Comprehensive functional characterization of Complement factor I rare variant genotypes identified in the SCOPE Geographic Atrophy cohort.

Rare variants (RVs) in the gene encoding the regulatory enzyme complement factor I (CFI; FI) that reduce protein function or levels increase age-related macular degeneration (AMD) risk. A total of 3357 subjects underwent screening in the SCOPE natural history study for Geographic Atrophy (GA) secondary to AMD, including CFI sequencing followed by serum FI measurement. Eleven CFI RV genotypes that were challenging to categorise as Type I (low serum level) or Type II (normal serum level but reduced enzymatic function) were characterized in the context of pure FI protein in C3b and C4b fluid phase cleavage assays and a novel bead-based functional assay (BBFA) of surface-bound C3b cleavage. A further 4 variants predicted or previously characterized as benign, were analysed using the BBFA to add confidence to their classification. In all, 3 variants [W51S, C67R, I370T] resulted in low expression. A further 4 variants [P64L, R339Q, G527V and P528T] were identified as being highly deleterious with IC50s for C3b breakdown >1 log increased vs the WT protein, while 2 variants [K476E and R474Q] were ∼1 log reduced in function. Meanwhile, 6 variants [P50A, T203I, K441R, E548Q, P553S, S570T] had IC50s similar to wild-type (WT). Odds ratios (ORs) and BBFA IC50s were positively correlated (r=0.76, P<0.01), whilst ORs vs combined annotation dependent depletion (CADD) scores were not (r=0.43, P=0.16). Overall, 15 CFI RVs were functionally characterized which may aid future patient stratification approaches for complement-targeted therapies. Pure protein in vitro analysis remains the gold standard for determining the functional consequence of CFI RVs.

Effect of aerobic exercise training on pulse wave velocity in adults with and without long-term conditions: a systematic review and meta-analysis.

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.

Understanding the effectiveness of different exercise training programme designs on V̇O2peak in COPD: a component network meta-analysis.

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 V̇O2peak in COPD. The included 59 studies involving 2191 participants demonstrated that V̇O2peak 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.

Exercise rehabilitation in COPD and heart failure: comparison of two national audits.

Background: Pulmonary (PR) and cardiac rehabilitation (CR) are recommended in the management of chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF); the impact of coexisting COPD and CHF on completion and outcomes of rehabilitation programmes is unknown. We examined enrolment, completion and clinical outcomes of CR and PR in adults with COPD, CHF and coexisting COPD and CHF. Methods: The National Audit of CR and National COPD Audit Programme: clinical audits of PR were analysed (211 PR and 237 CR programmes); adults with a diagnosis of CHF, COPD or coexisting COPD and CHF were identified (COPD+CHF or CHF+COPD according to database). Propensity matching was conducted (age, sex, body mass index and functional status) between COPD+CHF and COPD, and CHF+COPD and CHF. Group by time interaction was examined using mixed 2×2 analysis of variance. Results: Those with CHF+COPD had lower enrolment and completion of CR compared to those with CHF; there were no differences in PR enrolment or completion between the two groups. Adults with COPD made a significantly larger gain in the incremental shuttle walk test compared to adults with COPD+CHF following PR (59.3 m versus 37.4 m); the improvements following CR were similar (CHF 77.3 m versus CHF+COPD 58.3 m). Similar improvements were made in the 6-min walk test following CR (CHF 45.1 m versus CHF+COPD 38.8 m) and PR (COPD 48.2 m versus COPD+CHF 44.0 m). Comparable improvements in quality of life and mood state were made following CR and PR, regardless of diagnosis. Conclusion: We have demonstrated that multi-morbid adults benefit from exercise-based rehabilitation, yet efforts are needed to promote completion. These findings support group-based, tailored, multi-morbid exercise rehabilitation.

An assessment of prevalence of Type 1 CFI rare variants in European AMD, and why lack of broader genetic data hinders development of new treatments and healthcare access.

