were also available.Results122 participants (61/61 OPEP/control) were recruited, 40% female, 17% smokers, FEV1 38 (25–56)% predicted, and age 62±10 years. 103 completed the study (55/48 OPEP/control). Use of OPEP was associated with an improvement in LCQ compared with controls; MD (95% CI) 1.03 (0.71 to 2.10); (p=0.03), FACIT score 4.68 (1.34 to 8.02); (p<0.001) and EQ-5D 4.00 (0.49 to 19.75); (p=0.04). There was also an improvement in cough frequency −60 (−43 to −95) coughs/24 hours (p<0.001), but no statistically significant effect on sleep disturbance was identified.ConclusionsRegular use of an Acapella device improves symptoms and quality of life in people with COPD who produce sputum daily or most days.Trial registration number ISRCTN44651852.

RationaleDietary nitrate supplementation has been proposed as a strategy to improve exercise performance, both in healthy individuals and in people with COPD. We aimed to assess whether it could enhance the effect of pulmonary rehabilitation (PR) in COPD.MethodsThis double-blind, placebo-controlled, parallel group, randomised controlled study performed at four UK centres, enrolled adults with Global Initiative for Chronic Obstructive Lung Disease grade II–IV COPD and Medical Research Council dyspnoea score 3–5 or functional limitation to undertake a twice weekly 8-week PR programme. They were randomly assigned (1:1) to either 140 mL of nitrate-rich beetroot juice (BRJ) (12.9 mmol nitrate), or placebo nitrate-deplete BRJ, consumed 3 hours prior to undertaking each PR session. Allocation used computer-generated block randomisation.MeasurementsThe primary outcome was change in incremental shuttle walk test (ISWT) distance. Secondary outcomes included quality of life, physical activity level, endothelial function via flow-mediated dilatation, fat-free mass index and blood pressure parameters.Results165 participants were recruited, 78 randomised to nitrate-rich BRJ and 87 randomised to placebo. Exercise capacity increased more with active treatment (n=57) than placebo (n=65); median (IQR) change in ISWT distance +60 m (10, 85) vs +30 m (0, 70), estimated treatment effect 30 m (95% CI 10 to 40); p=0.027. Active treatment also impacted on systolic blood pressure: treatment group −5.0 mm Hg (−5.0, –3.0) versus control +6.0 mm Hg (−1.0, 15.5), estimated treatment effect −7 mm Hg (95% CI 7 to −20) (p<0.0005). No significant serious adverse events or side effects were reported.ConclusionsDietary nitrate supplementation appears to be a well-tolerated and effective strategy to augment the benefits of PR in COPD.Trial registration number ISRCTN27860457.

Lung volume reduction surgery improves survival in selected patients with emphysema, and has generated interest in bronchoscopic approaches that might achieve the same effect with less morbidity and mortality. Previous trials with endobronchial valves have yielded modest group benefits because when collateral ventilation is present it prevents lobar atelectasis. We did a single-centre, double-blind sham-controlled trial in patients with both heterogeneous emphysema and a target lobe with intact interlobar fissures on CT of the thorax. We enrolled stable outpatients with chronic obstructive pulmonary disease who had a forced expiratory volume in 1 s (FEV1) of less than 50% predicted, significant hyperinflation (total lung capacity >100% and residual volume >150%), a restricted exercise capacity (6 min walking distance <450 m), and substantial breathlessness (MRC dyspnoea score ≥3). Participants were randomised (1:1) by computer-generated sequence to receive either valves placed to achieve unilateral lobar occlusion (bronchoscopic lung volume reduction) or a bronchoscopy with sham valve placement (control). Patients and researchers were masked to treatment allocation. The study was powered to detect a 15% improvement in the primary endpoint, the FEV1 3 months after the procedure. Analysis was on an intention-to-treat basis. The trial is registered at controlled-trials.com, ISRCTN04761234. 50 patients (62% male, FEV1 [% predicted] mean 31·7% [SD 10·2]) were enrolled to receive valves (n=25) or sham valve placement (control, n=25) between March 1, 2012, and Sept 30, 2013. In the bronchoscopic lung volume reduction group, FEV1 increased by a median 8·77% (IQR 2·27–35·85) versus 2·88% (0–8·51) in the control group (Mann-Whitney p=0·0326). There were two deaths in the bronchoscopic lung volume reduction group and one control patient was unable to attend for follow-up assessment because of a prolonged pneumothorax. Unilateral lobar occlusion with endobronchial valves in patients with heterogeneous emphysema and intact interlobar fissures produces significant improvements in lung function. There is a risk of significant complications and further trials are needed that compare valve placement with lung volume reduction surgery. Efficacy and Mechanism Evaluation Programme, funded by the Medical Research Council (MRC) and managed by the National Institute for Health Research (NIHR) on behalf of the MRC-NIHR partnership.

