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 risk. A total of 3357 subjects underwent screening in the SCOPE natural history study for geographic atrophy secondary to age-related macular degeneration, including CFI sequencing and serum FI measurement. Eleven CFI RV genotypes that were challenging to categorize as type I (low serum level) or type II (normal serum level, 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 C3b cleavage. Four variants predicted or previously characterized as benign were analyzed by BBFA for comparison. In all, three variants (W51S, C67R, and I370T) resulted in low expression. Furthermore, four variants (P64L, R339Q, G527V, and P528T) were identified as being highly deleterious with IC50s for C3b breakdown >1 log increased versus the WT protein, while two variants (K476E and R474Q) were ∼1 log reduced in function. Meanwhile, six variants (P50A, T203I, K441R, E548Q, P553S, and S570T) had IC50s similar to WT. Odds ratios and BBFA IC50s were positively correlated (r = 0.76, p < 0.01), while odds ratios versus 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 for complement-targeted therapies. Pure protein in vitro analysis remains the gold standard for determining the functional consequence of CFI RVs.

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.

GWAS of self-reported mosquito bite size, itch intensity and attractiveness to mosquitoes implicates immune-related predisposition loci.

Understanding the interaction between humans and mosquitoes is a critical area of study due to the phenomenal burdens on public health from mosquito-transmitted diseases. In this study, we conducted the first genome-wide association studies (GWAS) of self-reported mosquito bite reaction size (n = 84,724), itchiness caused by bites (n = 69,057), and perceived attractiveness to mosquitoes (n = 16,576). In total, 15 independent significant (P < 5×10-8) associations were identified. These loci were enriched for immunity-related genes that are involved in multiple cytokine signalling pathways. We also detected suggestive enrichment of these loci in enhancer regions that are active in stimulated T-cells, as well as within loci previously identified as controlling central memory T-cell levels. Egger regression analysis between the traits suggests that perception of itchiness and attractiveness to mosquitoes is driven, at least in part, by the genetic determinants of bite reaction size.Our findings illustrate the complex genetic and immunological landscapes underpinning human interactions with mosquitoes.

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.

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.

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.

Genetic and Environmental Risk for Chronic Pain and the Contribution of Risk Variants for Major Depressive Disorder: A Family-Based Mixed-Model Analysis.

BACKGROUND: Chronic pain is highly prevalent and a significant source of disability, yet its genetic and environmental risk factors are poorly understood. Its relationship with major depressive disorder (MDD) is of particular importance. We sought to test the contribution of genetic factors and shared and unique environment to risk of chronic pain and its correlation with MDD in Generation Scotland: Scottish Family Health Study (GS:SFHS). We then sought to replicate any significant findings in the United Kingdom Biobank study. METHODS AND FINDINGS: Using family-based mixed-model analyses, we examined the contribution of genetics and shared family environment to chronic pain by spouse, sibling, and household relationships. These analyses were conducted in GS:SFHS (n = 23,960), a family- and population-based study of individuals recruited from the Scottish population through their general practitioners. We then examined and partitioned the correlation between chronic pain and MDD and estimated the contribution of genetic factors and shared environment in GS:SFHS. Finally, we used data from two independent genome-wide association studies to test whether chronic pain has a polygenic architecture and examine whether genomic risk of psychiatric disorder predicted chronic pain and whether genomic risk of chronic pain predicted MDD. These analyses were conducted in GS:SFHS and repeated in UK Biobank, a study of 500,000 from the UK population, of whom 112,151 had genotyping and phenotypic data. Chronic pain is a moderately heritable trait (heritability = 38.4%, 95% CI 33.6% to 43.9%) that is significantly concordant in spouses (variance explained 18.7%, 95% CI 9.5% to 25.1%). Chronic pain is positively correlated with depression (ρ = 0.13, 95% CI 0.11 to 0.15, p = 2.72x10-68) and shows a tendency to cluster within families for genetic reasons (genetic correlation = 0.51, 95%CI 0.40 to 0.62, p = 8.24x10-19). Polygenic risk profiles for pain, generated using independent GWAS data, were associated with chronic pain in both GS:SFHS (maximum ß = 6.18x10-2, 95% CI 2.84 x10-2 to 9.35 x10-2, p = 4.3x10-4) and UK Biobank (maximum ß = 5.68 x 10-2, 95% CI 4.70x10-2 to 6.65x10-2, p < 3x10-4). Genomic risk of MDD is also significantly associated with chronic pain in both GS:SFHS (maximum ß = 6.62x10-2, 95% CI 2.82 x10-2 to 9.76 x10-2, p = 4.3x10-4) and UK Biobank (maximum ß = 2.56x10-2, 95% CI 1.62x10-2 to 3.63x10-2, p < 3x10-4). Limitations of the current study include the possibility that spouse effects may be due to assortative mating and the relatively small polygenic risk score effect sizes. CONCLUSIONS: Genetic factors, as well as chronic pain in a partner or spouse, contribute substantially to the risk of chronic pain for an individual. Chronic pain is genetically correlated with MDD, has a polygenic architecture, and is associated with polygenic risk of MDD.

Inactivation of polycomb repressive complex 2 components in myeloproliferative and myelodysplastic/myeloproliferative neoplasms.

