Inseparable RNA binding and chromatin modification activities of a nucleosome-interacting surface in EZH2.

Polycomb repressive complex 2 (PRC2) interacts with RNA in cells, but there is no consensus on how RNA regulates PRC2 canonical functions, including chromatin modification and the maintenance of transcription programs in lineage-committed cells. We assayed two separation-of-function mutants of the PRC2 catalytic subunit EZH2, defective in RNA binding but functional in methyltransferase activity. We find that part of the RNA-binding surface of EZH2 is required for chromatin modification, yet this activity is independent of RNA. Mechanistically, the RNA-binding surface within EZH2 is required for chromatin modification in vitro and in cells, through interactions with nucleosomal DNA. Contrarily, an RNA-binding-defective mutant exhibited normal chromatin modification activity in vitro and in lineage-committed cells, accompanied by normal gene repression activity. Collectively, we show that part of the RNA-binding surface of EZH2, rather than the RNA-binding activity per se, is required for the histone methylation in vitro and in cells, through interactions with the substrate nucleosome.

mRNA display reveals a class of high-affinity bromodomain-binding motifs that are not found in the human proteome.

Bromodomains (BDs) regulate gene expression by recognizing protein motifs containing acetyllysine. Although originally characterized as histone-binding proteins, it has since become clear that these domains interact with other acetylated proteins, perhaps most prominently transcription factors. The likely transient nature and low stoichiometry of such modifications, however, has made it challenging to fully define the interactome of any given BD. To begin to address this knowledge gap in an unbiased manner, we carried out mRNA display screens against a BD-the N-terminal BD of BRD3-using peptide libraries that contained either one or two acetyllysine residues. We discovered peptides with very strong consensus sequences and with affinities that are significantly higher than typical BD-peptide interactions. X-ray crystal structures also revealed modes of binding that have not been seen with natural ligands. Intriguingly, however, our sequences are not found in the human proteome, perhaps suggesting that strong binders to BDs might have been selected against during evolution.

Global Alliance for the Promotion of Physical Activity: the Hamburg Declaration.

Non-communicable diseases (NCDs), including coronary heart disease, stroke, hypertension, type 2 diabetes, dementia, depression and cancers, are on the rise worldwide and are often associated with a lack of physical activity (PA). Globally, the levels of PA among individuals are below WHO recommendations. A lack of PA can increase morbidity and mortality, worsen the quality of life and increase the economic burden on individuals and society. In response to this trend, numerous organisations came together under one umbrella in Hamburg, Germany, in April 2021 and signed the 'Hamburg Declaration'. This represented an international commitment to take all necessary actions to increase PA and improve the health of individuals to entire communities. Individuals and organisations are working together as the 'Global Alliance for the Promotion of Physical Activity' to drive long-term individual and population-wide behaviour change by collaborating with all stakeholders in the community: active hospitals, physical activity specialists, community services and healthcare providers, all achieving sustainable health goals for their patients/clients. The 'Hamburg Declaration' calls on national and international policymakers to take concrete action to promote daily PA and exercise at a population level and in healthcare settings.

De novo variants in GATAD2A in individuals with a neurodevelopmental disorder: GATAD2A-related neurodevelopmental disorder.

GATA zinc finger domain containing 2A (GATAD2A) is a subunit of the nucleosome remodeling and deacetylase (NuRD) complex. NuRD is known to regulate gene expression during neural development and other processes. The NuRD complex modulates chromatin status through histone deacetylation and ATP-dependent chromatin remodeling activities. Several neurodevelopmental disorders (NDDs) have been previously linked to variants in other components of NuRD's chromatin remodeling subcomplex (NuRDopathies). We identified five individuals with features of an NDD that possessed de novo autosomal dominant variants in GATAD2A. Core features in affected individuals include global developmental delay, structural brain defects, and craniofacial dysmorphology. These GATAD2A variants are predicted to affect protein dosage and/or interactions with other NuRD chromatin remodeling subunits. We provide evidence that a GATAD2A missense variant disrupts interactions of GATAD2A with CHD3, CHD4, and CHD5. Our findings expand the list of NuRDopathies and provide evidence that GATAD2A variants are the genetic basis of a previously uncharacterized developmental disorder.

Use of the behaviour change wheel to improve everyday person-centred conversations on physical activity across healthcare.

