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A Chamilya H Perera,1,2 Akila R Jayamaha,1,2 Amy V Jones,1,3 Zainab K Yusuf,1,3 KDC Upendra Wijayasiri,4 Thamara Amarasekara,5 Anthony Seneviratne,6 Ruhme Miah,1,3 Andy Barton,1 Michael C Steiner,1,3 Savithri W Wimalasekara,7 Mark W Orme,1,3,* Sally J Singh1,3,* 1Department of Respiratory Science, University of Leicester, Leicester, UK; 2Faculty of Nursing, KIU, Colombo, Sri Lanka; 3Centre for Exercise and Rehabilitation Science, NIHR Leicester Biomedical Research Centre-Respiratory, University Hospitals of Leicester NHS Trust, Leicester, UK; 4National Hospital of Sri Lanka, Colombo, Sri Lanka; 5Faculty of Allied Health Sciences, University of Sri Jayewardenepura, Nugegoda, Sri Lanka; 6Primary Care Respiratory Group, Colombo, Sri Lanka; 7Faculty of Medical Sciences, University of Sri Jayewardenepura, Nugegoda, Sri Lanka*These authors contributed equally to this workCorrespondence: A Chamilya H Perera, Email chp22@leicester.ac.ukIntroduction: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide, corresponding to 5% of all deaths globally, with more than 90% occurring in low- and middle-income countries (LMIC). Pulmonary Rehabilitation (PR) is a routine clinical service for COPD management, often used in western countries. At present, there is no formal PR in Sri Lanka; a culturally appropriate programme is required that considers the views of adults living with COPD and healthcare providers (HCPs) who would be involved in the referral or delivery of PR.Purpose: The study assessed the attitudes and preferences of Sri Lankan adults living with COPD and attitudes and barriers of HCPs making PR referrals to inform an appropriate PR programme.Methodology: A descriptive cross-sectional study was conducted with the ethical clearance of Colombo south teaching hospital ERC committee (ERC Application No. 674), among adults living with COPD and HCPs in Colombo district, Sri Lanka. Adults living with COPD were enrolled August 2018–December 2018 using systematic random sampling from Colombo South Teaching Hospital and were assessed using a pre-tested interviewer administered questionnaire. HCPs were recruited from Colombo South Teaching Hospital and Jaffna Teaching Hospital between August 2018 and November 2018 and assessed using self-administered questionnaire.Results: Responses from 138 adults living with COPD (53% male, 52% aged ≥ 60 years) and 277 HCPs were collected. The majority of adults living with COPD were interested in participating in PR (80%) and would prefer PR to be delivered in a supervised, group-based, setting with hospital-based (49%). Adults living with COPD were mostly (73%) willing to spend between 30 minutes and 2 hours per day for PR-related activities. Among HCPs, 234 (83%) were nurses, 29 (11%) were hospital doctors and 14 (4%) were family physicians. The majority of HCPs stated that they were unsure about referring adults with COPD for PR (86%) and 61% stated considerable uncertainty regarding the availability of resources for PR. Nearly half of the HCPs (45%) felt they were not adequately prepared to refer adults living with COPD to PR programmes. Most HCPs (92%) reported that PR is worthwhile for COPD management.Conclusion: Adults living with COPD in Sri Lanka are willing to attend PR and would prefer group-based programmes delivered in hospitals, under the supervision of qualified personnel. Awareness about PR is poor and there is a lack of readiness to refer to PR amongst HCPs. There is an urgent need to train HCPs on PR and develop effective referral strategies to support PR uptake and delivery for adults living with COPD in Sri Lanka.Keywords: pulmonary rehabilitation, opinion, patients, healthcare providers