PURPOSE: Advanced age-related macular degeneration (AAMD) risk is associated with rare complement Factor I (FI) genetic variants associated with low FI protein levels (termed 'Type 1'), but it is unclear how variant prevalences differ between AMD patients from different ethnicities. METHODS: Collective prevalence of Type 1 CFI rare variant genotypes were examined in four European AAMD datasets. Collective minor allele frequencies (MAFs) were sourced from the natural history study SCOPE, the UK Biobank, the International AMD Genomics Consortium (IAMDGC), and the Finnish Biobank Cooperative (FINBB), and compared to paired control MAFs or background population prevalence rates from the Genome Aggregation Database (gnomAD). Due to a lack of available genetic data in non-European AAMD, power calculations were undertaken to estimate the AAMD population sizes required to identify statistically significant association between Type 1 CFI rare variants and disease risk in different ethnicities, using gnomAD populations as controls. RESULTS: Type 1 CFI rare variants were enriched in all European AAMD cohorts, with odds ratios (ORs) ranging between 3.1 and 7.8, and a greater enrichment was observed in dry AMD from FINBB (OR 8.9, 95% CI 1.49-53.31). The lack of available non-European AAMD datasets prevented us exploring this relationship more globally, however a statistical association may be detectable by future sequencing studies that sample approximately 2,000 AAMD individuals from Ashkenazi Jewish and Latino/Admixed American ethnicities. CONCLUSIONS: The relationship between Type 1 CFI rare variants increasing odds of AAMD are well established in Europeans, however the lack of broader genetic data in AAMD has adverse implications for clinical development and future commercialisation strategies of targeted FI therapies in AAMD. These findings emphasise the importance of generating more diverse genetic data in AAMD to improve equity of access to new treatments and address the bias in health care.

Evaluating a Causal Relationship between Complement Factor I Protein Level and Advanced Age-Related Macular Degeneration Using Mendelian Randomization.

Importance: Risk of advanced age-related macular degeneration (AAMD) is associated with rare genetic variants in the gene encoding Complement factor I (CFI), which is associated with lower circulating CFI protein levels, but the nature of the relationship is unclear. Objective: Can genetic factors be used to infer whether low circulating CFI is associated with AAMD risk? Design: Two-sample inverse variance weighted Mendelian Randomisation (MR) was used to evaluate evidence for a relationship between CFI levels and AAMD risk, comparing CFI levels from genetically predefined subsets in AAMD and control cohorts. Setting: Published genetic and proteomic data was combined with data from cohorts of Geographic Atrophy (GA) patients in a series of MR analyses. Participants: We derived genetic instruments for systemic CFI level in 3,301 healthy European participants in the INTERVAL study. To evaluate a genetic causal odds ratio (OR) for the effect of CFI levels on AAMD risk, we used results from a genome-wide association study of 12,711 AAMD cases and 14,590 European controls from the International AMD Genomics Consortium (IAMDGC), and CFI levels from patients entered into the research studies SCOPE and SIGHT. Results: We identified one common CFI variant rs7439493 which was strongly associated with low CFI level, explaining 4.8% of phenotypic variance. Using rs7439493 our MR analysis estimated that AAMD odds increased per standard deviation (SD) decrease in CFI level; OR 1.47 (95% confidence interval (CI) 1.30-1.65, P=2.1×10-10). We identified one rare variant (rs141853578 encoding p.Gly119Arg) which was genome-wide significantly associated with CFI levels after imputation; based on this, a 1 SD decrease in CFI leads to increased AAMD odds of 1.79 (95% CI 1.46-2.19, P=1.9×10-8). The rare variant rs141853578 explained a further 1.7% of phenotypic variance. To benchmark the effect of low CFI levels on AAMD odds using a CFI-specific proteomic assay, we estimated the effect using CFI levels from 24 rs141853578 positive GA patients; each 1 SD (3.5µg/mL) reduction in CFI was associated with 1.67 fold increased odds of AAMD (95% CI 1.40-2.00, P=1.85×10-8). Conclusion and relevance: Excellent concordance in direction and effect size derived from rare and common variant calculations provide good genetic evidence for a potentially causal role of lower CFI level increasing AAMD risk.