BACKGROUND: An implementation gap exists between the evidence supporting physical activity in the prevention and management of long-term medical conditions and clinical practice. Person-centred conversations, i.e. focussing on the values, preferences and aspirations of each individual, are required from healthcare professionals. However, many currently lack the capability, opportunity, and motivation to have these conversations. This study uses the Behaviour Change Wheel (BCW) to inform the development of practical and educational resources to help bridge this gap. METHODS: The BCW provides a theoretical approach to enable the systematic development of behaviour change interventions. Authors followed the described eight-step process, considered results from a scoping review, consulted clinical working groups, tested and developed ideas across clinical pathways, and agreed on solutions to each stage by consensus. RESULTS: The behavioural diagnosis identified healthcare professionals' initiation of person-centred conversations on physical activity at all appropriate opportunities in routine medical care as a suitable primary target for interventions. Six intervention functions and five policy categories met the APEASE criteria. We mapped 17 Behavioural Change Techniques onto BCW intervention functions to define intervention strategies. CONCLUSIONS: This study uses the BCW to outline a coherent approach for intervention development to improve healthcare professionals' frequency and quality of conversations on physical activity across clinical practice. Time-sensitive and role-specific resources might help healthcare professionals understand the focus of their intervention. Educational resources aimed at healthcare professionals and patients could have mutual benefit, should fit into existing care pathways and support professional development. A trusted information source with single-point access via the internet is likely to improve accessibility. Future evaluation of resources built and coded using this framework is required to establish the effectiveness of this approach and help improve understanding of what works to change conversations around physical activity in clinical practice.

What do healthcare professionals want from a resource to support person-centred conversations on physical activity? A mixed-methods, user-centric approach to developing educational resources.

Objectives: Healthcare is a fundamental action area in population efforts to address the global disease burden from physical inactivity. However, healthcare professionals lack the knowledge, skills and confidence to have regular conversations about physical activity. This study aimed to: (1) understand the requirements of healthcare professionals and patients from a resource to support routine physical activity conversations in clinical consultations and (2) develop such a resource. Methods: This study used codesign principles across two phases, actively involving relevant stakeholders in an iterative development process. The preparatory phase included a scoping literature review and workshops with multidisciplinary healthcare professionals and patients. The Delphi phase included the development of a draft resource, a three-stage modified online Delphi study and an external review. Results: The scoping review highlighted the importance of addressing time restrictions, a behaviour change skill deficit, the need for resources to fit into existing systems and meeting patient expectations. Consultation included 69 participants across two clinical workshops. They recommended using the internet, valued guidance on all aspects of physical activity conversations and were concerned about how to use a person-centred approach. The Delphi phase, including 15 expert participants, met agreement criteria in two stages to develop the resource. Conclusion: This mixed-methods study delivered an online resource that was codesigned with and based on the requirements of healthcare professionals and patients. The resource presents condition-specific '1-minute', '5-minute' and 'more minute' person-centred and evidence-based conversation templates on physical activity in an accessible and usable format to meet the needs of real-life clinical practice.

Benefits outweigh the risks: a consensus statement on the risks of physical activity for people living with long-term conditions.

INTRODUCTION: The benefits of physical activity for people living with long-term conditions (LTCs) are well established. However, the risks of physical activity are less well documented. The fear of exacerbating symptoms and causing adverse events is a persuasive barrier to physical activity in this population.This work aimed to agree clear statements for use by healthcare professionals about medical risks of physical activity for people living with LTCs through expert consensus. These statements addressed the following questions: (1) Is increasing physical activity safe for people living with one or more LTC? (2) Are the symptoms and clinical syndromes associated with common LTCs aggravated in the short or long term by increasing physical activity levels? (3) What specific risks should healthcare professionals consider when advising symptomatic people with one or more LTCs to increase their physical activity levels? METHODS: Statements were developed in a multistage process, guided by the Appraisal of Guidelines for Research and Evaluation tool. A patient and clinician involvement process, a rapid literature review and a steering group workshop informed the development of draft symptom and syndrome-based statements. We then tested and refined the draft statements and supporting evidence using a three-stage modified online Delphi study, incorporating a multidisciplinary expert panel with a broad range of clinical specialties. RESULTS: Twenty-eight experts completed the Delphi process. All statements achieved consensus with a final agreement between 88.5%-96.5%. Five 'impact statements' conclude that (1) for people living with LTCs, the benefits of physical activity far outweigh the risks, (2) despite the risks being very low, perceived risk is high, (3) person-centred conversations are essential for addressing perceived risk, (4) everybody has their own starting point and (5) people should stop and seek medical attention if they experience a dramatic increase in symptoms. In addition, eight symptom/syndrome-based statements discuss specific risks for musculoskeletal pain, fatigue, shortness of breath, cardiac chest pain, palpitations, dysglycaemia, cognitive impairment and falls and frailty. CONCLUSION: Clear, consistent messaging on risk across healthcare will improve people living with LTCs confidence to be physically active. Addressing the fear of adverse events on an individual level will help healthcare professionals affect meaningful behavioural change in day-to-day practice. Evidence does not support routine preparticipation medical clearance for people with stable LTCs if they build up gradually from their current level. The need for medical guidance, as opposed to clearance, should be determined by individuals with specific concerns about active symptoms. As part of a system-wide approach, consistent messaging from healthcare professionals around risk will also help reduce cross-sector barriers to engagement for this population.

