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Introduction: Research has found that a high percentage of people with diabetes experience stigma, with perceptions of stigma being significantly higher among people with Type 1 diabetes compared to those with Type 2 diabetes. These experiences of diabetes stigma can lead to psychological, behavioural and medical consequences. The aim of the current study was to explore the perceptions of diabetes stigma and propose strategies for addressing this from the perspective of key stakeholders., Methods: A mixed methods design was used, commencing with an online qualitative survey (n = 128) and followed by a World Café (n = 11), where attendees reflected on their own experiences with stigma and discussed the survey findings., Results: The survey indicated that 75% of those with Type 1 diabetes and 51% with Type 2 had experienced diabetes stigma. The World Café identified three main areas that participants felt impacted their experiences with stigma or had the potential to help improve stigma: healthcare interactions, public awareness and media representations., Conclusions: The findings supported previous research showing that diabetes stigma is prevalent among people with diabetes. The World Café was an excellent means of sharing knowledge and experiences among stakeholders, the findings of which will inform strategies to bring about change., Patient or Public Contribution: World Café is a collaborative method where stakeholders contribute to the production and analysis of data through rounds of discussion and feedback., (© 2024 The Author(s). Health Expectations published by John Wiley & Sons Ltd.)

Background: Urinary incontinence (UI) negatively affects the well-being of women globally. Pelvic Floor Muscle Training (PFMT) is a complex intervention that aims to decrease UI symptoms. Information about how the multiple complex components involved in PFMT achieve and maintain the desired effect are rarely studied as a whole. The evidence base lacks data about how women experience PFMT over time and in the longer-term. This study explored women's experiences of biofeedback-assisted PFMT and PFMT alone, to identify and understand what influenced self-reported adherence to PFMT, and UI outcomes over time., Methods: This rigorous longitudinal qualitative case study, nested within a randomised controlled trial, recruited forty cases (women with stress or mixed UI; 20 in biofeedback-assisted and 20 in PFMT alone group). A case included up to four semi-structured interviews with each woman (prior to starting PFMT, end of treatment [6 months], 12 months, 24 months). Analysis followed case study analytic traditions, resulting in a Programme Theory about PFMT from the perspectives of women with UI., Findings: The theory demonstrates factors that motivated women to seek UI treatment, and how these influenced long-term adherence. Therapists who delivered PFMT played a crucial role in supporting women to know how to undertake PFMT (to have capability). Some, but not all, women developed self-efficacy for PFMT. Where women did not have PFMT self-efficacy, adherence tended to be poor. When women had PFMT self-efficacy, the conditions to support adherence were present, but contextual factors could still intercede to inhibit adherence. The intercession of contextual factors was individual to a woman and her life, meaning any particular contextual factor had inconsistent influences on PFMT adherence over time for individual women and exerted varying influences across different women., Conclusion: Long term adherence to PFMT is a complex interaction between many different factors. Enquiring about an individual woman's motivation to seek treatment and understanding the contextual factors that affect an individual woman will enable a practitioner to support longer-term adherence., (© 2024. The Author(s).)

