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Aims: Patients with haemochromatosis (HFE) are known to have an increased risk of developing hepatocellular carcinoma (HCC). Available data are conflicting on whether such patients have poorer prognosis, and there is lack of data regarding the biology of HFE-HCC. We compared the course of HFE-HCC with a matched non-HFE-HCC control group and examined tumour characteristics using immunohistochemistry., Methods: In this tertiary care-based retrospective analysis, 12 patients with HFE and 34 patients with alcohol/non-alcoholic steatohepatitis who underwent initially successful curative HCC therapy with ablation or resection were identified from our registry. Time to tumour progression was compared. Resected liver tissue from a separate cohort of 11 matched patients with HFE-HCC and without HFE-HCC was assessed for the expression of progenitor and epithelial-mesenchymal transition markers using immunohistochemistry., Results: The median follow-up was 24.39 and 24.28 months for patients with HFE-HCC and those without HFE-HCC, respectively (p>0.05). The mean time to progression was shorter in the HFE group compared with the non-HFE group (12.87 months vs 17.78 months; HR 3.322, p<0.05). Patients with HFE-HCC also progressed to more advanced disease by the end of follow-up (p<0.05). Immunohistochemical analysis of matched HFE-HCC and non-HFE-HCC explants demonstrated increased expression of the cancer stem cell markers EpCAM (epithelial cell adhesion molecule) and EpCAM/SALL4 (spalt-like transcription factor 4) coexpression in HFE-HCC specimens (p<0.05). There was a high frequency of combined tumour subtypes within the HFE cohort., Conclusions: This study demonstrates that the clinical course of patients with HFE-HCC is more aggressive and provides the first data indicating that their tumours have increased expression of progenitor markers. These findings suggest patients with HFE-HCC may need to be considered for transplant at an earlier stage., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background: Four out of five people living with osteoarthritis (OA) also suffer with at least one other long-term health condition. The complex interaction between OA and multiple long-term conditions (MLTCs) can result in difficulties with self-care, restricted mobility, pain, anxiety, depression and reduced quality of life. The aim of the MulTI-domain Self-management in Older People wiTh OstEoarthritis and Multi-Morbidities (TIPTOE) trial is to evaluate the clinical and cost-effectiveness of the Living Well self-management support intervention, co-designed with people living with OA, integrated into usual care, in comparison to usual care alone., Methods: TIPTOE is a multi-centre, two-arm, individually randomised controlled trial where 824 individuals over 65 years old with knee and/or hip joint pain from their OA affected joint and at least one other long-term health condition will be randomised to receive either the Living Well Self-Management support intervention or usual care. Eligible participants can self-refer onto the trial via a website or be referred via NHS services across Wales and England. Those randomised to receive the Living Well support intervention will be offered up to six one-to-one coaching sessions with a TIPTOE-trained healthcare practitioner and a co-designed book. Participants will be encouraged to nominate a support person to assist them throughout the study. All participants will complete a series of self-reported outcome measures at baseline and 6- and 12-month follow-up. The primary outcome is symptoms and quality of life as assessed by the Musculoskeletal Health Questionnaire (MSK-HQ). Routine data will be used to evaluate health resource use. A mixed methods process evaluation will be conducted alongside the trial to inform future implementation should the TIPTOE intervention be found both clinically and cost-effective. An embedded 'Study Within A Project' (SWAP) will explore and address barriers to the inclusion of under-served patient groups (e.g. oldest old, low socioeconomic groups, ethnic groups)., Discussion: TIPTOE will evaluate the clinical and cost-effectiveness of a co-designed, living well personalised self-management support intervention for older individuals with knee and/or hip OA and MLTCs. The trial has been designed to maximise inclusivity and access., Trial Registration: ISRCTN 16024745 . Registered on October 16, 2023., (© 2024. The Author(s).)

Introduction: There is a lack of community-based rehabilitation for stroke in the Philippines, and research on this topic is limited. Different challenges may be encountered in urban and rural settings. The aim of the Tulong, Ugnayan ng Lingap At gabaY (TULAY) project is to develop a context-appropriate, community-based stroke support programme, consisting of self-management and training resources to augment the rehabilitation and recovery process. An important stage in the development of this programme is to qualitatively explore the experiences and needs of all stakeholders., Materials and Methods: Using co-designed and evidence-based topic guides, in-depth semi-structured interviews will be conducted with people living with stroke, household carers and care providers. We will aim to gain a representation of different regions (within Luzon, Visayas, and Northern Mindanao), socioeconomic levels, and urban and rural locations. For people with stroke and household carers, interviews will be supplemented by auto-photography and visual elicitation to widen access for those that prefer to share their experiences visually or have communication problems. An interpretivist paradigm will be applied across all interview data and the consolidated criteria for reporting qualitative research (COREQ) will be followed. Thematic analysis will be undertaken using guidance by Braun and Clarke., Discussion: To our knowledge, this study is the first of its kind in the Philippines. It has several methodological strengths, including the capture of perspectives from multiple stakeholders in diverse settings, the inclusion of people with communication difficulties, use of visual methods, and analysis in the native language. The findings will have various applications, including the potential to influence policy, practice and guidelines, and to inform the development of the TULAY stroke support programme., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Buckingham et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: To translate and cross-culturally adapt the Stroke Self-Efficacy Questionnaire (SSEQ) from English to Swedish and to evaluate psychometric properties of the questionnaire., Methods: A cross-sectional study design, where the translation followed a process including initial translation, synthesis, backward translation, expert committee, and pretest. Content validity was assessed using Content validity index (CVI). Psychometric assessments included floor-ceiling effects and internal consistency., Results: Language and cultural congruence were achieved, and content validity index scores were high (0.923-1). The psychometric evaluations provided acceptable outcomes concerning internal consistency, with Cronbach's alpha scores for the total scale (0.902), the activities subscale (0.861) and the self-management subscale (0.818) respectively. Ceiling effects were evident, but no floor effects., Conclusion: This study found the Swedish version of the SSEQ promising as a tool for assessment of self-efficacy in a Swedish stroke care setting, although further psychometric assessments are recommended in future studies., (© 2024. The Author(s).)

Background: Performance arts can benefit people with acquired brain injury (ABI). This study explored the online delivery during COVID-19 restrictions, of a performance art intervention through the experiences of participants, artists and facilitators., Methods: Two community-based programmes were delivered. Online ethnographic observations and semi-structured interviews with participants, artists and facilitators were completed., Results: The programmes benefited participants by addressing loneliness and isolation; building confidence through peer support; improving physical limitations through movement; improving communication through music and vocal work; and using poetry, visual arts, metaphor and performance to make sense of participants' experiences. Participants had mixed experiences of participation, but it was an acceptable alternative to in-person arts interventions for those who overcame digital challenges., Conclusions: ABI survivors can engage in online performance art programmes and find participation valuable for their health, well-being, and recovery. More work is needed to explore the generalisability of these findings, especially given digital poverty.

Purpose: People with rare neurological conditions (RNCs) struggle to achieve regular physical activity (PA). This study explored experiences of people with RNC engaging in PA, their carers, and health care professionals (HCPs) working with them., Materials & Methods: We developed three surveys: for individuals living with RNCs, their carers, and HCPs working with them. Themes from interviews with RNC charity representatives were used to co-design questions, together with people living with RNCs, their representatives, and an expert panel. Surveys were disseminated via charity mailing lists, social media accounts, and professional networks (HCPs)., Results: We received 436 responses (225 people with RNC, 94 carers, 117 HCPs). Most respondents with RNC achieved some level of regular PA but needed motivation to maintain it. Many felt they lacked knowledge on starting and staying active, with scarce resources and support. Most HCP respondents worked in specialist services, and overwhelmingly agreed that people with RNC should be physically active, while acknowledging lack of evidence and resources., Conclusions: We identified key barriers at environmental/organisational, interpersonal, and intrapersonal levels, highlighting a critical lack of support for people with RNC across UK health services. These factors can be targeted to increase engagement in PA.Implications for rehabilitationPeople living with rare neurological conditions experience barriers to engaging in physical activity, with some common to more prevalent neurological diseases, e.g. access and facilities, but some notable differences due to the rarity of the conditionFor people living with rare neurological conditions, and their carers, there is a lack of knowledge on safe and appropriate engagement in physical activityIncreasing the knowledge of health and exercise professionals may improve how they support people with rare neurological disease to engage with physical activity.Evidence based resources and recommendations for people living with rare neurological conditions, and professionals working with them, may facilitate engagement in physical activity.