Systematic Review of Physical Activity, Sedentary Behaviour and Sleep Among Adults Living with Chronic Respiratory Disease in Low- and Middle-Income Countries.

Abstract: Physical activity (PA), sedentary behaviour (SB) and sleep are important lifestyle behaviours associated with chronic respiratory disease (CRD) morbidity and mortality. These behaviours need to be understood in low- and middle-income countries (LMIC) to develop appropriate interventions. Purpose: Where and how have free-living PA, SB and sleep data been collected for adults living with CRD in LMIC? What are the free-living PA, SB and sleep levels of adults living with CRD? Patients and Methods: The literature on free-living PA, SB and sleep of people living with CRD in LMIC was systematically reviewed in five relevant scientific databases. The review included empirical studies conducted in LMIC, reported in any language. Reviewers screened the articles and extracted data on prevalence, levels and measurement approach of PA, SB and sleep using a standardised form. Quality of reporting was assessed using bespoke criteria. Results: Of 89 articles, most were conducted in Brazil (n=43). PA was the commonest behaviour measured (n=66). Questionnaires (n=52) were more commonly used to measure physical behaviours than device-based (n=37) methods. International Physical Activity Questionnaire was the commonest for measuring PA/SB (n=11). For sleep, most studies used Pittsburgh Sleep Quality Index (n=18). The most common ways of reporting were steps per day (n=21), energy expenditure (n=21), sedentary time (n=16), standing time (n=13), sitting time (n=11), lying time (n=10) and overall sleep quality (n=32). Studies revealed low PA levels [steps per day (range 2669-7490steps/day)], sedentary lifestyles [sitting time (range 283-418min/day); standing time (range 139-270min/day); lying time (range 76-119min/day)] and poor sleep quality (range 33-100%) among adults with CRD in LMIC. Conclusion: Data support low PA levels, sedentary lifestyles and poor sleep among people in LMIC living with CRDs. More studies are needed in more diverse populations and would benefit from a harmonised approach to data collection for international comparisons.

Developing Appropriate Pulmonary Rehabilitation Services in Sri Lanka: Assessment of People Living with COPD and Healthcare Providers in Urban and Semi Urban Areas in Sri Lanka.

Introduction: 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.

What should pulmonary rehabilitation look like for people living with post-tuberculosis lung disease in the Bishkek and Chui region of the Kyrgyz Republic? A qualitative exploration.

OBJECTIVE: After experiencing tuberculosis (TB), many people develop post-tuberculosis lung disease (PTBLD). Pulmonary rehabilitation (PR) centrally comprising of education and exercise is recommended internationally for people living with chronic respiratory diseases. However, no such service exists in Kyrgyzstan. This study investigated the opinions of healthcare professionals who would be expected to be potential future referrers to PR and adults living with PTBLD about what a PR programme could look like in Kyrgyzstan. DESIGN: A qualitative study using interviews and focus groups. Grounded theory and thematic analysis were used for data collection and analysis. PARTICIPANTS: 63 participants; 15 referrers (12 male, 3 female; 12 pulmonolgists, 3 TB specialists) and 48 adults (26 male, 22 female) living with PTBLD. SETTING: Participants were recruited from hospital settings in Bishkek and Chuy Region, Kygryzstan. METHODS: Fifteen semistructured interviews were conducted with referrers and nine focus group discussions were conducted with adults living with PTBLD. RESULTS: Five key themes were developed: (1) living with PTBLD; (2) attitude to PR, which emphasised the perceived importance and potential benefits of implemention; (3) barriers/facilitators to PR, which included time and cost, and the importance of appropriate communication in enabling participation; (4) interventional components of PR, which described culturally and demographically appropriate physical activities including rhythmic movements, dance and volleyball; and (5) psychosocial support, which demonstrated the importance of psychological support for patients coping with the effects of stigma. CONCLUSIONS: Potential referrers and adults living with PTBLD expressed their support for the implementation of PR. The culture-specific and population-specific issues highlighted in this work demonstrate the need to address stigma and provide certain types of exercise training/education modules for this specific clinical population. In other respects the currently known attitudes/barriers to PR, identified in Western research, appear to apply. The principles of culturally adapting PR may be helpful for those looking to establish similar clinical services in other low-income and middle-income countries and in Central Asia in particular. TRIAL REGISTRATION NUMBER: ISRCTN11122503.