Regional heterothermy describes when body regions differ in temperature, which can have important ramifications for performance because most biological processes are temperature dependent. However, the relationship between regional heterothermy and environmental temperature is not well known, particularly for ectotherms. The relationship between environmental heterogeneity and regional heterothermy might also yield insight into how the latter is regulated. We examined the thermal dependence of regional heterothermy (between the head and the cloaca) in live ring-necked snakes (Diadophis punctatus) in both the lab and the field, as well as in one dead and preserved individual. We found that the magnitude of the head-cloaca difference declined with average environmental temperature, that the relationship between head temperature and ambient temperature differed from that of cloaca temperature and ambient temperature, and that the preserved snake specimen did not display a consistent head-cloaca temperature difference. Our results suggest that (1) cloacal and head temperatures are regulated differently, (2) the head-cloaca temperature difference is not merely due to differences in the material properties of the head and cloaca, and (3) this difference may arise from altered circulation and perhaps even endogenous heat-generating mechanisms. Our results also suggest that the thermal dependence of regional heterothermy likely has ramifications for organismal function., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Introduction: Interventions to support behaviour change in people living with chronic health conditions increasingly use patient groups as the mode of delivery, but these are often designed without consideration of the group processes that can shape intervention outcomes. This article outlines a new approach to designing group-based behaviour change interventions that prioritizes recipients' shared social identity as group members in facilitating the adoption of established behaviour change techniques (BCTs). The approach is illustrated through an example drawn from research focused on people living with severe obesity., Methods: A prioritization process was undertaken in collaboration with stakeholders, including behaviour change experts, clinicians, and a former patient to develop an evidence-based, group intervention informed by the social identity approach to health. Three phases of development are reported: (1) identification of the health problem; (2) delineation of intervention mechanisms and operationalization of BCTs for group delivery and (3) intervention manualization. The fourth phase, intervention testing and optimization, is reported elsewhere., Results: A group-based behaviour change intervention was developed, consisting of 12 group sessions and 3 one-to-one consultations. The intervention aimed to support the development of shared social identity among recipients, alongside the delivery of evidence-based BCTs, to improve the likelihood of successful intervention and health outcomes among people living with severe obesity., Conclusions: A manualized intervention, informed by the social identity approach to health, was systematically designed with input from stakeholders. The development approach employed can inform the design of behavioural interventions in other health contexts where group-based delivery is planned., (© 2024 The Author(s). British Journal of Health Psychology published by John Wiley & Sons Ltd on behalf of British Psychological Society.)

ANK3 encodes ankyrin-G, a protein involved in neuronal development and signaling. Alternative splicing gives rise to three ankyrin-G isoforms comprising different domains with distinct expression patterns. Mono- or biallelic ANK3 variants are associated with non-specific syndromic intellectual disability in 14 individuals (seven with monoallelic and seven with biallelic variants). In this study, we describe the clinical features of 13 additional individuals and review the data on a total of 27 individuals (16 individuals with monoallelic and 11 with biallelic ANK3 variants) and demonstrate that the phenotype for biallelic variants is more severe. The phenotypic features include language delay (92%), autism spectrum disorder (76%), intellectual disability (78%), hypotonia (65%), motor delay (68%), attention deficit disorder (ADD) or attention deficit hyperactivity disorder (ADHD) (57%), sleep disturbances (50%), aggressivity/self-injury (37.5%), and epilepsy (35%). A notable phenotypic difference was presence of ataxia in three individuals with biallelic variants, but in none of the individuals with monoallelic variants. While the majority of the monoallelic variants are predicted to result in a truncated protein, biallelic variants are almost exclusively missense. Moreover, mono- and biallelic variants appear to be localized differently across the three different ankyrin-G isoforms, suggesting isoform-specific pathological mechanisms., (© 2024 The Author(s). Clinical Genetics published by John Wiley & Sons Ltd.)