Introduction: Many Covid-19 survivors are living with unresolved, relapsing and remitting symptoms and no 'one size' of treatment is likely to be effective for everyone. Supported self-management for the varied symptoms of Long Covid (LC) is recommended by the National Institute for Health and Care Excellence in the United Kingdom. We aimed to develop a new personalised support intervention for people living with LC using a structured co-design framework to guide replication and evaluation., Methods: We used the improvement methodology, Experience-Based Co-Design, in an accelerated form to harness the collective experiences of people with LC. Incorporating evidence from 'Bridges Self-Management' (Bridges) an approach in which healthcare professionals (HCPs)are trained to support knowledge, confidence and skills of individuals living with long term conditions. Co-designed resources are also central to Bridges. Adults who self-identified as living with or recovered from LC, from England or Wales, aged 18 years and over were recruited, and HCPs, with experience of supporting people with LC. Participants took part in a series of small co-design group meetings and larger mixed meetings to agree priorities, core principles and generate resources and intervention content., Results: People with LC (n = 28), and HCPs (n = 9) supported co-design of a book (hard-copy and digital form) to be used in 1:1 support sessions with a trained HCP. Co-design stages prioritised stories about physical symptoms first, and psychological and social challenges which followed, nonlinear journeys and reconceptualising stability as progress, rich descriptions of strategies and links to reputable advice and support for navigating healthcare services. Co-design enabled formulation of eight core intervention principles which underpinned the training and language used by HCPs and fidelity assessments., Conclusion: We have developed a new personalised support intervention, with core principles to be used in one-to-one sessions delivered by trained HCPs, with a new co-designed book as a prompt to build personalised strategies and plans using narratives, ideas, and solutions from other people with LC. Effectiveness and cost effectiveness of the 'LISTEN' intervention will be evaluated in a randomised controlled trial set within the context of the updated Framework for Developing and Evaluating Complex Interventions., Patient and Public Contribution: The LISTEN Public and Patient Involvement (PPI) group comprised seven people living with LC. They all contributed to the design of this study and five members were part of a larger co-design community described in this paper. They have contributed to this paper by interpreting stages of intervention design and analysis of results. Three members of our PPI group are co-authors of this paper., (© 2024 The Author(s). Health Expectations published by John Wiley & Sons Ltd.)

Background: Around one in ten people who contract Covid-19 report ongoing symptoms or 'Long Covid'. Without any known interventions to cure the condition, forms of self-management are routinely prescribed by healthcare professionals and described by people with the condition. However, there is limited research exploring what strategies are used to navigate everyday life with Long Covid, and experiences that initiate development of these strategies. Our study aimed to explore the range and influence of self-generated strategies used by people with Long Covid to navigate everyday life within the context of their own condition., Methods: Forming part of the Long Covid Personalised Self-managemenT support co-design and EvaluatioN (LISTEN) project, we conducted a qualitative study using narrative interviews with adults who were not hospitalised with Covid-19. Participants aged over 18 years, who self-identified with Long Covid, were recruited from England and Wales. Data were analysed with patient contributors using a reflexive thematic analysis., Results: Eighteen participants (mean age = 44 years, SD = 13 years) took part in interviews held between December 2021 and February 2022. Themes were constructed which depicted 1) the landscape behind the Long Covid experience and 2) the everyday experience of participants' Long Covid. The everyday experience comprised a combination of physical, emotional, and social factors, forming three sub-themes: centrality of physical symptoms, navigating 'experts' and the 'true colour' of personal communities, and a rollercoaster of psychological ambiguity). The third theme, personal strategies to manage everyday life was constructed from participants' unique presentations and self-generated solutions to manage everyday life. This comprised five sub-themes: seeking reassurance and knowledge, developing greater self-awareness through monitoring, trial and error of 'safe' ideas, building in pleasure and comfort, and prioritising 'me'., Conclusions: Among this sample of adults with Long Covid, their experiences highlighted the unpredictable nature of the condition but also the use of creative and wide ranging self-generated strategies. The results offer people with Long Covid, and healthcare professionals supporting them, an overview of the collective evidence relating to individuals' self-management which can enable ways to live 'better' and regain some sense of identity whilst facing the impact of a debilitating, episodic condition., Trial Registration: LISTEN ISRCTN36407216., (© 2024. Crown.)

Evidence-informed interventions for stroke self-management support can influence functional capability and social participation. People with stroke should be offered self-management support after hospital discharge. However, in Portugal, there are no known programs of this nature. This study aimed to develop a person-centered and tailored blended care program for post-stroke self-management, taking into account the existing evidence-informed interventions and the perspectives of Portuguese people with stroke, caregivers, and health professionals. An exploratory sequential mixed methods approach was used, including qualitative methods during stakeholder consultation (stage 1) and co-production (stage 2) and quantitative assessment during prototyping (stage 3). After ethical approval, recruitment occurred in three health units. Results from a literature search led to the adaptation of the Bridges Stroke Self-Management Program. In stage one, 47 participants were interviewed, with two themes emerging: (i) Personalized support and (ii) Building Bridges through small steps. In stage two, the ComVida program was developed, combining in-person and digital approaches, supported by a workbook and a mobile app. In stage three, 56 participants evaluated prototypes, demonstrating a strong level of quality. Understandability and actionability of the developed tools obtained high scores (91-100%). The app also showed good usability (A-grade) and high levels of recommendation (5 stars).

Purpose: The impact of a stroke is particularly evident during the transition home, with reported unmet needs. However, little is known about post-stroke adaptation in Portugal. This study aimed to understand how Portuguese people with stroke and their informal carers/family adapt over time, and how health professionals support their adaptation., Methods: A multi-perspective, longitudinal qualitative study was conducted using in-depth semi-structured interviews one and six months after inpatient discharge. A purposive sample of 24 participants (8 triads) participated. Thematic and narrative analysis strategies were used., Results: Three themes were identified: Managing change over time; Balancing support over time; Changing priorities . These suggest the importance of time and gradual adjustment of health professionals' approach throughout the rehabilitation process tailored to people with stroke' and carers' needs. Both valued positive thoughts and support from others to adjust life goals and find a balance between a mutual/bidirectional support and time for themselves., Conclusions: Findings show that the manner in which changes after a stroke are approached may be positively transformed to provide strength. As a result of the deeper understanding gained from this study, health professionals may be better placed to acknowledge the needs of people with stroke and carers and find effective ways of supporting them.

Purpose: People living with stroke and neurological conditions access rehabilitation at different times but self-management is often viewed as what happens post-discharge. Personalised models that integrate self-management support within everyday care are now advocated but this may require practitioners to change their behaviour to adopt and sustain new ways of working. The People1st project evaluated integration of an existing Supported Self-Management programme ("Bridges") across varied stroke and neurorehabilitation service contexts., Materials and Methods: Mixed-method evaluation of training for groups of healthcare practitioners across 24 UK National Health Service (NHS) Trusts, exploring how learning from Bridges was assimilated and enacted in practice, on an individual and collective basis., Results: Staff growth in confidence and skill around supported self-management was demonstrated. Transformations to practice included changes to: the structure of, and language used in, patient interactions; induction/training processes to increase potential for sustainability; and sharing of successes. Bridges helped practitioners make changes that brought them closer to their professional ideals. Engaged leadership was considered important for successful integration., Conclusions: Bridges was successfully integrated within a wide range of stroke and neurorehabilitation service contexts, enabled by an approach in line with practitioners' values-based motivations. Further work is required to explore sustainability and impact on service users. Implications for rehabilitationPersonalised models of care and support for self-management are advocated for people living with stroke and neurological conditions; this requires practitioners to be supported to change behaviour and practices to adopt and sustain new ways of working.Staff from a wide variety of backgrounds in neurorehabilitation and stroke can learn collaboratively about self-management practices via the Bridges programme and can integrate those practices into their service contexts.Bridges can take practitioners closer to their professional ideals of caring and making a difference and empowers them to initiate change.Organisational commitment and engaged leadership are required to facilitate a culture of support for self-management in practice.