Winceslaus Katagira,1 Amy V Jones,2,3 Mark W Orme,2,3 Zainab K Yusuf,2,3 Pauline Ndagire,1 Jaliah Nanyonga,1 Richard Kasiita,4 Josephine N Kasolo,5 Ruhme B Miah,2,3 Michael C Steiner,2,3 Rupert Jones,6 Andy Barton,2 Bruce Kirenga,1 Sally J Singh2,3 1Makerere University Lung Institute, Kampala, Uganda; 2Department of Respiratory Sciences, University of Leicester, Leicester, UK; 3Centre for Exercise and Rehabilitation Science (CERS), NIHR Leicester Biomedical Research Centre – Respiratory, University Hospitals of Leicester NHS Trust - Leicester, Leicester, UK; 4Department of Physiotherapy, Mulago Hospital, Kampala, Uganda; 5Physiology Department, College of Health Sciences, Makerere University, Kampala, Uganda; 6University of Plymouth, Plymouth, UKCorrespondence: Winceslaus Katagira Email wincegira@gmail.comIntroduction: Pulmonary rehabilitation (PR) is a low cost, high impact intervention that ameliorates the disability associated with chronic respiratory diseases (CRD). PR is becoming increasingly recognized in low resource settings where the burden of CRD is rapidly increasing. To aid the implementation of PR in Uganda, we conducted a study to assess the attitudes and opinions towards PR among patients with CRD in Uganda and explore barriers faced by health care workers (HCWs) in referring to PR.Methods: A cross-sectional study comprising two survey populations: people living with CRD and HCWs regarded as potential PR referrers and PR deliverers. This exploratory study sought initial opinions and thoughts regarding PR, as well as baseline knowledge and potential barriers faced in the referral process.Results: Overall, 30 HCWs (53% female, 43% doctors) and 51 adults with CRD (63% female) participated in the survey. Among those with CRD, the majority reported breathlessness as a major problem (86%) and breathlessness affected their ability to do paid and unpaid work (70%). Interest in PR was high amongst adults with CRD (92%) with preference for a hospital-based programme (67%) as opposed to community-based (16%) or home-based (17%). All HCWs considered PR important in lung disease management, but 77% do not refer patients due to a lack of information about PR. HCWs’ free-text responses identified the need for training in PR, patient education and streamlining the referral process as key elements to develop successful PR referral services.Conclusion: To successfully set up a PR service for people with CRD in Uganda, there is a great need for appropriately tailored training and education of prospective referrers about CRD and PR programs. Educating patients about the benefits of PR as well as streamlining the referral process is critical in expanding PR services across Uganda to fulfill this unmet need.Keywords: respiratory rehabilitation, chronic chest symptoms, medical workers, enthusiasm, knowledge, training

Philip W Stone,1 Katherine Hickman,2 Michael C Steiner,3 C Michael Roberts,4,5 Jennifer K Quint,1,* Sally J Singh3,* 1National Heart and Lung Institute, Imperial College London, London, UK; 2West Yorkshire and Harrogate Health and Care Partnership, Bradford, Yorkshire, UK; 3NIHR Leicester Respiratory Biomedical Research Centre, Department of Respiratory Sciences, University of Leicester, Leicester, UK; 4Royal College of Physicians, London, UK; 5QMUL, London, UK*These authors contributed equally to this workCorrespondence: Philip W Stone Email p.stone@imperial.ac.ukBackground: A large proportion of people with COPD are not referred to pulmonary rehabilitation (PR) despite its proven benefits. No previous studies have examined predictors of referral to PR.Objective: To determine the characteristics of people with COPD associated with referral to PR.Methods: Cross-sectional analysis of a primary care cohort of 82,696 Welsh people with COPD generated as part of a UK national audit of COPD care. Data represent care received by patients as of 31/03/2017. Referral to PR was defined as any code in the patient record indicating referral to PR in the last 3 years. Potential predictors of referral to PR were chosen based on clinical judgement and data availability. Independent predictors of PR referral were determined using backward stepwise mixed-effects logistic regression with a random effect for practice. Variables assessed