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Nicholas Cross and colleagues report the identification of somatic mutations altering the histone methyltransferase EZH2 in myeloid disorders. They identify monoallelic and biallelic EZH2 mutations in 7% of myeloid disorders, most commonly myelodysplastic and/or myeloproliferative neoplasms and myelofibrosis. Abnormalities of chromosome 7q are common in myeloid malignancies, but no specific target genes have yet been identified. Here, we describe the finding of homozygous EZH2 mutations in 9 of 12 individuals with 7q acquired uniparental disomy. Screening of a total of 614 individuals with myeloid disorders revealed 49 monoallelic or biallelic EZH2 mutations in 42 individuals; the mutations were found most commonly in those with myelodysplastic/myeloproliferative neoplasms (27 out of 219 individuals, or 12%) and in those with myelofibrosis (4 out of 30 individuals, or 13%). EZH2 encodes the catalytic subunit of the polycomb repressive complex 2 (PRC2), a highly conserved histone H3 lysine 27 (H3K27) methyltransferase that influences stem cell renewal by epigenetic repression of genes involved in cell fate decisions. EZH2 has oncogenic activity, and its overexpression has previously been causally linked to differentiation blocks in epithelial tumors. Notably, the mutations we identified resulted in premature chain termination or direct abrogation of histone methyltransferase activity, suggesting that EZH2 acts as a tumor suppressor for myeloid malignancies.

Nick Cross and colleagues report that the JAK2 V617F somatic mutation that drives the development of chronic myeloproliferative neoplasms is associated with the presence of a specific inherited haplotype in JAK2 . Chronic myeloproliferative neoplasms (MPNs) are a group of related conditions characterized by the overproduction of cells from one or more myeloid lineages. More than 95% of cases of polycythemia vera, and roughly half of essential thrombocythemia and primary myelofibrosis acquire a unique somatic 1849G>T JAK2 mutation (encoding V617F) that is believed to be a critical driver of excess proliferation 1 , 2 , 3 , 4 . We report here that JAK2 V617F -associated disease is strongly associated with a specific constitutional JAK2 haplotype, designated 46/1, in all three disease entities compared to healthy controls (polycythemia vera, n = 192, P = 2.9 × 10 −16 ; essential thrombocythemia, n = 78, P = 8.2 × 10 −9 and myelofibrosis, n = 41, P = 8.0 × 10 −5 ). Furthermore, JAK2 V617F specifically arises on the 46/1 allele in most cases. The 46/1 JAK2 haplotype thus predisposes to the development of JAK2 V617F -associated MPNs (OR = 3.7; 95% CI = 3.1–4.3) and provides a model whereby a constitutional genetic factor is associated with an increased risk of acquiring a specific somatic mutation.

ObjectiveAfter 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.DesignA qualitative study using interviews and focus groups. Grounded theory and thematic analysis were used for data collection and analysis.Participants63 participants; 15 referrers (12 male, 3 female; 12 pulmonolgists, 3 TB specialists) and 48 adults (26 male, 22 female) living with PTBLD.SettingParticipants were recruited from hospital settings in Bishkek and Chuy Region, Kygryzstan.MethodsFifteen semistructured interviews were conducted with referrers and nine focus group discussions were conducted with adults living with PTBLD.ResultsFive 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.ConclusionsPotential 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 numberISRCTN11122503.

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. Keywords: respiratory rehabilitation, chronic chest symptoms, medical workers, enthusiasm, knowledge, training

IntroductionPulmonary 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 analysisThe 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 disseminationThe 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 numberISRCTN11122503.

IntroductionThe 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 analysisThis 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 disseminationThe 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 numberISRCTN18256843.Protocol versionVersion 1.0 July 2019.

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. 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? 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. 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. 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.

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. 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. 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. 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. 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.

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.

RationaleThere is conflicting evidence whether aerobic exercise training (AET) reduces pulse wave velocity (PWV) in adults with and without long-term conditions (LTCs).ObjectiveTo 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 sourcesCENTRAL, MEDLINE and EMBASE were among the databases searched.Eligibility criteriaWe 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.DesignControlled 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.Results79 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.DiscussionShort-term AET similarly reduces PWV in adults with and without LTC. Whether this effect is sustained and the clinical implications require further investigation.