Protocol for a multicenter, randomised controlled trial of surgeon-directed home therapy vs. outpatient rehabilitation by physical therapists for reverse total shoulder arthroplasty: the SHORT trial.

BACKGROUND: Reverse total shoulder arthroplasty (RTSA) has emerged as a successful surgery with expanding indications. Outcomes may be influenced by post-operative rehabilitation; however, there is a dearth of research regarding optimal rehabilitation strategy following RTSA. The primary purpose of this study is to compare patient reported and clinical outcomes after RTSA in two groups: in one group rehabilitation is directed by formal, outpatient clinic-based physical therapists (PT group) as compared to a home therapy group, in which patients are instructed in their rehabilitative exercises by surgeons at post-operative appointments (HT group). Secondary aims include comparisons of complications, cost of care and quality of life between the two groups. METHODS: This randomised controlled trial has commenced at seven sites across the United States. Data is being collected on 200 subjects by clinical research assistants pre-operatively and post-operatively at 2, 6, and 12 weeks, 6 months, 1 and 2 year visits. The following variables are being assessed: American Shoulder and Elbow Surgeons (ASES), pain level using the numeric pain scale, the Single Assessment Numeric Evaluation (SANE) score, and shoulder active and passive range of motion for analysis of the primary aim. Chi square and t-tests will be used to measure differences in baseline characteristics of both groups. Repeated measures linear mixed effects modeling for measurement of differences will be used for outcomes associated with ASES and SANE and scores, and range of motion measures. Secondary aims will be analyzed for comparison of complications, cost, and quality of life assessment scores using data obtained from the PROMIS 29 v. 2, questionnaires administered at standard of care post-operative visits, and the electronic health record. Subjects will be allowed to crossover between the PT and HT groups, and analysis will include both intention-to-treat including patients who crossed over, and a second with cross-over patients removed, truncated to the time they crossed over. DISCUSSION: RTSA is being performed with increasing frequency, and the optimal rehabilitation strategy is unclear. This study will help clarify the role of formal physical therapy with particular consideration to outcomes, cost, and complications. In addition, this study will evaluate a proposed rehabilitation strategy. TRIAL REGISTRATION: This study is registered as NCT03719859 at ClincialTrials.gov .

The Active Hospital pilot: A qualitative study exploring the implementation of a Trust-wide Sport and Exercise Medicine-led physical activity intervention.

BACKGROUND: In 2017 Public Health England and Sport England commissioned a Consultant-led Sport and Exercise Medicine (SEM) pilot to test the feasibility and acceptability of embedding physical activity interventions in secondary care clinical pathways. The aim of this paper is to report qualitative findings exploring the experience of healthcare professionals (HCPs) and patients involved in the Active Hospital pilot. METHODS: Qualitative data was collected by semi-structured interviews with Active Hospital pilot SEM Consultants, and staff and patients involved in three clinical pathways. Interviews with SEM Consultants explored the experience of developing and implementing the pilot. Interviews with staff and patients explored the experience of delivering and receiving Active Hospital interventions. Data were analysed thematically. RESULTS: Interviews identified the importance of the Active Hospital pilot being Consultant-led for the following reasons; i) having trusting relationships with decision makers, ii) having sufficient influence to effect change, iii) identifying champions within the system, and iv) being adaptable to change and ensuring the programme fits within the wider strategic frameworks. HCPs emphasised the importance of the Active Hospital interventions fitting easily within existing work practices, the need for staff training and to tailor interventions for individual patient needs. The Active Hospital pilot was well received by patients, however a lack of dedicated resource and capacity to deliver the intervention was highlighted as a challenge by both patients and HCPs. CONCLUSION: The SEM Consultants' ability to navigate the political climate of a large National Health Service (NHS) Trust with competing agendas and limited resource was valuable. The interventions were well received and a valued addition to usual clinical care. However, implementation and ongoing delivery of the pilot encountered challenges including lack of capacity within the system and delays with recruiting to the delivery teams in each pathway.