Culturally adapted pulmonary rehabilitation for adults living with post-tuberculosis lung disease in Kyrgyzstan: protocol for a randomised controlled trial with blinded outcome measures.

INTRODUCTION: Pulmonary rehabilitation (PR) is a programme of individually prescribed physical exercise, education and self-management activities. PR is recommended in international guidelines for managing chronic obstructive pulmonary disease (COPD) and other chronic respiratory diseases. PR is still under-recognised in tuberculosis (TB) guidelines and PR is not available in many low and middle-income countries and for people with post-TB lung disease (PTBLD). The main aims of the study are to adapt and define a culturally appropriate PR programme in Kyrgyzstan for people living with PTBLD and to test, in a fully powered randomised controlled trial (RCT), the effectiveness of PR in improving exercise capacity for people living with PTBLD. METHODS AND ANALYSIS: The study will be divided into three stages: stage 1: focus group discussions with patients living with PTBLD and interviews with PR referrers will be conducted to explore initial perceptions and inform the cultural adaptation, structure and content of PR. Stage 2a: a single-blind RCT evaluating the effectiveness of a culturally adapted 6-week PR programme on maximal exercise capacity, assessed by the incremental shuttle walking test, before and after PR. Participants will be additionally followed-up 12 weeks postbaseline. Additional outcomes will include health-related quality of life, respiratory symptoms, psychological well-being and physical function. Stage 2b: participants' experience of PR will be collected through interviews and using a log book and a patient evaluation form. Staff delivering PR will be interviewed to explore their experience of delivering the intervention and refining the delivery for future implementation. ETHICS AND DISSEMINATION: The study was approved 22/07/2019 by Ethics Committee National Center for Cardiology and Internal Medicine (reference number 17) and by University of Leicester ethics committee (reference number 22293). Study results will be disseminated through appropriate peer-reviewed journals, national and international respiratory/physiotherapy conferences, social media, and through patient and public involvement events in Kyrgyzstan and in the UK. TRIAL REGISTRATION NUMBER: ISRCTN11122503.

Potential for integrating yoga within pulmonary rehabilitation and recommendations of reporting framework.

There is a rising burden of chronic obstructive pulmonary disease (COPD) in India. Pulmonary rehabilitation (PR), is a universally recommended multidisciplinary therapeutic strategy for the management of COPD; however, its needs are unmet. The diversity in the healthcare systems, availability of PR specialists and sociocultural multiformity requires contextualised and innovative PR models. Culturally sensitive elements, such as yoga, have some evidence of a positive impact in the management of COPD. Yoga and PR are based on similar principles with a holistic approach of involving physical activities, behaviour change techniques and psychological support to improve disease outcomes. Arguably the principles of PR and yoga are complementary but there are some important differences in the intensities of activities, exercise types and inclusion of mindfulness in components that must be considered. Components of PR enable aerobic capacity building, strengthening of muscles of the upper and lower extremities and building awareness towards disease management. Yoga, on the other hand, primarily can focus on core strengthening, breathing control, mindfulness and self-awareness. We discuss the potential of integrating the sociocultural appeal of yoga with PR delivered at international standards, and how an integrated approach may lead to optimal referral, uptake and completion.