were: age, gender, deprivation, MRC recorded in past year, MRC grade, smoking status recorded in past year, smoking status, number of exacerbations in past year, inhaled therapy prescription, influenza vaccination, and comorbidities of diabetes, hypertension, coronary heart disease, stroke, heart failure, lung cancer, asthma, bronchiectasis, depression, anxiety, severe mental illness, osteoporosis, and painful condition.Results: A total of 13,297 people (16%) with COPD were referred from primary care for PR. Patients with a comorbidity of bronchiectasis or depression, MRC recorded in the last year, higher MRC grade, more exacerbations in the last year, a greater level of inhaled therapy, an influenza vaccination, or were an ex-smoker had significantly higher odds of referral to PR. Patients that were older, female, more deprived, or had a comorbidity of diabetes, asthma, or painful condition had significantly lower odds of referral to PR.Conclusion: Generally appropriate patients are being prioritised for PR referral; however, it is concerning that women, current smokers, and more deprived patients appear to have lower odds of referral.Keywords: COPD, chronic obstructive pulmonary disease, GP, general practitioner, observational study

Lorna E Latimer,1,2,* Despina Constantin,3–5,* Neil J Greening,1,2 Lori Calvert,6 Manoj K Menon,7 Michael C Steiner,1,2,* Paul L Greenhaff3–5,*1Department of Respiratory Sciences, University of Leicester, Leicester, UK; 2Institute for Lung Health, National Institute for Health Research (NIHR) Leicester Biomedical Research Centre - Respiratory, Glenfield Hospital, Leicester, UK; 3Medical Research Council/Arthritis Research UK (MRC/ARUK) Centre for Musculoskeletal Ageing Research, University of Nottingham, Nottingham, UK; 4Centre for Sport, Exercise and Osteoarthritis Research, University of Nottingham, Nottingham, UK; 5NIHR Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, UK; 6Peterborough and Stamford Hospitals NHS Foundation Trust, Peterborough City Hospital, Bretton, UK; 7Barking, Havering and Redbridge University Hospitals NHS Trust, Chest Clinic, King George Hospital, Ilford, UK*These authors contributed equally to this work 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

Mark W Orme,1–3 Michael C Steiner,1–3 Mike D Morgan,1 Andrew P Kingsnorth,2,3 Dale W Esliger,2–4 Sally J Singh,1–3,* Lauren B Sherar2–4,* 1Centre for Exercise and Rehabilitation Science, NIHR Leicester Biomedical Research Centre – Respiratory, Leicester, UK; 2School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK; 3National Centre for Sport and Exercise Medicine, Loughborough, UK; 4NIHR Leicester Biomedical Research Centre, Leicester, UK *These authors contributed equally to this work Background: The constructs and interdependency of physical behaviors are not well described and the complexity of physical activity (PA) data analysis remains unexplored in COPD. This study examined the interrelationships of 24-hour physical behaviors and investigated their associations with participant characteristics for individuals with mild–moderate airflow obstruction and healthy control subjects. Patients and methods: Vigorous PA (VPA), moderate-to-vigorous PA (MVPA), light PA (LPA), stationary time (ST), average movement intensity (vector magnitude counts per minute), and sleep duration for 109 individuals with COPD and 135 healthy controls were obtained by wrist-worn accelerometry. Principal components analysis (PCA) examined interrelationships of physical behaviors to identify distinct behavioral constructs. Using the PCA component loadings, linear regressions examined associations with participant (+, positive correlation; -, negative correlation), and were compared between COPD and healthy control groups. Results: For both groups PCA revealed ST, LPA, and average movement intensity as distinct behavioral constructs to MVPA and VPA, labeled “low-intensity movement” and “high-intensity movement,” respectively. Sleep was also found to be its own