Objectives and Design: National guidelines emphasise the need to enhance arm and hand recovery poststroke. OnTrack is a 12-week package aiming to address this need. Feasibility was evaluated in a single-arm feasibility study (reported separately). This paper presents findings from a nested process evaluation. The objectives were to explore users' experiences of OnTrack and fidelity of delivery, in order to inform a definitive trial of effectiveness and future delivery., Setting: Participants were interviewed in a range of settings in hospital, home or via telephone, at the end of their intervention cycle. Session observations for a selection of coaching sessions were carried out in person at home or remotely, post-COVID-19., Participants: Eleven participants who completed the intervention following a stroke were interviewed. Seven coaching sessions were observed., Intervention: This process evaluation was part of a larger feasibility study of OnTrack, which involves setting movement targets and monitoring activity using a tracker on the wrist, motivational messaging via a Smartphone and self-management coaching. Preliminary analysis of data collected was conducted with a public and patient involvement group formed of stroke survivors. This informed changes in intervention delivery., Results: Participants reported finding the OnTrack programme beneficial, with the coaching role seen as particularly important. Participants found activity tracking motivating, but some noted discrepancies between tracked movement and what they considered useful activity. Motivational messages were sometimes irritating. Most felt ready to sustain their own activity practice at the end of the programme., Conclusions: This process evaluation supported initial theoretical assumptions that OnTrack would enable activity practice through the use of remote monitoring. There was a strong emphasis on the coaching role as a mechanism of impact supporting the technological intervention. These findings will inform the next stages of delivery in a definitive trial., Trial Registration Number: NCT03944486., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Self-management support can improve quality of life, mood, self-efficacy, and physical function following a stroke. Knowledge of how people with stroke understand and experience self-management in different contexts is crucial to developing effective self-management support. This study explored how people with stroke understand and practice self-management during the post-acute phase., Method: A descriptive study using qualitative content analysis to explore data from semistructured interviews RESULTS: Eighteen participants were interviewed. Most participants interpreted self-management as 'taking care of their business' and 'being independent". However, they encountered difficulties performing daily activities, for which they felt unprepared. Although interest in implementing self-management support increases, participants did not report receiving specific advice from healthcare professionals., Conclusion: People continue to feel unprepared to manage everyday activities after hospital discharge and must largely work things out for themselves. There is an overlooked opportunity to start the process of self-management support earlier in the stroke pathway, with healthcare professionals and people with stroke combining their skills, ideas and expertise. This would enable confidence to self-management to flourish rather than decrease during the transition from hospital to home., Practical Implications: Individual tailored self-management support could help people with stroke more successfully manage their daily lives post-stroke., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

The gut microbiota regulates chronic inflammation and has been implicated in the pathogenesis of a broad spectrum of disease including autoimmunity and cancer. Microbial short-chain fatty acids (SCFAs) e.g., butyrate have demonstrated immunomodulatory effects and are thought to be key mediators of the host-microbiome interaction. Here, we investigated the effect of butyrate on effector functions of blood derived human NK cells stimulated for 18 h with a combination of IL-12/IL-15, a potent mix of cytokines that drive NK cell activation. We show that butyrate has a strong anti-inflammatory effect on NK cells. NK cells cultured in the presence of butyrate expressed lower levels of activating receptors (TRAIL, NKp30, NKp44) and produced lower levels of cytokines (IFNγ, TNF-α, IL-22, granzyme B, granzyme A, perforin) in response to IL-12/IL-15. Butyrate restricted NK cell function by downregulation of mTORC1 activity, c-Myc mRNA expression and metabolism. Using a shotgun proteomic approach, we confirmed the effect of butyrate on NK cell cytokine signaling and metabolism and identified BRD2, MAT2A and EHD1 as downstream mediators of these effects. This insight into the immunomodulatory activity of butyrate on human NK cell function might help to develop new ways to limit NK cell function during chronic inflammation., (© 2023. The Author(s).)

Background: Individuals living with long COVID experience multiple, interacting and fluctuating symptoms which can have a dramatic impact on daily living. The aim of the Long Covid Personalised Self-managemenT support EvaluatioN (LISTEN) trial is to evaluate effects of the LISTEN co-designed self-management support intervention for non-hospitalised people living with long COVID on participation in routine activities, social participation, emotional well-being, quality of life, fatigue, and self-efficacy. Cost-effectiveness will also be evaluated, and a detailed process evaluation carried out to understand how LISTEN is implemented., Methods: The study is a pragmatic randomised effectiveness and cost-effectiveness trial in which a total of 558 non-hospitalised people with long COVID will be randomised to either the LISTEN intervention or usual care. Recruitment strategies have been developed with input from the LISTEN Patient and Public Involvement and Engagement (PPIE) advisory group and a social enterprise, Diversity and Ability, to ensure inclusivity. Eligible participants can self-refer into the trial via a website or be referred by long COVID services. All participants complete a range of self-reported outcome measures, online, at baseline, 6 weeks, and 3 months post randomisation (the trial primary end point). Those randomised to the LISTEN intervention are offered up to six one-to-one sessions with LISTEN-trained intervention practitioners and given a co-designed digital resource and paper-based book. A detailed process evaluation will be conducted alongside the trial to inform implementation approaches should the LISTEN intervention be found effective and cost-effective., Discussion: The LISTEN trial is evaluating a co-designed, personalised self-management support intervention (the LISTEN intervention) for non-hospitalised people living with long COVID. The design has incorporated extensive strategies to minimise participant burden and maximise access. Whilst the duration of follow-up is limited, all participants are approached to consent for long-term follow-up (subject to additional funding being secured)., Trial Registration: LISTEN ISRCTN36407216. Registered on 27/01/2022., (© 2023. The Author(s).)

The pragmatic (i.e., practical) quality of quantitative implementation measures has received increased attention in the implementation science literature in recent years. Implementation measures that are judged to be pragmatic by implementation stakeholders are thought to be more likely to be applied in research and practice. Despite the need for pragmatic implementation measures, ambiguity and uncertainty regarding what constitutes a pragmatic measure remains. This study sought to identify and critically appraise the published literature to understand (i) how pragmatism is defined as a measurement construct/quality of implementation determinants and outcome instruments; (ii) how pragmatic qualities of instruments are evaluated; (iii) identify key gaps and limitations of the current evidence-base and (iv) identify recommendations for future research. We conducted a scoping review of the literature also employing methods of critical review. PubMed and PsycINFO databases, using the OVID interface, were searched for relevant articles published between January 2010 and September 2020. Articles that contained a definition and/or described characteristics of "pragmatism" as a measurement construct of quantitative implementation outcomes (as defined by Proctor's Implementation Outcomes taxonomy) and/or implementation determinants were eligible for inclusion. Nine articles met inclusion criteria. A degree of overlap in definitions and terms used to describe the pragmatic qualities of quantitative implementation determinant and outcome instruments were found. The most frequently cited descriptors of pragmatism were "not burdensome", "brief", "reliable", "valid" and "sensitive to change". 3 of the 9 included articles involved international implementation stakeholders in defining and conceptualizing pragmatism and employed specific methods to do so, including a systematic literature review, stakeholder interviews, concept mapping, and a Delphi process. All other articles defined pragmatism, with or without citing relevant literature. One article objectively assessed the pragmatic qualities, above and beyond the psychometric qualities, of implementation measures, using the Psychometric and Pragmatic Evidence Rating Scale (PAPERS). The evidence base within the implementation instrumentation literature on what pragmatism is and how it might be assessed is limited. Some of the research identified in the review provides a strong foundation to build upon, by testing its applicability in other settings (including healthcare areas and countries) and among a more diverse group of stakeholders. We discuss directions for further development of the concept of pragmatism relating to the measurement of implementation determinants and outcomes., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society of Behavioral Medicine.)

Muscle stem cells (MuSCs) are indispensable for muscle regeneration. A multitude of extracellular stimuli direct MuSC fate decisions from quiescent progenitors to differentiated myocytes. The activity of these signals is modulated by coreceptors such as syndecan-3 (SDC3). We investigated the global landscape of SDC3-mediated regulation of myogenesis using a phosphoproteomics approach which revealed, with the precision level of individual phosphosites, the large-scale extent of SDC3-mediated regulation of signal transduction in MuSCs. We then focused on INSR/AKT/mTOR as a key pathway regulated by SDC3 during myogenesis and mechanistically dissected SDC3-mediated inhibition of insulin receptor signaling in MuSCs. SDC3 interacts with INSR ultimately limiting signal transduction via AKT/mTOR. Both knockdown of INSR and inhibition of AKT restore Sdc3 -/- MuSC differentiation to wild type levels. Since SDC3 is rapidly downregulated at the onset of differentiation, our study suggests that SDC3 acts a timekeeper to restrain proliferating MuSC response and prevent premature differentiation., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Long Covid is recognised as a complex condition characterised by multiple, interacting and fluctuating symptoms which impact everyday life in diverse ways. The extent of symptom clusters and variability supports interventions that can accommodate heterogeneity, such as personalised self-management support. This approach is also advocated by people living with long Covid and guidelines published by the UK's National Institute for Health and Care Excellence. Long Covid Personalised Self-managemenT support co-design and EvaluatioN (LISTEN) is one of 15 research projects funded by the UK's National Institute of Health Research long Covid research programme. LISTEN aims to work with people living with or recovered from long Covid to co-design self-management resources, and a training programme for rehabilitation practitioners to deliver personalised support. The intervention will focus on people not hospitalised for Covid. The protocol presented here details the co-design of the LISTEN intervention which, on completion, will be evaluated in a randomised controlled trial., Methods: The study will utilise an Accelerated Experience-Based Co-Design approach, and involve 30 people from England and Wales with lived experience of long Covid, and 15 rehabilitation practitioners living with, or supporting people with, long Covid. Through online meetings, participants will share their stories of long Covid, their challenges and strategies to live better with or recover from long Covid, their priorities for self-management resources and the practitioner training andcreate, review and refine these resources and the training. Throughout, LISTEN will draw upon the UK standards of public involvement in research., Discussion: If effective and cost-effective, the intervention will be available across the UK's National Health Service. The first of its kind, this study could make a difference to the lives of people with long Covid. To ensure impact, we have developed strategies to involve people from diverse backgrounds and mitigate potential barriers to involvement., Competing Interests: The authors have declared that no competing interests exist.