Identifying Appropriate Delivery of and Referral to Pulmonary Rehabilitation in Uganda: A Survey Study of People Living with Chronic Respiratory Disease and Health Care Workers.

Introduction: 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.

Study protocol for a randomised controlled trial assessing the impact of pulmonary rehabilitation on maximal exercise capacity for adults living with post-TB lung disease: Global RECHARGE Uganda.

INTRODUCTION: The burden of post-tuberculosis (TB) lung disease (PTBLD) is steadily increasing in sub-Saharan Africa, causing disability among TB survivors. Without effective medicines, the mainstay of PTBLD treatment evolves around disease prevention and supportive treatment. Pulmonary rehabilitation (PR), a low-cost, non-pharmacological intervention has shown effectiveness in a group of PTBLD individuals but has not been tested in a clinical trial. This study aims to assess the impact of a 6-week PR programme on maximal exercise capacity and other outcomes among adults in Uganda living with PTBLD. METHODS AND ANALYSIS: This is a randomised waiting-list controlled trial with blinded outcome measures, comparing PR versus usual care for patients with PTBLD. A total of 114 participants will be randomised (1:1) to receive either usual care (on the waiting list) or PR, with follow-up assessments at 6 weeks and 12 weeks postintervention. The primary outcome is change in walking distance measured by the Incremental Shuttle Walk Test from baseline to the end of 6 weeks of PR. All secondary outcomes will be compared between the PR and usual care arms from baseline to 6-week and 12-week follow-ups. Secondary outcomes include self-reported respiratory symptoms, physical activity, psychological well-being, health-related quality of life and cost-benefit analysis. All randomised participants will be included in the intention-to-treat analysis population. The primary efficacy analysis will be based on both per-protocol and modified intention-to-treat populations. ETHICS AND DISSEMINATION: The trial has received ethical clearance from the Mulago Hospital Research and Ethics Committee (MHREC 1478), Kampala, Uganda as well as the Uganda National Council for Science and Technology (SS 5105). Ethical approval has been obtained from the University of Leicester, UK research ethics committee (Ref No. 22349). Study findings will be published in appropriate peer-reviewed journals and disseminated at appropriate local, regional and international scientific meetings and conferences. TRIAL REGISTRATION NUMBER: ISRCTN18256843. PROTOCOL VERSION: Version 1.0 July 2019.

Protocol for the cultural adaptation of pulmonary rehabilitation and subsequent testing in a randomised controlled feasibility trial for adults with chronic obstructive pulmonary disease in Sri Lanka.

INTRODUCTION: International guidelines recommend pulmonary rehabilitation (PR) should be offered to adults living with chronic obstructive pulmonary disease (COPD), but PR availability is limited in Sri Lanka. Culturally appropriate PR needs to be designed and implemented in Sri Lanka. The study aims to adapt PR to the Sri Lankan context and determine the feasibility of conducting a future trial of the adapted PR in Sri Lanka. METHODS AND ANALYSIS: Eligible participants will be identified and will be invited to take part in the randomised controlled feasibility trial, which will be conducted in Central Chest Clinic, Colombo, Sri Lanka. A total of 50 participants will be recruited (anticipated from April 2021) to the trial and randomised (1:1) into one of two groups; control group receiving usual care or the intervention group receiving adapted PR. The trial intervention is a Sri Lankan-specific PR programme, which will consist of 12 sessions of exercise and health education, delivered over 6 weeks. Focus groups with adults living with COPD, caregivers and nurses and in-depth interviews with doctors and physiotherapist will be conducted to inform the Sri Lankan specific PR adaptations. After completion of PR, routine measures in both groups will be assessed by a blinded assessor. The primary outcome measure is feasibility, including assessing eligibility, uptake and completion. Qualitative evaluation of the trial using focus groups with participants and in-depth interviews with PR deliverers will be conducted to further determine feasibility and acceptability of PR, as well as the ability to run a larger future trial. ETHICS AND DISSEMINATION: Ethical approval was obtained from the ethics review committee of Faculty of Medical Sciences, University of Sri Jayewardenepura, Sri Lanka and University of Leicester, UK. The results of the trial will be disseminated through patient and public involvement events, local and international conference proceedings, and peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN13367735.