Background: It remains unclear how to meaningfully classify people living with multimorbidity (multiple long-term conditions (MLTCs)), beyond counting the number of conditions. This paper aims to identify clusters of MLTCs in different age groups and associated risks of adverse health outcomes and service use., Methods: Latent class analysis was used to identify MLTCs clusters in different age groups in three cohorts: Secure Anonymised Information Linkage Databank (SAIL) (n = 1,825,289), UK Biobank (n = 502,363), and the UK Household Longitudinal Study (UKHLS) (n = 49,186). Incidence rate ratios (IRR) for MLTC clusters were computed for: all-cause mortality, hospitalisations, and general practice (GP) use over 10 years, using <2 MLTCs as reference. Information on health outcomes and service use were extracted for a ten year follow up period (between 01 st Jan 2010 and 31st Dec 2019 for UK Biobank and UKHLS, and between 01 st Jan 2011 and 31st Dec 2020 for SAIL)., Findings: Clustering MLTCs produced largely similar results across different age groups and cohorts. MLTC clusters had distinct associations with health outcomes and service use after accounting for LTC counts, in fully adjusted models. The largest associations with mortality, hospitalisations and GP use in SAIL were observed for the " Pain+ " cluster in the age-group 18-36 years (mortality IRR = 4.47, hospitalisation IRR = 1.84; GP use IRR = 2.87) and the " Hypertension, Diabetes & Heart disease " cluster in the age-group 37-54 years (mortality IRR = 4.52, hospitalisation IRR = 1.53, GP use IRR = 2.36). In UK Biobank, the " Cancer, Thyroid disease & Rheumatoid arthritis " cluster in the age group 37-54 years had the largest association with mortality (IRR = 2.47). Cardiometabolic clusters across all age groups, pain/mental health clusters in younger groups, and cancer and pulmonary related clusters in older age groups had higher risk for all outcomes. In UKHLS, MLTC clusters were not significantly associated with higher risk of adverse outcomes, except for the hospitalisation in the age-group 18-36 years., Interpretation: Personalising care around MLTC clusters that have higher risk of adverse outcomes may have important implications for practice (in relation to secondary prevention), policy (with allocation of health care resources), and research (intervention development and targeting), for people living with MLTCs., Funding: This study was funded by the National Institute for Health and Care Research (NIHR; Personalised Exercise-Rehabilitation FOR people with Multiple long-term conditions (multimorbidity)-NIHR202020)., Competing Interests: SJS is Clinical Lead for National Respiratory Audit Programme–Pulmonary Rehabilitation and also a National Institute for Health Research (NIHR) Senior Investigator. This work was supported by the NIHR Leicester Biomedical Research Centre (BRC). KJ declares funding from NIHR Applied Research Collaboration West Midlands and Sub-committee chair for NIHR Programme Grants for Applied Health Research (payment to institution). BIN declares receiving funding from NIHR, vs. Arthritis, NIHR-EPSRC, Glasgow Knowledge Exchange Fund and for external PhD examination. RAE declares receipt of speaker fees (Boeringher June 2021; Moderna April 2023) and ERS Group 01.02 Pulmonary Rehabilitation and Chronic Care Secretary (unpaid), and ATS Pulmonary Rehabilitation Assembly Chair (unpaid). SD declares NIHR Applied Research Collaboration: South West Peninsula (PenARC; payment to institution), receipt of the following NIHR grants (payment to institution): NIHR151938; NIHR204099; RP-PG-0514-20,002; NIHR201038; NIHR201070; NIHR200428, receipt of grants (payment to institution): Gillings Family foundation (ID 943008); The Stroke Association (ID 901902); NIHR School for Primary Care Research—Exeter internal fund (ID 856766); Academic Health Science Network South West (ID 1355693), receipt of textbook royalties (John Wiley & Sons), support for meeting attendance from NIHR (p-PG-0514- 20,002) and Health Research Council New Zealand (21/826; 18/254), and membership of NIHR Programme Grant for Applied Research funding panel committee and The Stroke Association research funding panel. SJK declares receipt of conference funding from School of Health and Wellbeing, University of Glasgow. SAS declares presidency of the UK Society of Behavioural Medicine, membership of HTA Clinical Evaluations and Trials Committee (2016–2020), membership of Commissioning Panel for the National Institute of Health Research (NIHR) Policy Research Programme (2019–2022), and membership of Chief Scientist Office HIPS committee (2018–2023). FSM declares grants from NIHR during the conduct of the study; grants from Wellcome, grants from Innovate UK, grants from Innovative Medicines Initiative (IMI2), grants from UKRI, grants from EPSRC, grants from MRC, grants from Chief Scientist office Scotland, outside the submitted work; and MRC CARP Panel membership. Dr Greaves reports grants from National Institute for Health Research (NIHR) during the conduct of the study., (© 2024 The Authors.)