distinct behavioral construct. Results from linear regressions supported the identification of distinct behavioral constructs from PCA. In COPD, low-intensity movement was associated with limitations with mobility (-), daily activities (-), health status (+), and body mass index (BMI) (-) independent of high-intensity movement and sleep. High-intensity movement was associated with age (-) and self-care limitations (-) independent of low-intensity movement and sleep. Sleep was associated with gender (0= female, 1= male; [-]), lung function (-), and percentage body fat (+) independent of low-intensity and high-intensity movement. Conclusion: Distinct behavioral constructs comprising the 24-hour day were identified as “low-intensity movement,” “high-intensity movement,” and “sleep” with each construct independently associated with different participant characteristics. Future research should determine whether modifying these behaviors improves health outcomes in COPD. Keywords: accelerometry, COPD, physical activity, principal components analysis, sedentary behavior

Linzy Houchen-Wolloff,1 Johanna EA Williams,1 Ruth H Green,2 Gerrit Woltmann,2 Michael C Steiner,1,2 Louise Sewell,1 Michael DL Morgan,1,2 Sally J Singh1 1NIHR Leicester Biomedical Research Centre – Respiratory, University Hospitals of Leicester NHS Trust, Glenfield Hospital, Leicester, 2Department of Respiratory Medicine, University Hospitals of Leicester NHS Trust, Glenfield Hospital, Leicester, UK Rationale: Pulmonary rehabilitation (PR) in patients with COPD has consistently been shown to produce benefits in exercise capacity, symptoms, and health status. The data surrounding survival following PR are less clear. Our aims were to compare the long-term survival in two cohorts of patients referred for PR; those who successfully completed PR, and a comparator group constructed from patients who either did not complete PR or did not start the program. Additionally, we compared survival between those people who were able to achieve a clinically meaningful improvement in exercise capacity (incremental shuttle walking test) following PR with those who were not. Methods: A retrospective longitudinal analysis of clinical service outcomes was conducted to compare the long-term survival in “completers” and “non-completers” of rehabilitation at two hospitals within the University Hospitals of Leicester NHS Trust from January 1, 2000 to February 23, 2012. For “completers”, we also analyzed survival in those meeting (and not meeting) the desired level of change in the incremental shuttle walking test (≥50 m vs 50 m change in walking distance) was also associated with improved survival. Keywords: survival, COPD, exercise

Ali Hakamy,1,2 Tricia M McKeever,2 Michael C Steiner,3 C Michael Roberts,4 Sally J Singh,3 Charlotte E Bolton1 1Nottingham Respiratory Research Unit, NIHR Nottingham Biomedical Research Centre, 2Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, Nottingham, 3Leicester Respiratory Biomedical Research Unit, Institute for Lung Health, University Hospitals of Leicester NHS Trust, Leicester, 4Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK Abstract: Our aim was to evaluate the use and impact of the practice walk test on enrolment, completion, and clinical functional response to pulmonary rehabilitation (PR) using the 2015 UK National Chronic Obstructive Pulmonary Disease (COPD) Pulmonary Rehabilitation audit data. Patients were assessed according to whether a baseline practice walk test was performed or not. Study outcomes included use of the practice walk test, baseline and change in incremental shuttle walk test distance (ISWD) or 6-minute walk test distance (6MWD), and enrolment to and completion of PR program. Of 7,355 patients, only 1,666 (22.6%) had a baseline practice test. At baseline, the practice walk test group walked further as compared to the no practice walk test group: ISWD, 17.9 m [95% confidence interval (CI) 8.2–27.5 m] and 6MWD, 34.8 m (95% CI 24.7–44.9 m). The practice walk test group were 2.2 times (95% CI 1.8–2.6) more likely to enroll and 17% (95% CI 1.03–1.34) more likely to complete PR. Although the change in ISWD and 6MWD with PR was lower in the practice walk test group, they walked further at discharge assessment. Only 22.6% of the patients in the 2015 National PR audit had a practice walk test at assessment. Those who did had better enrolment, completion, and better baseline walking distance, from which the prescription is set. Keywords: pulmonary rehabilitation, COPD, functional performance test, functional exercise test