Aims: Miscarriage and stillbirth have been included in cardiovascular disease (CVD) risk guidelines, however heterogeneity in exposures and outcomes and the absence of reviews assessing induced abortion, prevented comprehensive assessment. We aimed to perform a systematic review and meta-analysis of the risk of cardiovascular diseases for women with prior pregnancy loss (miscarriage, stillbirth, and induced abortion)., Methods and Results: Observational studies reporting risk of CVD, coronary heart disease (CHD), and stroke in women with pregnancy loss were selected after searching MEDLINE, Scopus, CINAHL, Web of Knowledge, and Cochrane Library (to January 2020). Data were extracted, and study quality were assessed using the Newcastle-Ottawa Scale. Pooled relative risk (RR) and 95% confidence intervals (CIs) were calculated using inverse variance weighted random-effects meta-analysis.Twenty-two studies involving 4 337 683 women were identified. Seven studies were good quality, seven were fair and eight were poor. Recurrent miscarriage was associated with a higher CHD risk (RR = 1.37, 95% CI: 1.12-1.66). One or more stillbirths was associated with a higher CVD (RR = 1.41, 95% CI: 1.09-1.82), CHD (RR = 1.51, 95% CI: 1.04-1.29), and stroke risk (RR = 1.33, 95% CI: 1.03-1.71). Recurrent stillbirth was associated with a higher CHD risk (RR = 1.28, 95% CI: 1.18-1.39). One or more abortions was associated with a higher CVD (RR = 1.04, 95% CI: 1.02-1.07), as was recurrent abortion (RR = 1.09, 95% CI: 1.05-1.13)., Conclusion: Women with previous pregnancy loss are at a higher CVD, CHD, and stroke risk. Early identification and risk factor management is recommended. Further research is needed to understand CVD risk after abortion., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objectives: The primary objective was to gain insight into the lived experiences of using day-to-day strategies to manage post-stroke fatigue., Design: Qualitative, descriptive study., Setting: Community telephone interviews., Participants: A purposive sample of 20 stroke survivors with current, or previous, post-stroke fatigue, and 8 caregivers, who provided informal care or support, were recruited., Main Measures: Semi-structured telephone interviews were undertaken. Data were analysed using a framework approach., Results: Most participants had found their own ways of coping and their personal strategies included acceptance of having fatigue; 'pacing' (spreading activities out and interspersing with rest periods); keeping a diary in order to plan activities and to identify 'trigger' activities which induced fatigue; talking to (and educating) others about having fatigue; using relaxation; and accessing professional advice and support. The burden placed on caregivers was considerable and they often had to oversee the post-stroke fatigue management strategies used., Conclusions: Post-stroke fatigue is managed in different ways and there was not one particular strategy that seemed effective for everyone. Most people in our study had had to devise their own ways of coping practically. Given the scale of this problem, which profoundly impacts the lives of both stroke survivors and caregivers, the management of post-stroke fatigue merits more attention and evaluation. However, this must be directly informed by those with lived experience.

Objectives: Arm weakness is common after stroke; repetitive activity is critical for recovery but people struggle with knowing what to do, volume, and monitoring progress. We studied the feasibility and acceptability of OnTrack, a digital intervention supporting arm and hand rehabilitation in acute and home settings., Design: A mixed-method, single-arm study evaluating the feasibility of OnTrack for hospital and home use. An independent process evaluation assessed the intervention's fidelity, dose and reach. Amendments to the protocol were necessary after COVID-19., Setting: Acute stroke services and home settings in North West London., Participants: 12 adults with a stroke diagnosis <6 months previously (first or recurrent) requiring arm rehabilitation in hospital and/or home., Intervention: 12 weeks using the OnTrack system comprising arm tracking and coaching support for self-management., Primary and Secondary Outcome Measures: Recruitment, retention and completion rates; compliance and adherence to the intervention; reasons for study decline/withdrawal.Intervention fidelity and acceptability, evaluated through an independent process evaluation.Patient measures including activity baseline, healthcare activation, arm function and impairment collected at baseline, week 7 and week 14 of participation to assess suitability for a randomised controlled trial (RCT)., Results: 181 individuals screened, 37 met eligibility criteria, 24 recruited (65%); of these, 15 (63%) were recruited before COVID-19, and 9 (37%) during. 12 completed the intervention (50%). Despite COVID-19 disruptions, recruitment, retention and completion were in line with prestudy expectations and acceptable for a definitive trial. Participants felt the study requirements were acceptable and the intervention usable. Fidelity of delivery was acceptable according to predetermined fidelity markers. Outcome measures collected helped determine sample size estimates and primary outcomes for an RCT., Conclusions: The intervention was found to be usable and acceptable by participants; study feasibility objectives were met and demonstrated that a definitive RCT would be viable and acceptable., Trial Registration Number: NCT03944486., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Health research has begun to pay increasing attention to inactivity in its broadest sense as lack of meaningful activity and boredom. Few studies however have taken a critical look at this phenomenon. We explore (in)activity drawing on ethnographic data from observations in an acute stroke unit and post-discharge interviews with stroke survivors and their families. Four themes emerged that explain patients' (in)activity: (i) planned activities; (ii) 'doing nothing', (iii) the material environment of the unit; (iv) interactions with staff. Considering these themes, we seek to problematise received conceptual and methodological approaches to understanding (in)activity. We argue that (in)activity is best conceived not as lack of action or meaning, but as a situated practice encompassing both bodily and mental activities that reflect and reproduce the way in which life is collectively organised within a specific healthcare setting.

Background: Self-management programs are recognized as a valuable approach to supporting people with long-term conditions, such as stroke, in managing their daily lives. Bridges Self-Management (Bridges) focuses on how practitioners interact and support patients' confidence, skills, and knowledge, and it is an example of a complex intervention. Bridges has been developed and used across multiple health care pathways in the United Kingdom and is theoretically informed by social cognition theory and self-efficacy principles. Evidence shows that self-management programs based on the construct of self-efficacy can be effective. There is still much to learn about how health care services or pathways should implement support for self-management in a sustainable way and whether this implementation process is different depending on the context or culture of the team or service provided., Objective: The aim of this study is to tailor and evaluate an intervention (Bridges) to support self-management after stroke in a Swedish context., Methods: We will use a pretest-posttest design with a case study approach to evaluate the feasibility and implementation of self-management support in two stroke settings. This project includes a complex intervention and depends on the actions of individuals, different contexts, and the adaptation of behavior over time. A mixed methods approach was chosen to understand both outcomes and mechanisms of impact. Data collection will comprise outcome measurements and assessment tools as well as qualitative interviews. Data will be collected concurrently and integrated into a mixed methods design., Results: Recruitment and data collection for the first site of the project ran from September 1, 2021, to January 17, 2022. The intervention at the first site was conducted from November 1, 2021, to March 5, 2022. The evaluation will start after the implementation phase. The second site has been recruited, and the baseline data collection will start in spring 2022. The intervention will start in early autumn 2022. Data collection will be completed by the end of 2022., Conclusions: This study represents a unique, highly relevant, and innovative opportunity to maximize knowledge and minimize practice gaps in rehabilitation stroke care. The study will produce robust data on the intervention and in-depth data on the contextual factors and mechanisms related to the feasibility of the intervention and for whom it is feasible. Bridges has been used in the United Kingdom for more than 10 years, and this study will explore its contextualization and implementation within a Swedish stroke environment. The evaluation will study results at the patient, staff, and organizational levels and provide recommendations for the adoption and refinement of future efforts to support self-management., International Registered Report Identifier (irrid): DERR1-10.2196/37672., (©Marie Elf, Erika Klockar, Maya Kylén, Lena von Koch, Charlotte Ytterberg, Lars Wallin, Tracy Finch, Catharina Gustavsson, Fiona Jones. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 06.05.2022.)