Background: Low back pain (LBP) is the leading cause of disability worldwide. A recent realist review identified the behavioural mechanisms of trust, motivation, and confidence as key to optimising exercise prescription for persistent LBP., Objectives: Our objectives were to (1) design and develop an online training programme, and (2) gain end-user feedback on the useability, usefulness, informativeness and confidence in using the online training programme using a mixed-methods, pre-post study design., Participants and Intervention: The online training programme was designed and developed using the results from a realist review, and input from a multi-disciplinary stakeholder group. A five-module online training programme was piloted by the first 10 respondents who provided feedback on the course. Further modifications were made prior to additional piloting. The satisfaction, usefulness, ease of use, and confidence of clinicians in applying the learned principles were assessed on completion., Results: The online programme was advertised to clinicians using social media. Forty-four respondents expressed initial interest, of which 22 enrolled and 18 completed the course. Of the participants, most were physiotherapists (n = 16/18, 88.9%), aged between 30 and 49 (n = 11/18, 61.1%). All participants were satisfied with the course content, rated the course platform as easy to use and useful, and reported that they were very confident to apply the learning. Most (n = 10/14, 71.4%) reported that their manner of prescribing exercise had changed after completion of the course., Conclusions: An online training programme to optimise exercise prescription for persistent LBP appears to be easy to use, informative and improves confidence to apply the learning., (© 2024 The Author(s). Musculoskeletal Care published by John Wiley & Sons Ltd.)

Background: Almost half of the global population face significant challenges from long-term conditions (LTCs) resulting in substantive health and socioeconomic burden. Exercise is a potentially key intervention in effective LTC management., Methods: In this overview of systematic reviews (SRs), we searched six electronic databases from January 2000 to October 2023 for SRs assessing health outcomes (mortality, hospitalisation, exercise capacity, disability, frailty, health-related quality of life (HRQoL), and physical activity) related to exercise-based interventions in adults (aged >18 years) diagnosed with one of 45 LTCs. Methodological quality was assessed using AMSTAR-2. International Prospective Resister of Systematic Reviews (PROSPERO) ID: CRD42022319214., Findings: Forty-two SRs plus three supplementary RCTs were included, providing 990 RCTs in 936,825 people across 39 LTCs. No evidence was identified for six LTCs. Predominant outcome domains were HRQoL (82% of SRs/RCTs) and exercise capacity (66%); whereas disability, mortality, physical activity, and hospitalisation were less frequently reported (≤25%). Evidence supporting exercise-based interventions was identified in 25 LTCs, was unclear for 13 LTCs, and for one LTC suggested no effect. No SRs considered multimorbidity in the delivery of exercise. Methodological quality varied: critically-low (33%), low (26%), moderate (26%), and high (12%)., Interpretation: Exercise-based interventions improve HRQoL and exercise capacity across numerous LTCs. Key evidence gaps included limited mortality and hospitalisation data and consideration of multimorbidity impact on exercise-based interventions., Funding: This study was funded by the National Institute for Health and Care Research (NIHR; Personalised Exercise-Rehabilitation FOR people with Multiple long-term conditions (multimorbidity)-NIHR202020)., Competing Interests: GOD is co-author of one, and RST is co-author of two of the SRs included in this overview. LG is currently in receipt of/undertaking a Wellcome Trust doctoral fellowship (UNS144807) and declares receipt of payment for lecture on pulmonary rehabilitation (University College London, annual), Council of Allied Health Professions Research (CAHPR)/National Institute for Health and Care Research (NIHR) Research Champion: West Midlands (unpaid), British Thoracic Society (BTS): Pulmonary Rehabilitation (PR) Specialist Advisory Group (SAG) member (unpaid), Association of Chartered Physiotherapists in Respiratory Care (ACPRC) committee (honoraria received). HMLY is funded by the NIHR Advanced Fellowship (NIHR202926). SJS is Clinical Lead for National Respiratory Audit Programme—Pulmonary Rehabilitation. KJ declares funding from NIHR Applied Research Collaboration West Midlands and Sub-committee chair for NIHR Programme Grants for Applied Health Research (payment to institution). RAE declares receipt of speaker fees (Boeringher June 2021; Moderna April 2023) and ERS Group 01.02 Pulmonary Rehabilitation and Chronic Care Secretary (unpaid), and ATS Pulmonary Rehabilitation Assembly Chair (unpaid). SD declares NIHR Applied Research Collaboration: South West Peninsula (PenARC; payment to institution), receipt of the following NIHR grants (payment to institution): NIHR151938; NIHR204099; RP-PG-0514-20002; NIHR201038; NIHR201070; NIHR200428, receipt of grants (payment to institution): Gillings Family foundation (ID 943008); The Stroke Association (ID 901902); NIHR School for Primary Care Research—Exeter internal fund (ID 856766); Academic Health Science Network South West (ID 1355693), receipt of textbook royalties (John Wiley & Sons), support for meeting attendance from NIHR (p-PG-0514-20002) and Health Research Council New Zealand (21/826; 18/254), and membership of NIHR Programme Grant for Applied Research funding panel committee and The Stroke Association research funding panel. SJK declares receipt of conference funding from School of Health and Wellbeing, University of Glasgow. SAS declares presidency of the UK Society of Behavioural Medicine, membership of HTA Clinical Evaluations and Trials Committee (2016–2020), membership of Commissioning Panel for the National Institute of Health Research (NIHR) Policy Research Programme (2019–2022), and membership of Chief Scientist Office HIPS committee (2018–2023)., (© 2024 The Authors.)

The rate of progression of Alzheimer's disease (AD) differs dramatically between patients. Identifying the most is critical because when their numbers differ between treated and control groups, it distorts the outcome, making it impossible to tell whether the treatment was beneficial. Much recent effort, then, has gone into identifying RPs. We pooled de-identified placebo-arm data of three randomized controlled trials (RCTs), EXPEDITION, EXPEDITION 2, and EXPEDITION 3, provided by Eli Lilly and Company. After processing, the data included 1603 mild-to-moderate AD patients with 80 weeks of longitudinal observations on neurocognitive health, brain volumes, and amyloid-beta (Aβ) levels. RPs were defined by changes in four neurocognitive/functional health measures. We built deep learning models using recurrent neural networks with attention mechanisms to predict RPs by week 80 based on varying observation periods from baseline (e.g., 12, 28 weeks). Feature importance scores for RP prediction were computed and temporal feature trajectories were compared between RPs and non-RPs. Our evaluation and analysis focused on models trained with 28 weeks of observation. The models achieved robust internal validation area under the receiver operating characteristic (AUROCs) ranging from 0.80 (95% CI 0.79-0.82) to 0.82 (0.81-0.83), and the area under the precision-recall curve (AUPRCs) from 0.34 (0.32-0.36) to 0.46 (0.44-0.49). External validation AUROCs ranged from 0.75 (0.70-0.81) to 0.83 (0.82-0.84) and AUPRCs from 0.27 (0.25-0.29) to 0.45 (0.43-0.48). Aβ plasma levels, regional brain volumetry, and neurocognitive health emerged as important factors for the model prediction. In addition, the trajectories were stratified between predicted RPs and non-RPs based on factors such as ventricular volumes and neurocognitive domains. Our findings will greatly aid clinical trialists in designing tests for new medications, representing a key step toward identifying effective new AD therapies., Competing Interests: PS is funded by the McCord Family Professorship in Neurology, the Umphrey Family Professorship in Neurodegenerative Disorders, multiple NIH grants and several foundation grants (1R01AG080137-01A1, 1RF1AG072491-01, 1R03AG077191-01, 1U01AG079847-01A1, 5R01AG66749-03, 1R01AG083039-01, 5R01AG067498-03, 1RF1AG055053-0A1, 1R01AG062690-01, 1R01AG059321-01A1, 1R01DE07027, 1R01AG082721-01, 2124789, AGT002985, AGT008724, AGT009122), and contracts with multiple pharmaceutical companies related to the performance of clinical trials (ALZ-80-AD301-AGT005383, AGT004414, AGT003423, AGT003882, AGT006620, AGT005768, AGT004564, AGT009188, AGT006056, AGT006764, AGT008197, AGT010139, AGT011949). He serves as a consultant and speaker for Eli Lilly, and Acadia Pharmaceuticals. No other authors have declarations to disclose., (Copyright: © 2024 Ma 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.)