The polycomb repressive complex 2 (PRC2) is a highly conserved histone H3 lysine 27 methyltransferase that regulates the expression of developmental genes. Inactivating mutations of the catalytic component of PRC2, EZH2, are seen in myeloid disorders. We reasoned that the other 2 core PRC2 components, SUZ12 and EED, may also be mutational targets in these diseases, as well as associated factors such as JARID2. SUZ12 mutations were identified in 1 of 2 patients with myelodysplastic syndrome/myeloproliferative neoplasms with 17q acquired uniparental disomy and in 2 of 2 myelofibrosis cases with focal 17q11 deletions. All 3 were missense mutations affecting the highly conserved VEFS domain. Analysis of a further 146 myelodysplastic syndrome/myeloproliferative neoplasm patients revealed an additional VEFS domain mutant, yielding a total mutation frequency of 1.4% (2 of 148). We did not find mutations of JARID2 or EED in association with acquired uniparental disomy for chromosome 6p or 11q, respectively; however, screening unselected cases identified missense mutations in EED (1 of 148; 1%) and JARID2 (3 of 148; 2%). All 3 SUZ12 mutations tested and the EED mutation reduced PRC2 histone methyltransferase activity in vitro, demonstrating that PRC2 function may be compromised in myeloid disorders by mutation of distinct genes.

EZH2 mutational status predicts poor survival in myelofibrosis.

We genotyped 370 subjects with primary myelofibrosis (PMF) and 148 with postpolycythemia vera/postessential thrombocythemia (PPV/PET) MF for mutations of EZH2. Mutational status at diagnosis was correlated with hematologic parameters, clinical manifestations, and outcome. A total of 25 different EZH2 mutations were detected in 5.9% of PMF, 1.2% of PPV-MF, and 9.4% of PET-MF patients; most were exonic heterozygous missense changes. EZH2 mutation coexisted with JAK2V617F or ASXL1 mutation in 12 of 29 (41.4%) and 6 of 27 (22.2%) evaluated patients; TET2 and CBL mutations were found in 2 and 1 patients, respectively. EZH2-mutated PMF patients had significantly higher leukocyte counts, blast-cell counts, and larger spleens at diagnosis, and most of them (52.6%) were in the high-risk International Prognostic Score System (IPSS) category. After a median follow-up of 39 months, 128 patients (25.9%) died, 81 (63.3%) because of leukemia. Leukemia-free survival (LFS) and overall survival (OS) were significantly reduced in EZH2-mutated PMF patients (P = .028 and P < .001, respectively); no such impact was seen for PPV/PET-MF patients, possibly due to the low number of mutated cases. In multivariate analysis, survival of PMF patients was predicted by IPSS high-risk category, a < 25% JAK2V617F allele burden, and EZH2 mutation status. We conclude that EZH2 mutations are independently associated with shorter survival in patients with PMF.

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.

The JAK2 46/1 haplotype predisposes to MPL-mutated myeloproliferative neoplasms.

The 46/1 JAK2 haplotype predisposes to V617F-positive myeloproliferative neoplasms, but the underlying mechanism is obscure. We analyzed essential thrombocythemia patients entered into the PT-1 studies and, as expected, found that 46/1 was overrepresented in V617F-positive cases (n = 404) versus controls (n = 1492, P = 3.9 x 10(-11)). The 46/1 haplotype was also overrepresented in cases without V617F (n = 347, P = .009), with an excess seen for both MPL exon 10 mutated and V617F, MPL exon 10 nonmutated cases. Analysis of further MPL-positive, V617F-negative cases confirmed an excess of 46/1 (n = 176, P = .002), but no association between MPL mutations and MPL haplotype was seen. An excess of 46/1 was also seen in JAK2 exon 12 mutated cases (n = 69, P = .002), and these mutations preferentially arose on the 46/1 chromosome (P = .029). No association between 46/1 and clinical or laboratory features was seen in the PT-1 cohort either with or without V617F. The excess of 46/1 in JAK2 exon 12 cases is compatible with both the "hypermutability" and "fertile ground" hypotheses, but the excess in MPL-mutated cases argues against the former. No difference in sequence, splicing, or expression of JAK2 was found on 46/1 compared with other haplotypes, suggesting that any functional difference of JAK2 on 46/1, if it exists, must be relatively subtle.

Decrease in JAK2 V617F allele burden is not a prerequisite to clinical response in patients with polycythemia vera.

BACKGROUND: Although reduction in the JAK2(V617F) allele burden (%V617F) has been suggested as a criterion for defining disease response to cytoreductive therapy in polycythemia vera, its value as a response monitor is unclear. The purpose of this study is to determine whether a reduction in %V617F in polycythemia vera is a prerequisite to achieving hematologic remission in response to cytoreductive therapy. DESIGN AND METHODS: We compared the clinical and hematologic responses to change in %V617F (molecular response) in 73 patients with polycythemia vera treated with either interferon (rIFNα-2b: 28, Peg-rIFNα-2a: 18) or non-interferon drugs (n=27), which included hydroxyurea (n=8), imatinib (n=12), dasatinib (n=5), busulfan (n=1), and radioactive phosphorus (n=1). Hematologic response evaluation employed Polycythemia Vera Study Group criteria, and molecular response evaluation, European Leukemia Net criteria. RESULTS: Of the 46 treated with interferon, 41 (89.1%) had a hematologic response, whereas only 7 (15.2%) had a partial molecular response. Of the 27 who received non-interferon treatments, 16 (59.3%) had a hematologic response, but only 2 (7.4%) had a molecular response. Median duration of follow up was 2.8 years. Statistical agreement between hematologic response and molecular response was poor in all treatment groups. CONCLUSIONS: Generally, hematologic response was not accompanied by molecular response. Therefore, a quantitative change in %V617F is not required for clinical response in patients with polycythemia vera.

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.

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.

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.

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.

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.

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.

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.