IntroductionOscillating positive expiratory pressure (OPEP) devices are intended to facilitate sputum clearance in chronic obstructive pulmonary disease (COPD), but there is uncertainty as to their place in treatment pathways. We aimed to review the existing literature to establish the evidence base for their use.MethodsA systematic search of records up to March 2020 was performed on PubMed, CINAHL, Medline (Ovid), Cochrane and Embase to retrieve clinical trials that evaluated the efficacy of OPEP devices in patients with COPD. Two independent reviewers retrieved the titles, abstracts and full texts, and completed the data extraction.ResultsFollowing full-text review of 77 articles, eight (six randomised control trials and 2 cross-over studies) were eligible for inclusion. Pooled analysis showed low-grade evidence that the use of OPEP devices was associated with decreased COPD symptoms and exacerbations (OR 0.37, 95% CI 0.19 to 0.72), and enhanced exercise capacity; 6 min walk distance (mean difference (95% CI), 49.8 m (14.2 m to 85.5 m); p=0.009]). However, studies were mostly short term with the majority having a high risk of bias. The average acceptance, completion and drop-out rates were 82%, 91% and 8%, respectively.ConclusionThe use of OPEP devices can have a positive impact in COPD, but confidence in effect sizes is low and there is a need for further, higher quality studies to examine their long-term efficacy in COPD as well as to identify specific patient phenotypes that are more likely to respond.PROSPERO registration numberCRD 42016041835.

Increasing physical activity is a key therapeutic aim in chronic obstructive pulmonary disease (COPD). Pulmonary rehabilitation (PR) improves exercise capacity, but there is conflicting evidence regarding its ability to improve physical activity levels. To determine whether using pedometers as an adjunct to PR can enhance time spent in at least moderate-intensity physical activity (time expending ≥3 metabolic equivalents [METs]) by people with COPD. In this single-blind randomized controlled trial, participants were assigned 1:1 to receive a control intervention (PR comprising 8 wk, two supervised sessions per week) or the trial intervention (PR plus pedometer-directed step targets, reviewed weekly for 8 wk). In the randomization process, we used minimization to balance groups for age, sex, FEV percent predicted, and baseline exercise capacity and physical activity levels. Outcome assessors and PR therapists were blinded to group allocation. The primary analysis was based on the intention-to-treat principle. The primary outcome was change from baseline to 8 weeks in accelerometer-measured daily time expending at least 3 METs. A total of 152 participants (72% male; mean [SD] FEV percent predicted, 50.5% [21.2]; median [first quartile, third quartile] time expending ≥3 METs, 46 [21, 92] min) were enrolled and assigned to the intervention (n = 76) or control (n = 76) arm. There was no significant difference in change in time expending at least 3 METs between the intervention and control groups at 8 weeks (median [first quartile, third quartile] difference, 0.5 [-1.0, 31.0] min; P = 0.87) or at the 6-month follow-up (7.0 [-9, 27] min; P = 0.16). Pedometer-directed step-count targets during an outpatient PR program did not enhance moderate-intensity physical activity levels in people with COPD. Clinical trial registered with www.clinicaltrials.gov (NCT01719822).

ObjectivesTo develop and validate a tool to predict the risk of an older adult experiencing medication-related harm (MRH) requiring healthcare use following hospital discharge.Design, setting, participantsMulticentre, prospective cohort study recruiting older adults (≥65 years) discharged from five UK teaching hospitals between 2013 and 2015.Primary outcome measureParticipants were followed up for 8 weeks in the community by senior pharmacists to identify MRH (adverse drug reactions, harm from non-adherence, harm from medication error). Three data sources provided MRH and healthcare use information: hospital readmissions, primary care use, participant telephone interview. Candidate variables for prognostic modelling were selected using two systematic reviews, the views of patients with MRH and an expert panel of clinicians. Multivariable logistic regression with backward elimination, based on the Akaike Information Criterion, was used to develop the PRIME tool. The tool was internally validated.Results1116 out of 1280 recruited participants completed follow-up (87%). Uncertain MRH cases (‘possible’ and ‘probable’) were excluded, leaving a tool derivation cohort of 818. 119 (15%) participants experienced ‘definite’ MRH requiring healthcare use and 699 participants did not. Modelling resulted in a prediction tool with eight variables measured at hospital discharge: age, gender, antiplatelet drug, sodium level, antidiabetic drug, past adverse drug reaction, number of medicines, living alone. The tool’s discrimination C-statistic was 0.69 (0.66 after validation) and showed good calibration. Decision curve analysis demonstrated the potential value of the tool to guide clinical decision making compared with alternative approaches.ConclusionsThe PRIME tool could be used to identify older patients at high risk of MRH requiring healthcare use following hospital discharge. Prior to clinical use we recommend the tool’s evaluation in other settings.