Introduction: Personalised Exercise-Rehabilitation FOR people with Multiple long-term conditions (PERFORM) is a research programme that seeks to develop and evaluate a comprehensive exercise-based rehabilitation intervention designed for people with multimorbidity, the presence of multiple long-term conditions (MLTCs). This paper describes the protocol for a randomised trial to assess the feasibility and acceptability of the PERFORM intervention, study design and processes., Methods and Analysis: A multicentre, parallel two-group randomised trial with individual 2:1 allocation to the PERFORM exercise-based intervention plus usual care (intervention) or usual care alone (control). The primary outcome of this feasibility trial will be to assess whether prespecified progression criteria (recruitment, retention, intervention adherence) are met to progress to the full randomised trial. The trial will be conducted across three UK sites and 60 people with MLTCs, defined as two or more LTCs, with at least one having evidence of the beneficial effect of exercise. The PERFORM intervention comprises an 8-week (twice a week for 6 weeks and once a week for 2 weeks) supervised rehabilitation programme of personalised exercise training and self-management education delivered by trained healthcare professionals followed by two maintenance sessions. Trial participants will be recruited over a 4.5-month period, and outcomes assessed at baseline (prerandomisation) and 3 months postrandomisation and include health-related quality of life, psychological well-being, symptom burden, frailty, exercise capacity, physical activity, sleep, cognition and serious adverse events. A mixed-methods process evaluation will assess acceptability, feasibility and fidelity of intervention delivery and feasibility of trial processes. An economic evaluation will assess the feasibility of data collection and estimate the costs of the PERFORM intervention., Ethics and Dissemination: The trial has been given favourable opinion by the West Midlands, Edgbaston Research Ethics Service (Ref: 23/WM/0057). Participants will be asked to give full, written consent to take part by trained researchers. Findings will be disseminated via journals, presentations and targeted communications to clinicians, commissioners, service users and patients and the public., Trial Registration Number: ISRCTN68786622., Protocol Version: 2.0 (16 May 2023)., Competing Interests: Competing interests: SAS is President of the UK Society of Behavioural Medicine. She has also been a member of the NIHR HTA Clinical Evaluations and Trials Committee (2016–2020), the Commissioning Panel for the NIHR Policy Research Programme (2019–2022); the Chief Scientist Office Health Improvement Protection and Services committee (2018–2023). RAE is ERS Group 01.02 Pulmonary Rehabilitation and Chronic Care Secretary and ATS Pulmonary Rehabilitation Assembly Chair. KJ is subcommittee chair for the NIHR Programme Grants for Applied Health Research, however, the honorarium for this role goes to KJ’s institution, the University of Birmingham. FM is co-lead for the international working group on Minimally Disruptive Medicine, which aims to improve care for people with multimorbidity. SMS is a board member of the ExWell medical in Ireland, which is a not-for-profit organisation that provides group based medical exercise classes in community settings for people living with chronic conditions. SJS has also conducted presentations for the Ministry of Justice, is on the NICE Expert Adviser Panel for Long COVID, and was previously on the Wales Long COVID Advisory Board and the NHS-E Long Covid Your Covid Recovery working group. SJS was previously Pulmonary Rehabilitation Assembly Chair, Clinical Lead for RCP Pulmonary Rehabilitation Accreditation Scheme and Clinical Lead for NACAP Audit for Pulmonary Rehabilitation. All coinvestigators on the grant funding this work are partially supported by the National Institute for Health and Social Care Research (grant number NIHR202020)., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The neurobiology of typical moral cognition