Incidence of Undiagnosed Celiac Disease Presenting as Bone Stress Injuries to a Sport and Exercise Medicine Clinic.

OBJECTIVE: To evaluate the incidence of undiagnosed celiac disease (CD) in patients presenting with bone stress injuries (BSI) to a NHS Sport and Exercise Medicine (SEM) clinic. DESIGN: Retrospective cohort study. SETTING: Single tertiary-level SEM clinic. PATIENT/PARTICIPANTS: One hundred consecutive patients with radiologically proven BSIs. INTERVENTIONS: Laboratory blood tests (LBT) can unmask underlying metabolic bone disorders. Anti-tissue transglutaminase antibody (TTG) testing has a high sensitivity and specificity for CD. In this SEM clinic, clinicians were encouraged to perform LBT including TTG, at time of diagnosis of BSI. A retrospective analysis of age, sex, fracture site, co-morbidities, TTG result, and subsequent investigations was performed. MAIN OUTCOME MEASURES: The primary outcome was the number and percentage of patients with BSIs and either positive TTG (CD seropositivity) or a diagnosis of CD. RESULTS: Of the 100 patients with radiologically proven BSIs, 70% were female, and the mean age was 37 years (range 16-69). Eighty-five percent had the appropriate LBTs, of which 70% (60/85) were female, and the mean age was 37(16-69). Metatarsal (35%) and tibial (21%) were the most common BSIs. Anti-tissue transglutaminase antibody was performed in 85 patients. Two patients (2/85) had pre-existing CD and were excluded from incidence calculations. Five patients [5/83 (6%), mean age 38 years (28-57), 80% female] had a positive TTG, of whom 3 have subsequently had CD confirmed by endoscopic biopsy. Four patients with a positive TTG underwent dual-energy X-ray absorptiometry with osteopenia found in 3 (75%) cases. CONCLUSIONS: In this cohort, the incidence of CD seropositivity was 6%, and the prevalence of biopsy-confirmed CD was 5%, approximately 5-fold higher than UK population estimates. Anti-tissue transglutaminase antibody screening for CD should be considered in all patients presenting with BSIs.

Heal the Healers: A pilot study evaluating the feasibility, acceptability, and exploratory efficacy of a Transcendental Meditation intervention for emergency clinicians during the coronavirus disease 2019 pandemic.

OBJECTIVE: Emergency clinicians face elevated rates of burnout that result in poor outcomes for clinicians, patients, and health systems. The objective of this single-arm pilot study was to evaluate the feasibility of a Transcendental Meditation (TM) intervention for emergency clinicians during the coronavirus disease 2019 (COVID-19) pandemic and to explore the potential effectiveness in improving burnout, sleep, and psychological health. METHODS: Emergency clinicians (physicians, nurses, and physician-assistants) from 2 urban hospitals were recruited to participate in TM instruction (8 individual or group in-person and remote sessions) for 3 months. Session attendance was the primary feasibility outcome (prespecified as attending 6/8 sessions), and burnout was the primary clinical outcome. Participant-reported measures of feasibility and validated measures of burnout, depression, anxiety, sleep disturbance, and stress were collected at baseline and the 1-month and 3-month follow-ups. Descriptive statistics and linear mixed-effects models were used. RESULTS: Of the 14 physicians (46%), 7 nurses (22%), and 10 physician-assistants (32%) who participated, 61% were female (n = 19/32). TM training and at-home meditation practice was feasible for clinicians as 90.6% (n = 29/32) attended 6/8 training sessions and 80.6% self-reported meditating at least once a day on average. Participants demonstrated significant reductions in burnout (P < .05; effect sizes, Cohen's d = 0.43-0.45) and in symptoms of depression, anxiety, stress, and sleep disturbance (P values < .001; Cohen's d = 0.70-0.87). CONCLUSION: TM training was feasible for emergency clinicians during the COVID-19 pandemic and led to significant reductions in burnout and psychological symptoms. TM is a safe and effective meditation tool to improve clinicians' well-being.