Introduction Acute muscle wasting in the critically ill is common and associated with significant morbidity and mortality. Although some aetiological factors are recognised and muscle wasting can be detected early with ultrasound, it not possible currently to predict in advance of muscle loss those who will develop muscle wasting. The ability to stratify the risk of muscle wasting associated with critical illness prior to it becoming clinically apparent would provide the opportunity to predict prognosis more accurately and to intervene at an early stage. MicroRNAs are small non-coding RNAs that modulate post-transcriptional regulation of translation, some are tissue specific and can be detected and quantified in plasma. We hypothesised that certain plasma microRNAs could be biomarkers of ICU acquired muscle weakness. Methods Plasma levels of selected microRNAs were measured in pre- and post-operative samples from a previously reported prospective observational study of 42 patients undergoing elective high-risk cardiothoracic surgery, 55% of whom developed muscle wasting. Results The rise in miR-181a was significantly higher on the second post-operative day in those who developed muscle wasting at 1 week compared to those who did not (p = 0.03). A rise in miR-181a of greater than 1.7 times baseline had 91% specificity and 56% sensitivity for subsequent muscle wasting. Other microRNAs did not show significant differences between the groups. Conclusion Plasma miR-181a deserves further investigation as a potential biomarker of muscle wasting. Additionally, since mir-181a is involved in both regulation of inflammation and muscle regeneration and differentiation; our observation therefore also suggests directions for future research.

Objectives Cardiovascular magnetic resonance (CMR) cine imaging by compressed sensing (CS) is promising for patients unable to tolerate long breath-holding. However, the need for a steady-state free-precession (SSFP) preparation cardiac cycle for each slice extends the breath-hold duration (e.g. for 10 slices, 20 cardiac cycles) to an impractical length. We investigated a method reducing breath-hold duration by half and assessed its reliability for biventricular volume analysis in a pediatric population. Methods Fifty-five consecutive pediatric patients (median age 12 years, range 7–17) referred for assessment of congenital heart disease or cardiomyopathy were included. Conventional multiple breath-hold SSFP short-axis (SAX) stack cines served as the reference. Real-time CS SSFP cines were applied without the steady-state preparation cycle preceding each SAX cine slice, accepting the limitation of omitting late diastole. The total acquisition time was 1 RR interval/slice. Volumetric analysis was performed for conventional and “single-cycle-stack-advance” (SCSA) cine stacks. Results Bland–Altman analyses [bias (limits of agreement)] showed good agreement in left ventricular (LV) end-diastolic volume (EDV) [3.6 mL (− 5.8, 12.9)], LV end-systolic volume (ESV) [1.3 mL (− 6.0, 8.6)], LV ejection fraction (EF) [0.1% (− 4.9, 5.1)], right ventricular (RV) EDV [3.5 mL (− 3.34, 10.0)], RV ESV [− 0.23 mL (− 7.4, 6.9)], and RV EF [1.70%, (− 3.7, 7.1)] with a trend toward underestimating LV and RV EDVs with the SCSA method. Image quality was comparable for both methods ( p = 0.37). Conclusions LV and RV volumetric parameters agreed well between the SCSA and the conventional sequences. The SCSA method halves the breath-hold duration of the commercially available CS sequence and is a reliable alternative for volumetric analysis in a pediatric population. Key Points • Compressed sensing is a promising accelerated cardiovascular magnetic resonance imaging technique. • We omitted the steady-state preparation cardiac cycle preceding each cine slice in compressed sensing and achieved an acquisition speed of 1 RR interval/slice. • This modification called “single-cycle-stack-advance” enabled the acquisition of an entire short-axis cine stack in a single short breath hold. • When tested in a pediatric patient group, the left and right ventricular volumetric parameters agreed well between the “single-cycle-stack-advance” and the conventional sequences.