This study applies a multilevel model approach to test the predictive effect of the theory of planned behaviour (TPB) plus moral norm, past behaviour and crash history to account for intentions to avoid traffic violations within the context of commuting to or from work. This study also extended the theory by adding psychological stressors of perceived stress and work-family conflict. In this study, we systematically tested the direct and mediated models. A sample of Malaysian drivers (N = 482; 44.6% were men and 55.4% women), with the average age of 36.7 years (SD = 10.0) was surveyed. The self-report questionnaire contained multiple observations nested within individual drivers, with respect to 3 different driving violations. As predicted, multi-level modelling showed that within-person predictor variables of all the TPB components emerged as independent predictors, with injunctive norm being the most predictive variable, followed by self-efficacy and cognitive attitude. Intention was also predicted by moral norms and crash history. Between-person variables, gender, commuting hours and work-family conflict also had direct influences on intention (i.e., men and those with longer commuting hours and higher work-family conflict reported lower intentions). Substantial support for the mediation model was found, confirming that stressors indirectly influence intentions through effects on the social cognitive components. The implications of the linkage between the social cognition and stressors for developing potential broader interventions focusing on multiple violation behaviours and designing appropriate safety policies to reduce commuting crashes are discussed., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The use of lumbar fusion surgery is increasing in developed economies. High levels of patient dissatisfaction are reported post-operatively. To address this need, we developed a theoretically informed rehabilitation programme for use following lumbar fusion surgery (the REFS programme). We conducted a mixed methods randomised controlled feasibility study (REFS v 'usual care'). The numerical and feasibility outcomes are reported separately. The current qualitative study was 'nested' within the main feasibility study to explore participants' experiences before and after lumbar fusion surgery including the impact of rehabilitation content. This facilitated a deeper understanding of potential mechanisms of action, for theoretical and programme refinement., Methods: A purposive sample (n = 10 'usual care', n = 10 REFS) was identified from the main feasibility study cohort. Individual semi-structured interviews were conducted post-operatively (median 8 months, range 5-11). Interview data were transcribed verbatim, coded, and analysed thematically., Results: Three themes were constructed: the breadth and severity of impact associated with a chronic lumbar disorder was summarised in theme 1, 'Ever-decreasing circles; living with a chronic lumbar disorder'. Theme 2, 'What have I done? Reflections on recovery from lumbar fusion surgery', illustrated participants post-operative helplessness, which was associated with worsening mental health, problematic use of opioids, fear related to the instillation of metalware, and the important mitigating effect of informal social support. Theme 3 'Rehabilitation experiences' identified critical rehabilitation programme content including exercise, a shared rehabilitation experience, the opportunity for vicarious learning, and professional expertise., Conclusions: To enhance patient benefit future REFS programme iterations should consider reinforcement of the identified valued programme content. Additional content should be considered to mitigate post-operative fear, which frequently aligned with the instillation of metalware into the spine. Participant's perceptions regarding the necessity of lumbar fusion surgery has potential implications for the surgical consent process., Trial Registration: Study registration; ISRCTN60891364 , date registered 10/7/2014., (© 2022. The Author(s).)

Introduction: Individuals living with acquired brain injury experience numerous psychological, physical, and social challenges. Since the COVID-19 pandemic, many have experienced additional isolation, mental health issues and have had limited access to social and physical activities otherwise available in the community., Materials and Methods: Brain Waves is a 12-week online performance arts programme developed during the COVID-19 pandemic, for people with acquired brain injury (ABI). The research component of Brain Waves is a qualitative study, using Interpretative Phenomenological Analysis (IPA) and ethnographic methods (Observations and Interviews). The study will recruit two distinct populations: individuals living with acquired brain injury (including people who have experienced traumatic brain injury and stroke who are participating in the programme) and stakeholders (facilitators, involved in the delivery of Brain Waves ). This paper presents the protocol for a project which aims to gain an understanding of the implementation and experiences of creating and participating in an online community-based performance arts programme., Competing Interests: CP reports Grants from Wellcome Trust, during the conduct of the study; Grants from National Institute for Health Research (NIHR), Grants from NIHR Senior Investigator, grants from Johnson and Johnson, grants from Wellcome Trust, outside the submitted work. LJ was employed by Rosetta Life. KM was employed by Wall2Wall Music C.I.C. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Estevao, Taylor, Jarrett, Fort, Murphy, Woods, Crane, Fancourt, Pariante and Jones.)

Introduction: Stroke survivors, once in the community, face challenges with their long-term rehabilitation care and present higher levels of loneliness, depression and anxiety than the rest of the population. A community-based performance arts programme, Stroke Odysseys (SO), has been devised to tackle the challenges of living with stroke in the UK. In this study, we aim to evaluate the implementation, impact and experiences of SO for stroke survivors., Methods and Analysis: Scaling-up Health Arts Programmes: Implementation and Effectiveness Research (SHAPER)-SO aims to scale-up SO to 75 participants and 47 stakeholders, while simultaneously evaluating the effectiveness and implementation of the programme. The main research aim is to evaluate the implementation, effectiveness, impact and experiences of a community-based performance arts programme (SO for stroke survivors). This mixed-methods study will evaluate the experience and impact of SO on those participating using mixed methods (interviews, observations and surveys) before and after each stage and carry out non-participant observations during a percentage of the workshops, training and tour. Data will be analysed using quantitative and qualitative approaches. This is a study within the SHAPER programme., Ethics and Dissemination: Ethical approval has been granted by the King's College London PNM Research Ethics Panel, REC reference: LRS/DP-20/21-21549. Written informed consent will be sought for participants and stakeholders. The results of the study will be reported and disseminated at international conferences and in peer-reviewed scientific journals., Trial Registration Number: NCT04864470., Competing Interests: Competing interests: NS is the director of London Safety and Training Solutions Ltd, which offers training in patient safety, implementation solutions and human factors to healthcare organisations and the pharmaceutical industry. CP reports grants from the Wellcome Trust, during the conduct of the study; and grants from the National Institute for Health Research (NIHR), NIHR Senior Investigator, Johnson & Johnson, and the Wellcome Trust, outside the submitted work. The other authors have no conflicts of interest to declare., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Introduction: A growing evidence base demonstrates the effectiveness of supported self-management in stroke for stroke survivors and their families. However, there is significant variation in its implementation in community stroke care and little understanding about how supported self-management works and is delivered across different settings, models used and contexts of community stroke rehabilitation., Methods and Analysis: Using a mixed method, realist approach across two phases, this protocol describes a study on community-based supported self-management. The aim is to identify the mechanisms and outcomes of supported self-management in stroke and to understand how supported self-management is implemented in different contexts of community stroke rehabilitation. Phase 1 involves (1) a realist synthesis, (2) a scoping and mapping of current community rehabilitation settings and (3) a Q-methodology study to develop initial programme theories about how community-based supported self-management works, for whom and in what contexts. Phase 2 involves realist informed interviews/focus groups with stroke survivors, community rehabilitation practitioners and team managers from across Scotland to test and refine programme theories and an explanatory model for how supported self-management works across different contexts of community-based stroke rehabilitation., Ethics and Dissemination: Ethical approval and R&D approvals have been granted from East of Scotland Research Ethics Committee (REC reference number: 19/ES/0055) and participating NHS boards. An understanding of how, for whom and in what contexts community-based supported self-management works will help to strengthen its delivery in practice. Such an understanding will enable the design of context-specific recommendations for policy and practice that genuinely reflect the challenges in implementing supported self-management in community stroke care. Results will be disseminated to clinical partners working in community stroke rehabilitation, stroke survivors and families and to policymakers and third sector partners involved in the provision of long-term support for people affected by stroke., Prospero Registration Number: CRD42020166208., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: People with progressive Multiple Sclerosis often struggle to access appropriate and inclusive support for regular physical activity. The Lifestyle, Exercise and Activity Package (LEAP-MS) intervention, is a co-designed web-based physical activity intervention for people with progressive Multiple Sclerosis (MS). It consists of two key components; (1) web-based physical activity coaching with physiotherapists using self-management support strategies and 2) an interactive web-based platform including a physical activity information suite, an activity selection and planning tool and a participant-physiotherapist messaging system. We aimed to evaluate recruitment, retention and uptake, in a single arm feasibility study., Methods: Participants with primary or secondary progressive MS with an Expanded Disability Status Scale score of 6 to 8 were recruited. Assessments included the MS Impact Scale (MSIS-29) and measures of participation at baseline, three and six months. All participants received the intervention which consisted of up to six web-based physiotherapy- led physical activity coaching sessions alongside access to web-based education and activity suites. Recruitment, retention and uptake data were summarised. Pre-defined progression criteria were used to guide feasibility assessment. Clinical outcome data were analysed descriptively., Results: Fifty-eight percent (21/36) of those submitting expressions of interest were recruited; 76% completed follow-up. Pre-specified progression criteria for retention were met but recruitment did not meet progression criteria. The intervention achieved set fidelity criteria. At three months, 12 participants (75%) reported improvements in routine activities after the intervention. MSIS-29 physical scores improved by an average of eight points (95% CI -12.6 to -3.3). Improvements were also seen in MSIS-29 psychological scores and fatigue. Some improvements were maintained at six months., Conclusions: The LEAP-MS intervention is feasible and associated with improvements in MSIS-29 scores. The intervention facilitated partnership working between physiotherapists and people with progressive MS. Users developed valuable skills in supported self-management by focussing on enhancing physical activity to support overall wellbeing. This work has laid the foundations for a large-scale evaluation of a co-designed intervention with potential for far reaching impact on the lives of people with progressive MS., (Copyright © 2021 Elsevier B.V. All rights reserved.)