Change in V˙O2peak in Response to Aerobic Exercise Training and the Relationship With Exercise Prescription in People With COPD: A Systematic Review and Meta-analysis.

BACKGROUND: Despite the wide-ranging benefits of pulmonary rehabilitation, conflicting results remain regarding whether people with COPD can improve their peak oxygen uptake (V˙O2peak) with aerobic training. RESEARCH QUESTION: The goal of this study was to investigate the effect of aerobic training and exercise prescription on V˙O2peak in COPD. STUDY DESIGN AND METHODS: A systematic review was performed by using MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature, and Cochrane databases for all studies measuring V˙O2peak prior to and following supervised lower-limb aerobic training in COPD. A random effects meta-analysis limited to randomized controlled trials comparing aerobic training vs usual care was conducted. Other study designs were included in a secondary meta-analysis and meta-regression to investigate the influence of program and patient factors on outcome. RESULTS: A total of 112 studies were included (participants, N = 3,484): 21 controlled trials (n = 489), of which 13 were randomized (n = 288) and 91 were uncontrolled (n = 2,995) studies. Meta-analysis found a moderate positive change in V˙O2peak (standardized mean difference, 0.52; 95% CI, 0.34-0.69) with the intervention. The change in V˙O2peak was positively associated with target duration of exercise session (P = .01) and, when studies > 1 year duration were excluded, greater total volume of exercise training (P = .01). Similarly, the change in V˙O2peak was greater for programs > 12 weeks compared with those 6 to 12 weeks when adjusted for age and sex. However, reported prescribed exercise intensity (P = .77), training modality (P > .35), and mode (P = .29) did not affect V˙O2peak. Cohorts with more severe airflow obstruction exhibited smaller improvements in V˙O2peak (P < .001). INTERPRETATION: Overall, people with COPD achieved moderate improvements in V˙O2peak through supervised aerobic training. There is sufficient evidence to show that programs with greater total exercise volume, including duration of exercise session and program duration, are more effective. Reduced effects in severe disease suggest alternative aerobic training methods may be needed in this population. CLINICAL TRIAL REGISTRATION: PROSPERO; No.: CRD42018099300; URL: https://www.crd.york.ac.uk/prospero/.

Outcome measures in a combined exercise rehabilitation programme for adults with COPD and chronic heart failure: A preliminary stakeholder consensus event.

Combined exercise rehabilitation for chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF) is potentially attractive. Uncertainty remains as to the baseline profiling assessments and outcome measures that should be collected within a programme. Current evidence surrounding outcome measures in cardiac and pulmonary rehabilitation were presented by experts at a stakeholder consensus event and all stakeholders (n = 18) were asked to (1) rank in order of importance a list of categories, (2) prioritise outcome measures and (3) prioritise baseline patient evaluation measures that should be assessed in a combined COPD and CHF rehabilitation programme. The tasks were completed anonymously and related to clinical rehabilitation programmes and associated research. Health-related quality of life, exercise capacity and symptom evaluation were voted as the most important categories to assess for clinical purposes (median rank: 1, 2 and 3 accordingly) and research purposes (median rank; 1, 3 and 4.5 accordingly) within combined exercise rehabilitation. All stakeholders agreed that profiling symptoms at baseline were 'moderately', 'very' or 'extremely' important to assess for clinical and research purposes in combined rehabilitation. Profiling of frailty was ranked of the same importance for clinical purposes in combined rehabilitation. Stakeholders identified a suite of multidisciplinary measures that may be important to assess in a combined COPD and CHF exercise rehabilitation programme.

Protocol for a feasibility trial to inform the development of a breathlessness rehabilitation programme for chronic obstructive pulmonary disease and chronic heart failure (the COHERE trial).

INTRODUCTION: Adults with chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF) commonly suffer from exertional dyspnoea and fatigue. Exercise training is recommended in the management of both diseases, yet many of the outcome measures traditionally reported are disease specific and may not fully acknowledge the multimorbid older adult. Based on our previous research, a breathlessness rehabilitation programme for patients with COPD/CHF or combined disease has been introduced as a service improvement within University Hospital Leicester National Health Service Trust and has amalgamated aspects of cardiac and pulmonary rehabilitation. This has created an opportunity to expand the outcome measures assessed and introduce a holistic approach in a population that share common symptoms. Therefore, this multisite trial will explore the feasibility of collecting novel outcome markers as part of a comprehensive assessment prior to enrolment in a breathlessness rehabilitation programme for participants with COPD and/or CHF. METHODS AND ANALYSIS: The rehabilitation programme consists of 12 sessions, twice weekly, over a 6-week period. In addition to usual rehabilitation outcome measures, the trial will collect measures of future cardiometabolic risk including arterial stiffness, body composition, physical activity/sedentary time, frailty and symptom burden in a comprehensive rehabilitation assessment. The primary outcome measures will centre around feasibility (eg, acceptability of the comprehensive rehabilitation assessment, intervention delivery and the experiences and attitudes of healthcare professionals and participants). Focus groups and interviews will be conducted to further explore barriers and facilitators to the operation and participation in a breathlessness rehabilitation programme and the trial. Thematic analysis will be used for the interpretation of all qualitative data. ETHICS AND DISSEMINATION: The research ethics committee East Midlands Leicester-Central has provided ethical approval for the conduct of this trial. The results of the trial will be disseminated through appropriate conference proceedings and peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN11636308.

A Novel t(1;9)(p36;p24.1) JAK2 Translocation and Review of the Literature.

The JAK2V617F point mutation has been implicated in the pathogenesis of the vast majority of myeloproliferative neoplasms (MPNs), but translocations involving JAK2 have increasingly been identified in patients with JAK2V617F-negativeMPNs. Here, we present a case of a patient diagnosed with JAK2V617F-negativepolycythemia vera (PV) that transformed to the MPN-blast phase. Cytogenetic and FISH analysis revealed a novel translocation of t(1;9)(p36;p24.1), causing a PEX14-JAK2 gene fusion product. The t(1;9)(p36;p24.1) represents a new addition to the list of known translocations involving JAK2that have been identified in hematologic malignancies. Although the prognostic and treatment implications of JAK2 translocations in MPNs have not been elucidated, positive outcomes have been described in case reports describing the use of JAK inhibitors in these patients. Further research into the role of JAK2 translocations in the pathogenesis and outcomes of hematologic malignancies is warranted.

Obesity and metabolic syndrome in COPD: Is exercise the answer?

Approximately half of all patients with chronic obstructive pulmonary disease (COPD) attending pulmonary rehabilitation (PR) programmes are overweight or obese which negatively impacts upon dyspnoea and exercise tolerance particularly when walking. Within the obese population (without COPD), the observed heterogeneity in prognosis is in part explained by the variability in the risk of developing cardiovascular disease or diabetes (cardiometabolic risk) leading to the description of metabolic syndrome. In obesity alone, high-intensity aerobic training can support healthy weight loss and improve the constituent components of metabolic syndrome. Those with COPD, obesity and/or metabolic syndrome undergoing PR appear to do as well in traditional outcomes as their normal-weight metabolically healthy peers in terms of improvement of symptoms, health-related quality of life and exercise performance, and should therefore not be excluded. To broaden the benefit of PR, for this complex population, we should learn from the extensive literature examining the effects of exercise in obesity and metabolic syndrome discussed in this review and optimize the exercise strategy to improve these co-morbid conditions. Standard PR outcomes could be expanded to include cardiometabolic risk reduction to lower future morbidity and mortality; to this end exercise may well be the answer.