Moving more: physical activity and its positive effects on long term conditions in children and young people.

While the benefits of regular participation in physical activity in children and young people are clear, misconceptions have developed about the possible negative effects and potential complications of exercise on long-term conditions such as epilepsy, asthma and diabetes. Over the last decade evidence has emerged supporting the positive impact that physical activity has on long-term conditions. Previous concerns were raised about the risks of hypoglycaemia in children with type 1 diabetes mellitus (T1DM) thus limiting participation in sports. Importantly, physical activity improves the metabolic profile, bone mineral density, cardiorespiratory fitness and insulin sensitivity while lowering mortality risk in children with T1DM. Children with asthma were prevented from doing exercise due to concerns about precipitating an acute asthmatic episode. To the contrary, physical activity interventions have consistently shown an increase in cardiovascular fitness, physical capacity, asthma-free days and quality of life in childhood asthmatics. Children with epilepsy are often excluded from sports due to concerns relating to increased seizure frequency, yet evidence suggests that this is not the case. The evidence supporting physical activity in childhood survivors of cancer is growing but still primarily confined to patients with acute lymphoblastic leukaemia. Participation in sports and physical activity also reduces mental health problems developing in adolescence. While further research is required to investigate benefits of physical activity on specific aspects of long-term conditions in children, in general this group should be advised to increase participation in sports and exercise as a means of improving long-term physical and mental health.

Correction: GATAD2B-associated neurodevelopmental disorder (GAND): clinical and molecular insights into a NuRD-related disorder.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

GATAD2B-associated neurodevelopmental disorder (GAND): clinical and molecular insights into a NuRD-related disorder.

PURPOSE: Determination of genotypic/phenotypic features of GATAD2B-associated neurodevelopmental disorder (GAND). METHODS: Fifty GAND subjects were evaluated to determine consistent genotypic/phenotypic features. Immunoprecipitation assays utilizing in vitro transcription-translation products were used to evaluate GATAD2B missense variants' ability to interact with binding partners within the nucleosome remodeling and deacetylase (NuRD) complex. RESULTS: Subjects had clinical findings that included macrocephaly, hypotonia, intellectual disability, neonatal feeding issues, polyhydramnios, apraxia of speech, epilepsy, and bicuspid aortic valves. Forty-one novelGATAD2B variants were identified with multiple variant types (nonsense, truncating frameshift, splice-site variants, deletions, and missense). Seven subjects were identified with missense variants that localized within two conserved region domains (CR1 or CR2) of the GATAD2B protein. Immunoprecipitation assays revealed several of these missense variants disrupted GATAD2B interactions with its NuRD complex binding partners. CONCLUSIONS: A consistent GAND phenotype was caused by a range of genetic variants in GATAD2B that include loss-of-function and missense subtypes. Missense variants were present in conserved region domains that disrupted assembly of NuRD complex proteins. GAND's clinical phenotype had substantial clinical overlap with other disorders associated with the NuRD complex that involve CHD3 and CHD4, with clinical features of hypotonia, intellectual disability, cardiac defects, childhood apraxia of speech, and macrocephaly.

15-Epi-LXA4 and MaR1 counter inflammation in stromal cells from patients with Achilles tendinopathy and rupture.