Bethan L Barker,1 Susan McKenna,1 Vijay Mistry,1 Mitesh Pancholi,1 Hemu Patel,2 Koirobi Haldar,3 Michael R Barer,3 Ian D Pavord,4 Michael C Steiner,1 Christopher E Brightling,1 Mona Bafadhel4 1Institute for Lung Health, NIHR Respiratory Biomedical Research Unit, Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, United Kingdom; 2Department of Clinical Microbiology, University Hospitals of Leicester NHS Trust, Leicester, United Kingdom; 3Department of Infection, Immunity, and Inflammation, University of Leicester, Leicester, United Kingdom; 4Respiratory Medicine Unit, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus, Oxford, United Kingdom Background: Nutritional depletion is an important manifestation of chronic obstructive pulmonary disease (COPD), which has been related to systemic inflammation. It remains unclear to what degree airway inflammation contributes to the presence or progression of nutritional depletion. Objectives: To determine whether airway inflammation and lung bacterial colonization are related to nutritional status or predict progressive weight loss and muscle atrophy in patients with COPD. Methods: Body composition using dual energy X-ray absorptiometry, indices of airway inflammation, and bacterial colonization were measured in 234 COPD patients. Systemic inflammation was assessed from serum C reactive protein (CRP) and circulating total and differential leukocyte counts. Nutritional depletion was defined as a body mass index (BMI) less than 21 kg/m2 and/or fat-free mass index (FFMI) less than 15 or 17 kg/m2 in women and men, respectively. FFMI was calculated as the fat-free mass (FFM) corrected for body surface area. Measurements were repeated in 94 patients after a median 16-month follow-up. Regression analysis was used to assess the relationships of weight change and FFM change with indices of bacterial colonization and airway and systemic inflammation. Results: Nutritional depletion occurred in 37% of patients. Lung function was worsened in patients with nutritional depletion compared to those without (forced expiratory volume in 1 second 1.17 L versus 1.41 L, mean difference 0.24, 95% confidence interval 0.10 to 0.38, P

Linzy Houchen-Wolloff,1 Carolyn J Sandland,1 Samantha L Harrison,1 Manoj K Menon,1 Mike D Morgan,1 Michael C Steiner,1 Sally J Singh1,21Centre for Exercise and Rehabilitation Science, Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester, UK; 2Faculty of Health and Life Sciences, Coventry University, Coventry, UKBackground: It is proposed that resistance training (RT) does not activate the cardiopulmonary system to the same extent as whole-body exercise. This is important for patients with chronic obstructive pulmonary disease (COPD) who are ventilatory limited.Objective: The aim was to assess the ventilatory response to an isokinetic quadriceps RT program in people with COPD and healthy controls.Design: Observational.Registration number: ISRCTN22764439.Setting: Outpatient, university teaching hospital.Participants and outcome measures: People with COPD (n=14) and healthy controls (n=11) underwent breath-by-breath analysis of their ventilation during an RT session (five sets of 30 maximal knee extensions at 180°/sec). Subjects performed a maximal cycle ergometry test (CET) at baseline. Peak ventilation (VE; L/min) and oxygen consumption (VO2; mL/kg/min) were collected. The same system measured VO2 and VE during the RT session. Parameters are presented as a percentage of the maximal CET. Isokinetic workload, symptom scores, heart rate (HR), and oxygen saturation were documented post-training.Results: People with COPD worked at higher percentages of their maximal capacity than controls (mean range between sets 1–5 for VO2 =49.1%–60.1% [COPD], 45.7%–51.43% [controls] and for VE =57.6%–72.2% [COPD], 49.8%–63.6% [controls]), although this was not statistically significant (P>0.1 in all cases). In absolute terms, the difference between groups was only significant for actual VO2 on set 2 (P