This paper describes an Experience-based Co-design (EBCD) project that aimed to increase patient activity within an acute stroke unit. We apply the concept of liminality to explore ways in which the EBCD process, a form of Participatory Action Research, may dilute or even dissolve social hierarchies and challenge assumptions about practices and constraints in this care setting, thereby opening up possibilities for transformation that enhances the therapeutic value of the space for patients and care providers alike. By occasioning a liminal phase of possibility for change, the work of one co-design group explored in detail here suggests that, in this process, the sociomaterial interactions involving patients, family members, staff, and the physical space are refashioned and re-inscribed in transformed 'emplaced' relationships of care., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Thyroid stimulating antibodies (TSAB) cause Graves' disease and contribute to Graves' Orbitopathy (GO) pathogenesis. We hypothesise that the presence of TSH binding proteins (truncated TSHR variants ( TSHRv )) and/or nonclassical ligands such as thyrostimulin ( α2β5 ) might provide a mechanism to protect against or exacerbate GO. We analysed primary human orbital preadipocyte-fibroblasts (OF) from GO patients and people free of GO (non-GO). Transcript (QPCR) and protein (western blot) expression levels of TSHRv were measured through an adipogenesis differentiation process. Cyclic-AMP production by TSHR activation was studied using luciferase-reporter and RIA assays. After differentiation, TSHRv levels in OF from GO were significantly higher than non-GO ( p = 0.039), and confirmed in ex vivo analysis of orbital adipose samples. TSHRv western blot revealed a positive signal at 46 kDa in cell lysates and culture media (CM) from non-GO and GO-OF. Cyclic-AMP decreased from basal levels when OF were stimulated with TSH or Monoclonal TSAB (M22) before differentiation protocol, but increased in differentiated cells, and was inversely correlated with the TSHRv : TSHR ratio (Spearman correlation: TSH r = -0.55, p = 0.23, M22 r = 0.87, p = 0.03). In the bioassay, TSH/M22 induced luciferase-light was lower in CM from differentiated GO-OF than non-GO, suggesting that secreted TSHRv had neutralised their effects. α2 transcripts were present but reduced during adipogenesis ( p < 0.005) with no difference observed between non-GO and GO. β5 transcripts were at the limit of detection. Our work demonstrated that TSHRv transcripts are expressed as protein, are more abundant in GO than non-GO OF and have the capacity to regulate signalling via the TSHR .

Rare neurological conditions (RNCs) encompass a variety of diseases that differ in progression and symptoms but typically include muscle weakness, sensory and balance impairment and difficulty with coordinating voluntary movement. This can limit overall physical activity, so interventions to address this are recommended. The aim of this study was to agree a core outcome measurement set for physical activity interventions in people living with RNCs. We followed established guidelines to develop core outcome sets. Broad ranging discussions in a series of stakeholder workshops led to the consensus that (1) physical well-being; (2) psychological well-being and (3) participation in day-to-day activities should be evaluated in interventions. Recommendations were further informed by a scoping review of physical activity interventions for people living with RNCs. Nearly 200 outcome measures were identified from the review with a specific focus on activities or functions (e.g, on lower limb function, ability to perform daily tasks) but limited consideration of participation based outcomes (e.g., social interaction, work and leisure). Follow on searches identified two instruments that matched the priority areas: the Oxford Participation and Activities Questionnaire and the Sources of Self-Efficacy for Physical Activity. We propose these scales as measures to assess outcomes that are particularly relevant to assess when evaluating physical activity interventions mong people with RNCs. Validation work across rare neurological conditions is now required to inform application of this core outcome set in future clinical trials to facilitate syntheses of results and meta-analyses., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ramdharry, Buscemi, Boaz, Dawes, Jaki, Jones, Marsden, Paul, Playle, Randell, Robling, Rochester and Busse.)

The cells of the immune system are highly dynamic, constantly sensing and adapting to changes in their surroundings. Complex metabolic pathways govern leukocytes' ability to fine-tune their responses to external threats. Mammalian target of rapamycin complex 1 and hypoxia inducible factor are important hubs of these pathways and play a critical role coordinating cell activation and proliferation and cytokine production. For this reason, these molecules are attractive therapeutic targets in inflammatory disease. Insight into perturbations in immune cell metabolic pathways and their impact on inflammatory bowel disease (IBD) progression are starting to emerge. However, it remains to be determined whether the aberrations in immune metabolism that occur in gut resident immune cells contribute to disease pathogenesis or are reflected in the peripheral blood of patients with IBD. In this review, we explore what is known about the metabolic profile of T cells, monocytes, macrophages, dendritic cells, and natural killer cells in IBD and discuss the potential of manipulating immune cell metabolism as a novel approach to treating IBD., (© 2021 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)

Metatorbernite [Cu(UO 2 ) 2 (PO 4 ) 2 ·8H 2 O] is a promising remediation material for environmental uranium contamination. Previous X-ray diffraction studies have been unable to definitively locate hydrogen positions within metatorbernite, which are key to determining the hydrogen-bond network that helps to stabilize the structure. Here, hydrogen positions have been determined using a combination of neutron powder diffraction and the computational modelling technique ab initio random structure searching (AIRSS). Atomic coordinates determined through Rietveld analysis of neutron powder diffraction data are in excellent agreement with the minimum energy configuration predicted by AIRSS; thus, simulations confirm that our proposed model likely represents the global minimum configuration. Two groups of water molecules exist within the metatorbernite structure: free water and copper-coordinating water. Free water molecules are held within the structure by hydrogen bonding only, whilst the coordinating water molecules bond to copper in the equatorial positions to produce a 4 + 2 Jahn-Teller octahedra. The successful agreement between neutron powder diffraction data and AIRSS suggests that this combined approach has excellent potential for the study of other (trans)uranium materials in which hydrogen bonding plays a key role in phase stability., (© Fiona M. MacIver-Jones et al. 2021.)

Aim: To understand how people with stroke and carers adapt over time, and how health professionals support transition to home., Method: A multi-perspective, prospective, qualitative, longitudinal study was conducted using in-depth semi-structured interviews one and six months after inpatient discharge. Twenty-four participants (eight triads, including people with stroke, carers and health professionals) were included. Thematic and narrative analysis facilitated identification of cross-cutting themes according to individual trajectories post-stroke., Findings: A major theme: "regaining control of life" suggested a shift in perspective after six months at home. Four sub-themes help to understand the triads' perspectives over time: i) importance of team involvement; ii) differences in perceived roles within the triad; iii) differences in expectations and collaboration within the triad and iv) planning a different future . People who were involved in supporting adaptation and rehabilitation processes were reported differently between triads and over time, showing the complexity of interrelations. A reduction in professional involvement was matched by changes in participants' goals and expectations., Conclusion: Findings suggest the importance of a dyadic perspective and a gradual increase in people with stroke and carers' active engagement. Professionals' approach throughout rehabilitation should be modified according to people with stroke and carers' changing needs and expectations.IMPLICATIONS FOR REHABILITATIONDivergence in perspectives about priorities and goals between the person with stroke their carers and healthcare professionals can lead to the creation of different agendas within rehabilitation.An open dialogue and decision-making process that involves both the person with stroke and carers is highly recommended for the identification of shared rehabilitation goals and to support ongoing recovery post discharge.A tailored approach to rehabilitation is required which focusses on shared priorities and includes individual or collective support for the person with stroke and their carers.Ongoing consultation about the desires of the person with stroke about rehabilitation, priorities and goals is important in order to tailor the professional approach to the stage individuals are at with their coping and adjustment post stroke.