Resolution of inflammation is poorly understood in Achilles tendon disorders. Herein, we investigated the bioactive lipid mediator profiles of tendon-derived stromal cells isolated from patients with Achilles tendinopathy (AT) or Achilles rupture (AR) under baseline and IL-1ß-stimulated conditions. We also determined whether incubating these cells with 2 of the mediators produced by tendon-derived stromal cells, 15-epi-Lipoxin A4 (15-epi-LXA4) or maresin (MaR)-1, moderated their proinflammatory phenotype. Under baseline conditions, AT cells showed concurrent increased levels of proinflammatory eicosanoids and proresolving mediators compared with AR cells. IL-1ß treatment induced profound prostaglandin E2 release in AR compared with AT cells. Incubation of IL-1ß treated AT and AR tendon-derived stromal cells in 15-epi-LXA4 or MaR1 reduced proinflammatory eicosanoids and potentiated the release of proresolving mediators. These mediators also induced specialized proresolving mediator (SPM) biosynthetic enzymes arachidonate lipoxygenase (ALOX) 12 and ALOX15 and up-regulated the proresolving receptor ALX compared with vehicle-treated cells. Incubation in 15-epi-LXA4 or MaR1 also moderated the proinflammatory phenotype of AT and AR cells, regulating podoplanin, CD90, signal transducer and activator of transcription (STAT)-1, IL-6, IFN regulatory factor (IRF) 5, and TLR4 and suppressed c-Jun N-terminal kinase 1/2/3, Lyn, STAT-3, and STAT-6 phosphokinase signaling. In summary, we identify proresolving mediators that are active in AT and AR and propose SPMs, including 15-epi-LXA4 or MaR1, as a potential strategy to counterregulate inflammatory processes in these cells.-Dakin, S. G., Colas, R. A., Newton, J., Gwilym, S., Jones, N., Reid, H. A. B., Wood, S., Appleton, L., Wheway, K., Watkins, B., Dalli, J., Carr, A. J. 15-Epi-LXA4 and MaR1 counter inflammation in stromal cells from patients with Achilles tendinopathy and rupture.

Chronic inflammation is a feature of Achilles tendinopathy and rupture.

BACKGROUND: Recent investigation of human tissue and cells from positional tendons such as the rotator cuff has clarified the importance of inflammation in the development and progression of tendon disease. These mechanisms remain poorly understood in disease of energy-storing tendons such as the Achilles. Using tissue biopsies from patients, we investigated if inflammation is a feature of Achilles tendinopathy and rupture. METHODS: We studied Achilles tendon biopsies from symptomatic patients with either mid-portion tendinopathy or rupture for evidence of abnormal inflammatory signatures. Tendon-derived stromal cells from healthy hamstring and diseased Achilles were cultured to determine the effects of cytokine treatment on expression of inflammatory markers. RESULTS: Tendinopathic and ruptured Achilles highly expressed CD14+ and CD68+ cells and showed a complex inflammation signature, involving NF-κB, interferon and STAT-6 activation pathways. Interferon markers IRF1 and IRF5 were highly expressed in tendinopathic samples. Achilles ruptures showed increased PTGS2 and interleukin-8 expression. Tendinopathic and ruptured Achilles tissues expressed stromal fibroblast activation markers podoplanin and CD106. Tendon cells isolated from diseased Achilles showed increased expression of pro-inflammatory and stromal fibroblast activation markers after cytokine stimulation compared with healthy hamstring tendon cells. CONCLUSIONS: Tissue and cells derived from tendinopathic and ruptured Achilles tendons show evidence of chronic (non-resolving) inflammation. The energy-storing Achilles shares common cellular and molecular inflammatory mechanisms with functionally distinct rotator cuff positional tendons. Differences seen in the profile of ruptured Achilles are likely to be attributable to a superimposed phase of acute inflammation and neo-vascularisation. Strategies that target chronic inflammation are of potential therapeutic benefit for patients with Achilles tendon disease.

Extracorporeal cellular therapy (ELAD) in severe alcoholic hepatitis: A multinational, prospective, controlled, randomized trial.

Severe alcoholic hepatitis (sAH) is associated with a poor prognosis. There is no proven effective treatment for sAH, which is why early transplantation has been increasingly discussed. Hepatoblastoma-derived C3A cells express anti-inflammatory proteins and growth factors and were tested in an extracorporeal cellular therapy (ELAD) study to establish their effect on survival for subjects with sAH. Adults with sAH, bilirubin ≥8 mg/dL, Maddrey's discriminant function ≥ 32, and Model for End-Stage Liver Disease (MELD) score ≤ 35 were randomized to receive standard of care (SOC) only or 3-5 days of continuous ELAD treatment plus SOC. After a minimum follow-up of 91 days, overall survival (OS) was assessed by using a Kaplan-Meier survival analysis. A total of 203 subjects were enrolled (96 ELAD and 107 SOC) at 40 sites worldwide. Comparison of baseline characteristics showed no significant differences between groups and within subgroups. There was no significant difference in serious adverse events between the 2 groups. In an analysis of the intent-to-treat population, there was no difference in OS (51.0% versus 49.5%). The study failed its primary and secondary end point in a population with sAH and with a MELD ranging from 18 to 35 and no upper age limit. In the prespecified analysis of subjects with MELD < 28 (n = 120), ELAD was associated with a trend toward higher OS at 91 days (68.6% versus 53.6%; P = .08). Regression analysis identified high creatinine and international normalized ratio, but not bilirubin, as the MELD components predicting negative outcomes with ELAD. A new trial investigating a potential benefit of ELAD in younger subjects with sufficient renal function and less severe coagulopathy has been initiated. Liver Transplantation 24 380-393 2018 AASLD.