Background: Impaired skeletal muscle function contributes to exercise intolerance in patients with COPD. Exercise-induced oxidative stress may initiate or accelerate impaired muscle function. Dichloroacetate (DCA) activates muscle pyruvate dehydrogenase complex (PDC) at rest, reducing inertia in mitochondrial energy delivery at the onset of exercise and thereby diminishing anaerobic energy production. This study aimed to determine whether DCA infusion also may reduce exercise-induced systemic oxidative stress and inflammatory response in patients with COPD.Methods: A randomized, double-blind crossover design was used in which 13 patients with COPD performed maximal cycle exercise after an IV infusion of DCA (50 mg/kg body mass) or saline solution (placebo). Venous blood was sampled before exercise, and immediately, 30 min, and 2 h after exercise. Urine samples were obtained before and 2 h after exercise.Results: Peak workload improved significantly after DCA infusion compared to placebo (10%; p < 0.01). Urinary uric acid levels after exercise were significantly lower in the DCA condition than in the placebo condition, whereas no significant difference was observed for urinary malondialdehyde levels. Oxidized glutathione (GSSG) levels were significantly increased 2 h after exercise in the placebo condition (p < 0.02) but not after DCA infusion. No changes in reduced glutathione (GSH), GSSG/GSH ratio, and superoxide dismutase activity were observed. Plasma interleukin (IL)-6 levels significantly increased 2 h after exercise only in the DCA condition (p < 0.01).Conclusions: This study shows that improved performance after a pharmacologic intervention known to activate PDC was accompanied by an enhanced IL-6 response and a limited reduction in exercise-induced systemic oxidative stress. [ABSTRACT FROM AUTHOR]

One key component of study design in population genetics is the "geographic breadth" of a sample (i.e., how broad a region across which individuals are sampled). How the geographic breadth of a sample impacts observations of rare, deleterious variants is unclear, even though such variants are of particular interest for biomedical and evolutionary applications. Here, in order to gain insight into the effects of sample design on ascertained genetic variants, we formulate a stochastic model of dispersal, genetic drift, selection, mutation, and geographically concentrated sampling. We use this model to understand the effects of the geographic breadth of sampling effort on the discovery of negatively selected variants. We find that samples which are more geographically broad will discover a greater number variants as compared geographically narrow samples (an effect we label "discovery"); though the variants will be detected at lower average frequency than in narrow samples (e.g. as singletons, an effect we label "dilution"). Importantly, these effects are amplified for larger sample sizes and moderated by the magnitude of fitness effects. We validate these results using both population genetic simulations and empirical analyses in the UK Biobank. Our results are particularly important in two contexts: the association of large-effect rare variants with particular phenotypes and the inference of negative selection from allele frequency data. Overall, our findings emphasize the importance of considering geographic breadth when designing and carrying out genetic studies, especially at biobank scale.