This study examined the under-studied relationship between work-family conflict and dangerous driving behaviours in a sample of employees, and job-related affect as a mediator of this relationship. The sample consisted of 476 Malaysian drivers (44.7% male; 55.3% female) aged 19-60 years. The participants completed scales measuring bidirectional work family conflict (work interference with family[ WIF]; family interference with work [FIW]), job-related negative affect, dangerous driving behaviours and socio-demographics. The data were analysed using structural equation modelling. Our findings indicate that dangerous driving was predicted by FIW, but not WIF. As predicted, job-related negative affect fully mediated the relationship between WIF and dangerous driving. Furthermore, the effect of FIW on dangerous driving behaviours was partially due to negative affect at work. Mediation path was conditional upon gender, suggesting the indirect effects of the relationship between FIW and dangerous driving behaviours via job affect occurs in males but not females. The findings of this study may be useful as a starting point for both applied and theoretical investigations of the role of the psychological effects of juggling work and family responsibilities and affect in traffic safety., (© 2021 John Wiley & Sons Ltd.)

Background and Aims: Inflammatory bowel diseases [IBD], comprising Crohn's disease [CD] and ulcerative colitis [UC], are chronic conditions characterized by severe dysregulation of innate and adaptive immunity resulting in the destruction of the intestinal mucosa. Natural killer [NK] cells play a pivotal role in the dynamic interaction between the innate and adaptive immune response. There is an increasing appreciation for the key role immunometabolism plays in the regulation of NK cell function, yet little remains known about the metabolic profile, cytokine secretion, and killing capacity of human NK cells during active IBD., Methods: Peripheral blood mononuclear cells were isolated from peripheral blood of patients with moderate to severely active IBD and healthy controls. NK cells were stained with a combination of cell surface receptors, intracellular cytokines, and proteins and analyzed by flow cytometry. For measurements of NK cell cytotoxicity, the calcein-AM release assay was performed. The metabolic profile was analyzed by an extracellular flux analyzer., Results: NK cells from IBD patients produce large quantities of pro-inflammatory cytokines, IL-17A and TNF-α ex vivo, but have limited killing capability. Furthermore, patient NK cells have reduced mitochondrial mass and oxidative phosphorylation. mTORC1, an important cell and metabolic regulator, demonstrated limited activity in both freshly isolated cells and cytokine-stimulated cells., Conclusions: Our results demonstrate that circulating NK cells of IBD patients have an unbalanced metabolic profile, with faulty mitochondria and reduced capacity to kill. These aberrations in NK cell metabolism may contribute to defective killing and thus the secondary infections and increased risk of cancer observed in IBD patients., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Background: Stroke patients are often inactive outside of structured therapy sessions - an enduring international challenge despite large scale organizational changes, national guidelines and performance targets. We examined whether experienced-based co-design (EBCD) - an improvement methodology - could address inactivity in stroke units., Aims: To evaluate the feasibility and impact of patients, carers, and staff co-designing and implementing improvements to increase supervised and independent therapeutic patient activity in stroke units and to compare use of full and accelerated EBCD cycles., Methods: Mixed-methods case comparison in four stroke units in England., Results: Interviews were held with 156 patients, staff, and carers in total; ethnographic observations for 364 hours, behavioral mapping of 68 patients, and self-report surveys from 179 patients, pre- and post-implementation of EBCD improvement cycles.Three priority areas emerged: (1) 'Space' (environment); (2) 'Activity opportunities' and (3) 'Communication'. More than 40 improvements were co-designed and implemented to address these priorities across participating units. Post-implementation interview and ethnographic observational data confirmed use of new social spaces and increased activity opportunities. However, staff interactions remained largely task-driven with limited focus on enabling patient activity. Behavioral mapping indicated some increases in social, cognitive, and physical activity post-implementation, but was variable across sites. Survey responses rates were low at 12-38% and inconclusive., Conclusion: It was feasible to implement EBCD in stroke units. This resulted in multiple improvements in stroke unit environments and increased activity opportunities but minimal change in recorded activity levels. There was no discernible difference in experience or outcome between full and accelerated EBCD; this methodology could be used across hospital stroke units to assist staff and other stakeholders to co-design and implement improvement plans.

Background: We have co-designed a tailored blended physiotherapy intervention for people with progressive multiple sclerosis (PwPMS) who often struggle to access support for physical activity. Underpinned by self-management principles, the Lifestyle, Exercise and Activity Package for people with Multiple Sclerosis (LEAP-MS) intervention incorporates face-to-face or online physiotherapy coaching sessions with an accompanying online physical activity platform. The LEAP-MS platform is a multi-user system enabling user and physiotherapist to co-create activity plans. The LEAP-MS platform consists of an information and activity suite, interactive components enabling selection of exercises into an activity programme, goal setting and activity logging. The platform also facilitates online remote support from a physiotherapist through an embedded online messaging function. We aim to evaluate the LEAP-MS platform in a feasibility trial., Methods: LEAP-MS will be evaluated within a single-arm feasibility study with embedded process evaluation. After registration and initial eligible screening, 21 participants will be required to complete baseline self-completion measures. This will be followed by an initial home-based or online coaching session with a physiotherapist (who has received tailored self-management and digital resource training) and access to the online intervention for an initial 3-month period. During this period, participants are given the option to request up to five further home-based or online physiotherapy coaching sessions. Follow-up questionnaires and semi-structured interviews will be administered 3 months after baseline with participants and intervention physiotherapists. The LEAP-MS platform will be available to participants for a further 3 months. Usage of the LEAP-MS platform will be tracked during the full 6-month period and final follow-up will be conducted 6 months after baseline., Discussion: Feasibility outcomes (recruitment, retention, intervention uptake and safety) will be reported. The process evaluation will be undertaken to identify possible mechanisms for any observed effects. The data will inform full-scale evaluations of this co-produced, blended physiotherapy intervention., Trial Registration: ClinicalTrials.gov , NCT03951181 . Registered 15 May 2019.

Objectives: People with progressive multiple sclerosis (PwPMS) report that they recognise the benefits of activity on their physical and psychological health but need support to achieve their physical activity goals. We aimed to systematically develop a theoretically informed intervention that would enable PwPMS to more readily engage in regular physical activity., Design: We used an intervention mapping approach to inform intervention development., Setting: We conducted semistructured interviews with PwPMS and their families/carers and physiotherapists recruited from secondary care settings., Participants: Fourteen PwPMS with an Expanded Disability Status Scale score of between 6 and 8 and 7 of their families/carers and 13 physiotherapists and 1 physiotherapy technician participated., Results: Interview data suggested that the development of supportive coaching relationships with physiotherapists could promote the ability of PwPMS to achieve a desirable and achievable physical activity plan. These interview data informed the prototype 'Lifestyle Exercise and Activity Package for Multiple Sclerosis' (LEAP-MS) consisting of a secure multiuser web-based platform (with an education and activity suite, interactive components enabling selection of exercises, goal setting and activity logging), up to six flexible face-to-face or web-based physiotherapy coaching sessions and remote support via an embedded web-based messaging function that all together draw on specific theory-based methods to achieve physical activity behaviour change, namely active learning, reinforcement, modelling, feedback, facilitation, goal setting and guided practice. Implementation is within a multiuser platform accessible to participants, trained physiotherapists and researchers., Conclusions: We have followed an inclusive, systematic and transparent process to develop the LEAP-MS intervention that enables detailed description of components, context and guiding principles to inform ongoing evaluation. Importantly, PwPMS expressed the need for autonomy in developing physical activity plans. This has been achieved through the embedding of self-management principles in the design and delivery of the LEAP-MS intervention., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Changes in the physical environment along the Antarctic Peninsula have been among the most rapid anywhere on the planet. In concert with environmental change, the potential for direct human disturbance resulting from tourism, scientific programs, and commercial fisheries continues to rise in the region. While seabirds, such as the gentoo penguin Pygoscelis papua , are commonly used to assess the impact of these disturbances on natural systems, research efforts are often hampered by limited spatial coverage and lack of temporal resolution. Using a large-scale remote time-lapse camera network and a modeling framework adapted from capture-recapture studies, we assess drivers of intra- and inter-annual dynamics in gentoo penguin breeding success across nearly the entire species' range in the Atlantic sector of the Southern Ocean. We quantify the precise timing of egg/chick mortality within each season and examine the role of precipitation events, tourism visitation, and fishing activity for Antarctic krill Euphausia superba (a principal prey resource in the Antarctic) in these processes. We find that nest failure rates are higher in the egg than the chick stage and that neither krill fishing nor tourism visitation had a strong effect on gentoo penguin breeding success. While precipitation events had, on average, little effect on nest mortality, results suggest that extreme weather events can precipitate sharp increases in nest failure. This study highlights the importance of continuous ecosystem monitoring, facilitated here by remote time-lapse cameras, in understanding ecological responses to environmental stressors, particularly with regard to the timing of events such as extreme weather., (© 2020 The Authors. Remote Sensing in Ecology and Conservation published by John Wiley & Sons Ltd on behalf of Zoological Society of London.)