The cost-effectiveness of exercise-based cardiac rehabilitation: a systematic review of the characteristics and methodological quality of published literature.

AIM: This descriptive review aimed to assess the characteristics and methodological quality of economic evaluations of cardiac rehabilitation (CR) programs according to updated economic guidelines for healthcare interventions. Recommendations will be made to inform future research addressing the impact of a physical exercise component on cost-effectiveness. METHODS: Electronic databases were searched for economic evaluations of exercise-based CR programs published in English between 2000 and 2014. The Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement was used to review the methodological quality of included economic evaluations. RESULTS: Fifteen economic evaluations met the review inclusion criteria. Assessed study characteristics exhibited wide variability, particularly in their economic perspective, time horizon, setting, comparators and included costs, with significant heterogeneity in exercise dose across interventions. Ten evaluations were based on randomised controlled trials (RCTs) spanning 6-24 months but often with weak or inconclusive results; two were modelling studies; and the final three utilised longer time horizons of 3.5-5 years from which findings suggest that long-term exercise-based CR results in lower costs, reduced hospitalisations and a longer cumulative patient lifetime. None of the 15 articles met all the CHEERS quality criteria, with the majority either fully or partially meeting a selection of the assessed variables. CONCLUSION: Evidence exists supporting the cost-effectiveness of exercise-based CR for cardiovascular disease patients. However, variability in CR program delivery and weak consistency between study perspective and design limits study comparability and therefore the accumulation of evidence in support of a particular exercise regime. The generalisability of study findings was limited due to the exclusion of patients with comorbidities as would typically be found in a real-world setting. The use of longer time-horizons would be more comparable with a chronic condition and enable economic assessments of the long-term effects of CR. As none of the articles met recent reporting standards for the economic assessment of healthcare interventions, it is recommended that future studies adhere to such guidelines.

An education programme influencing health professionals to recommend exercise to their type 2 diabetes patients - understanding the processes: a case study from Oxfordshire, UK.

BACKGROUND: Increasing levels of physical activity decreases the risk of premature mortality associated with chronic diseases e.g., coronary heart disease, type 2 diabetes, stroke. Despite this, most adults in England do not meet physical activity guidelines. Physical activity advice and signposting offered to at-risk patients by primary care providers is recommended. However, exercise medicine education is sparse, leading to poor practitioner knowledge of the risk reduction evidence and strategies to implement effective patient behaviour change. The 'Generation Games' intervention seeks physical activity increase in the 50+ population of Oxfordshire. It offers a Health Professional Education Programme (HPEP) providing exercise medicine education, and promotion of Generation Games to which health professionals can signpost patients. There is a poor evidence base concerning how such education translates into patient exercise behaviour change. METHODS: The research aimed to create more understanding of how an education programme can influence health professionals to recommend Generation Games to and increase exercise behaviour in type 2 diabetes patients. A case study method facilitated examination of the routines and cultures studied - the experience of Diabetes nurses was used as an example of best practice engagement with the HPEP. Observation, interviews and documentation were employed to triangulate data. Data analysis refined and developed themes within key theoretical frameworks. RESULTS: Firstly, there is a lack of knowledge about physical activity risk reduction benefits and a belief that efforts to motivate patients to increase their physical activity are ineffective, thus creating barriers to engagement with the HPEP. Secondly, practice nurses tasked with delivering lifestyle advice to diabetes patients - themselves suffering a motivational interviewing skill deficit - find ingrained physical activity behaviours extremely challenging, and therefore highly value the HPEP for providing helpful tools. Thirdly, patients who hear of Generation Games from a health professional may have mismatched expectations of how their exercise behaviour can change. CONCLUSIONS: Exercise medicine education has the potential to improve patient care and services. Before initiatives like the HPEP can succeed, primary care practice requires a more supportive exercise medicine culture. Also necessary is adequate resourcing of patient-centred behaviour change advice, training, encouragement and monitoring services.