Background: COPD is characterized by reduced exercise tolerance, and improving physical performance is an important therapeutic goal. A variety of exercise tests are commonly used to assess exercise tolerance, including laboratory and field-based tests. The responsiveness of these various tests to common COPD interventions is yet to be compared, but the results may inform test selection in clinical and research settings., Research Question: What exercise test possesses the greatest sensitivity to change from before to after intervention in patients with COPD?, Study Design and Methods: One hundred fifty-four patients with symptomatic COPD were recruited and randomized (2:1:1) to 6 weeks of long-acting muscarinic antagonist, pulmonary rehabilitation (PR), or usual care. Before and after intervention, participants performed an incremental cycle exercise test and constant work rate cycle test (CWRCT), incremental shuttle walk test and endurance shuttle walk test (ESWT), 6-min walk test, and 4-m gait speed test., Results: One hundred three participants (mean ± SD age, 67 ± 8 years; 75 male participants [73%]; FEV 1 , 50.6 ± 16.8% predicted) completed the study. Significant improvements in the incremental cycle exercise test, CWRCT, incremental cycle exercise test, ESWT, and 6-min walk test results were observed after PR (P < .05), with the greatest improvements seen in the constant work rate protocols (percentages change: CWRCT, 42%; ESWT, 41%)., Interpretation: The ESWT and CWRCT seemed to be the most responsive exercise test protocols to long-acting muscarinic antagonist and PR therapy. The magnitude of change was much greater after a program of rehabilitation compared with bronchodilator therapy., Clinical Trial Registry: International Standard Randomised Controlled Trial Number (ISRCTN): No. 64759523; URL: https://www.isrctn.com/ISRCTN64759523., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: R. T.-S. is a retiree and shareholder of GlaxoSmithKline since 2019. M. A. is a former employee of GlaxoSmithKline. A.H is a former employee of Boehringer Ingelheim (Canada) Ltd. M. C. S reports personal fees and non-financial support from Boehringer Ingelheim and GlaxoSmithKline, outside the submitted work. None declared (T. C.H.-D., M. M. B, M. I. P, M. R, S. A. E, M. D. M, S. J. S)., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

It is commonly reported that rare variants may be more functionally related to complex diseases than common variants. However, individual rare variant association tests remain challenging due to low minor allele frequency in the available samples. This paper proposes an expectation maximization variable selection (EMVS) method to simultaneously detect common and rare variants at the individual variant level using family trio data. TRIO&#95;RVEMVS was assessed in both large (1500 families) and small (350 families) datasets based on simulation. The performance of TRIO&#95;RVEMVS was compared with gene-level kernel and burden association tests that use pedigree data (PedGene) and rare-variant extensions of the transmission disequilibrium test (RV-TDT). At the region level, TRIO&#95;RVEMVS outperformed PedGene and RV-TDT when common variants were included. TRIO&#95;RVEMVS performed competitively with PedGene and outperformed RV-TDT when the analysis was only restricted to rare variants. At the individual variants level, with 1,500 trios, the average true positive rate of individual rare variants that were polymorphic across 500 datasets was 12.20%, and the average false positive rate was 0.74%. In the datasets with 350 trios, the average true and false positive rates of individual rare variants were 13.10% and 1.30%, respectively. When applying TRIO&#95;RVEMVS to real data from the Gabriella Miller Kids First Pediatric Research Program, it identified 3 rare variants in q24.21 and q24.22 associated with the risk of orofacial clefts in the Kids First European population., Competing Interests: The authors have declared that no competing interests exist. K.M. contributed to this article as an employee of the University of Texas Health Science Center and the views expressed no not necessarily represent the views of Regeneron Pharmaceuticals, Inc. This does not alter our adherence to PLOS ONE Polices on sharing data and materials., (Copyright: © 2024 Yu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Rationale: As the prevalence of multimorbidity increases, understanding the impact of isolated comorbidities in people COPD becomes increasingly challenging. A simplified model of common comorbidity patterns may improve outcome prediction and allow targeted therapy., Objectives: To assess whether comorbidity phenotypes derived from routinely collected clinical data in people with COPD show differences in risk of hospitalisation and mortality., Methods: Twelve clinical measures related to common comorbidities were collected during annual reviews for people with advanced COPD and k-means cluster analysis performed. Cox proportional hazards with adjustment for covariates was used to determine hospitalisation and mortality risk between clusters., Measurements and Main Results: In 203 participants (age 