The Scaling-up Health-Arts Programme: Implementation and Effectiveness Research (SHAPER) project is the world's largest hybrid study on the impact of the arts on mental health embedded into a national healthcare system. This programme, funded by the Wellcome Trust, aims to study the impact and the scalability of the arts as an intervention for mental health. The programme will be delivered by a team of clinicians, research scientists, charities, artists, patients and healthcare professionals in the UK's National Health Service (NHS) and the community, spanning academia, the NHS and the charity sector. SHAPER consists of three studies - Melodies for Mums, Dance for Parkinson's, and Stroke Odysseys - which will recruit over 800 participants, deliver the interventions and draw conclusions on their clinical impact, implementation effectiveness and cost-effectiveness. We hope that this work will inspire organisations and commissioners in the NHS and around the world to expand the remit of social prescribing to include evidence-based arts interventions.

Objective: To explore facilitators and barriers to using experience-based co-design (EBCD) and accelerated EBCD (AEBCD) in the development and implementation of interventions to increase activity opportunities for inpatient stroke survivors., Design: Mixed-methods process evaluation underpinned by normalisation process theory (NPT)., Setting: Four post-acute rehabilitation stroke units in England., Participants: Stroke survivors, family members, stroke unit staff, hospital managers, support staff and volunteers. Data informing our NPT analysis comprised: ethnographic observations, n=366 hours; semistructured interviews with 76 staff, 53 stroke survivors and 27 family members pre-EBCD/AEBCD implementation or post-EBCD/AEBCD implementation; and observation of 43 co-design meetings involving 23 stroke survivors, 21 family carers and 54 staff., Results: Former patients and families valued participation in EBCD/AEBCD perceiving they were equal partners in co-design. Staff engaged with EBCD/AEBCD, reporting it as a valuable improvement approach leading to increased activity opportunities. The structured EBCD/AEBCD approach was influential in enabling coherence and cognitive participation and legitimated staff involvement in the change process. Researcher facilitation of EBCD/AEBCD supported cognitive participation, collective action and reflexive monitoring; these were important in implementing and sustaining co-design activities. Observations and interviews post-EBCD/AEBCD cycles confirmed creation and use of new social spaces and increased activity opportunities in all units. EBCD/AEBCD facilitated engagement with wider hospital resources and local communities, further enhancing activity opportunities. However, outside of structured group activity, many individual staff-patient interactions remained task focused., Conclusions: EBCD/AEBCD facilitated the development and implementation of environmental changes and revisions to work routines which supported increased activity opportunities in stroke units providing post-acute and rehabilitation care. Former stroke patients and carers contributed to improvements. NPT's generative mechanisms were instrumental in analysis and interpretation of facilitators and barriers at the individual, group and organisational level, and can help inform future implementations of similar approaches., Competing Interests: Competing interests: GR teaches on the EBCD training courses run by ‘The Point of Care Foundation’ in London. GR is one of the originators of EBCD. The remaining authors declare no other competing interests., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Rheumatoid arthritis (RA) is a debilitating and painful inflammatory autoimmune disease characterised by the accumulation of leukocytes in the synovium, cartilage destruction and bone erosion. The immunomodulatory effects of bone marrow derived mesenchymal stem cells (MSCs) has been widely studied and the recent observations that syndecan-3 (SDC3) is selectively pro-inflammatory in the joint led us to hypothesise that SDC3 might play an important role in MSC biology. MSCs isolated from bone marrow of wild type and Sdc3 -/- mice were used to assess immunophenotype, differentiation, adhesion and migration properties and cell signalling pathways. While both cell types show similar differentiation potential and forward scatter values, the cell complexity in wild type MSCs was significantly higher than in Sdc3 -/- cells and was accompanied by lower spread surface area. Moreover, Sdc3 -/- MSCs adhered more rapidly to collagen type I and showed a dramatic increase in AKT phosphorylation, accompanied by a decrease in ERK1/2 phosphorylation compared with control cells. In a mouse model of antigen-induced inflammatory arthritis, intraarticular injection of Sdc3 -/- MSCs yielded enhanced efficacy compared to injection of wild type MSCs. In conclusion, our data suggest that syndecan-3 regulates MSC adhesion and efficacy in inflammatory arthritis, likely via induction of the AKT pathway.

Objective: To explore how primary care organizations assess and subsequently act upon the social determinants of noncommunicable diseases in their local populations., Methods: For this systematic review we searched the online databases of PubMed®, MEDLINE®, Embase® and the Health Management Information Consortium from inception to 28 June 2019, along with hand-searching of references. Studies of any design that examined a primary care organization assessing social determinants of noncommunicable diseases were included. For quality assessment we used Cochrane's tool for assessing risk of bias in non-randomized studies of interventions. We used narrative data synthesis to appraise the extent to which the assessments gathered data on the domains of the World Health Organization social determinants of health framework., Findings: We identified 666 studies of which 17 were included in the review. All studies used descriptive study designs. Clinic-based and household surveys and interviews were more commonly used to assess local social determinants than population-level data. We found no examples of organizations that assessed sociopolitical drivers of noncommunicable diseases; all focused on sociodemographic factors or circumstances of daily living. Nevertheless, the resulting actions to address social determinants ranged from individual-level interventions to population-wide measures and introducing representation of primary care organizations on system-level policy and planning committees., Conclusion: Our findings may help policy-makers to consider suitable approaches for assessing and addressing social determinants of health in their domestic context. More rigorous observational and experimental evidence is needed to ascertain whether measuring social determinants leads to interventions which mitigate unmet social needs and reduce health disparities., ((c) 2020 The authors; licensee World Health Organization.)

Background: Cardiovascular disease (CVD) is the leading cause of death in women, responsible for approximately a third of all female deaths. Pregnancy complications are known to be associated with a greater risk of incident CVD in mothers. However, the relationships between pregnancy loss due to miscarriage, stillbirth, or therapeutic abortion, and future maternal cardiovascular health are under-researched. This study seeks to provide an up-to-date systematic review and meta-analysis of the relationship between these three forms of pregnancy loss and the subsequent development of CVD., Methods: This systematic review will follow the Preferred Reporting Items for Systematic Review and Meta-Analysis checklist (PRISMA) and the Meta-analyses Of Observational Studies in Epidemiology (MOOSE) Checklist. A systematic search will be undertaken using publications identified in MEDLINE (PubMed), Scopus, Web of Knowledge, the CINAHL Nursing Database, and the Cochrane Library. The eligibility of each publication will be determined by predefined selection criteria. The quality of the included studies will be rated using the Newcastle-Ottawa Scale. Pooled measures of association will be computed using random-effects model meta-analyses. Between-study heterogeneity will be assessed using the I 2 statistic and the Cochrane χ 2 statistic. Small study effects will be evaluated for meta-analyses with sufficient studies through the use of funnel plots and Egger's test., Discussion: The results of this systematic review will discuss the long-term risks of multiple types of cardiovascular disease in women who have experienced miscarriage, stillbirth, and/or therapeutic abortion. It will contribute to the growing field of cardio-obstetrics as the first to consider the full breadth of literature regarding the association between all forms of pregnancy loss and future maternal cardiovascular disease., Systematic Review Registration: PROSPERO registration number [CRD42020167587].

The 48 national member societies and 17 specialist member societies which operate under the umbrella of United European Gastroenterology (UEG) increasingly develop clinical practice guidelines for both national and international implementation. The methodologies and strategies used in these guidelines vary considerably. The UEG Quality of Care Taskforce aimed to provide a framework for quality guidelines in order to assist member societies in the process of developing guidelines, and to provide a tool for readers of guidelines to critically appraise their quality. We outline the steps necessary to begin the guideline development process, how to build working groups, how to search for evidence, how to grade the quality of the evidence, how to reach consensus on statements and how to write the guideline document. We believe that using this framework will increase the potential to produce a high-quality guideline which is transparent, independent, reproducible and implementable.