66 ± 9 years, 60 % male, FEV 1 %predicted 31 ± 10 %) no comorbidity in isolation was predictive of worse admission or mortality risk. Four clusters were described: cluster A (cardiometabolic and anaemia), cluster B (malnourished and low mood), cluster C (obese, metabolic and mood disturbance) and cluster D (less comorbid). FEV 1 %predicted did not significantly differ between clusters. Mortality risk was higher in cluster A (HR 3.73 [95%CI 1.09-12.82] p = 0.036) and B (HR 3.91 [95%CI 1.17-13.14] p = 0.027) compared to cluster D. Time to admission was highest in cluster A (HR 2.01 [95%CI 1.11-3.63] p = 0.020). Cluster C was not associated with increased risk of mortality or hospitalisation., Conclusions: Despite presence of advanced COPD, we report striking differences in prognosis for both mortality and hospital admissions for different co-morbidity phenotypes. Objectively assessing the multi-system nature of COPD could lead to improved prognostication and targeted therapy for patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Considering a huge burden of chronic respiratory diseases (CRDs) in India, there is a need for locally relevant Pulmonary rehabilitation (PR) services. This cross-sectional survey was aimed to explore the interest, needs and challenges among various stakeholders for PR in Pune city, India. At the outpatient respiratory medicine department of a multi-speciality hospital in Pune, India, 403 eligible people with CRDs were invited to participate in the survey, of which 370 (92%) responded and agreed to participate. (220 males, mean ± SD age 56 ± 15 years). Out of the 370, 323 (87%) people with CRDs were keen to attend PR. In a multiple selection question, there was inclination towards paper-based manuals home-based (70%) and web-based (84%) programs. 207 healthcare providers (HCPs), including physicians, pulmonologists and physiotherapists involved in the care of people living with CRDs across Pune city were invited to participate in the survey. Out of the 207, (80%) of the HCPs believed that PR was an effective management strategy and highlighted the lack of information on PR and need for better understanding of PR (48%) and its referral process. The surveyed stakeholders are ready to take up PR, identifying specific needs around further knowledge of PR, modes of delivery, and referral processes, that could potentially feed the development of relevant PR programs in the Indian healthcare settings., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Rationale: There is conflicting evidence whether aerobic exercise training (AET) reduces pulse wave velocity (PWV) in adults with and without long-term conditions (LTCs)., Objective: To explore whether PWV improves with AET in adults with and without LTC, to quantify the magnitude of any effect and understand the influence of the exercise prescription., Data Sources: CENTRAL, MEDLINE and EMBASE were among the databases searched., Eligibility Criteria: We included studies with a PWV measurement before and after supervised AET of at least 3 weeks duration. Exclusion criteria included resistance exercise and alternative measures of arterial stiffness., Design: Controlled trials were included in a random effects meta-analysis to explore the effect of AET on PWV. Uncontrolled studies were included in a secondary meta-analysis and meta-regression exploring the effect of patient and programme factors on change in PWV. The relevant risk of bias tool was used for each study design., Results: 79 studies (n=3729) were included: 35 controlled studies (21 randomised control trials (RCT) (n=1240) and 12 non-RCT (n=463)) and 44 uncontrolled (n=2026). In the controlled meta- analysis, PWV was significantly reduced following AET (mean (SD) 11 (7) weeks) in adults with and without LTC (mean difference -0.63; 95% CI -0.82 to -0.44; p<0.0001). PWV was similarly reduced between adults with and without LTC (p<0.001). Age, but not specific programme factors, was inversely associated with a reduction in PWV -0.010 (-0.020 to -0.010) m/s, p<0.001., Discussion: Short-term AET similarly reduces PWV in adults with and without LTC. Whether this effect is sustained and the clinical implications require further investigation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Pulmonary rehabilitation programmes including aerobic training improve cardiorespiratory fitness in patients with COPD, but the optimal programme design is unclear. We used random effects additive component network meta-analysis to investigate the relative effectiveness of different programme components on fitness measured by V̇O 2peak in COPD. The included 59 studies involving 2191 participants demonstrated that V̇O 2peak increased after aerobic training of at least moderate intensity with the greatest improvement seen following high intensity training. Lower limb aerobic training (SMD 0.56 95% CI 0.32;0.81, intervention arms=86) and the addition of non-invasive ventilation (SMD 0.55 95% CI 0.04;1.06, intervention arms=4) appeared to offer additional benefit but there was limited evidence for effectiveness of other exercise and non-exercise components., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)