involves the interaction of frontal, limbic, and temporoparietal networks. There is still much to be understood mechanistically about how moral processing is disrupted; such understanding is key to combating antisociality. Neuroscientific models suggest a key role for attention mechanisms in atypical moral processing. We hypothesized that attention-bias toward alcohol cues in alcohol use disorder (AUD) leads to a failure to properly engage with morally relevant stimuli, reducing moral processing. We recruited patients with AUD ( n  = 30) and controls ( n  = 30). During functional magnetic resonance imaging, participants viewed pairs of images consisting of a moral or neutral cue and an alcohol or neutral distractor. When viewing moral cues paired with alcohol distractors, individuals with AUD had lower medial prefrontal cortex engagement; this pattern was also seen for left amygdala in younger iAUDs. Across groups, individuals had less engagement of middle/superior temporal gyri. These findings provide initial support for AUD-related attention bias interference in sociomoral processing. If supported in future longitudinal and causal study designs, this finding carries potential societal and clinical benefits by suggesting a novel, leverageable mechanism and in providing a cognitive explanation that may help combat persistent stigma.

Background: Acute respiratory distress syndrome (ARDS) is often seen in patients resuscitated from out-of-hospital cardiac arrest (OHCA). We aim to test whether inflammatory or endothelial injury markers are associated with the development of ARDS in patients hospitalized after OHCA., Methods: We conducted a prospective, cohort, pilot study at an urban academic medical center in 2019 that included a convenience sample of adults with non-traumatic OHCA. Blood and pulmonary edema fluid (PEF) were collected within 12 hours of hospital arrival. Samples were assayed for cytokines (interleukin [IL]-1, tumor necrosis factor-α [TNF-α], tumor necrosis factor receptor1 [TNFR1], IL-6), epithelial injury markers (pulmonary surfactant-associated protein D), endothelial injury markers (Angiopoietin-2 [Ang-2] and glycocalyx degradation products), and other proteins (matrix metallopeptidase-9 and myeloperoxidase). Patients were followed for 7 days for development of ARDS, as adjudicated by 3 blinded reviewers, and through hospital discharge for mortality and neurological outcome. We examined associations between biomarker concentrations and ARDS, hospital mortality, and neurological outcome using multivariable logistic regression. Latent phase analysis was used to identify distinct biological classes associated with outcomes., Results: 41 patients were enrolled. Mean age was 58 years, 29% were female, and 22% had a respiratory etiology for cardiac arrest. Seven patients (17%) developed ARDS within 7 days. There were no significant associations between individual biomarkers and development of ARDS in adjusted analyses, nor survival or neurologic status after adjusting for use of targeted temperature management (TTM) and initial cardiac arrest rhythm. Elevated Ang-2 and TNFR-1 were associated with decreased survival (RR = 0.6, 95% CI = 0.3-1.0; RR = 0.5, 95% CI = 0.3-0.9; respectively), and poor neurologic status at discharge (RR = 0.4, 95% CI = 0.2-0.8; RR = 0.4, 95% CI = 0.2-0.9) in unadjusted associations., Conclusion: OHCA patients have markedly elevated plasma and pulmonary edema fluid biomarker concentrations, indicating widespread inflammation, epithelial injury, and endothelial activation. Biomarker concentrations were not associated with ARDS development, though several distinct biological phenotypes warrant further exploration. Latent phase analysis demonstrated that patients with low biomarker levels aside from TNF-α and TNFR-1 (Class 2) fared worse than other patients. Future research may benefit from considering other tools to predict and prevent development of ARDS in this population., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Intimate partner violence (IPV) occurs at alarmingly high rates towards pregnant women in South Africa. Experiences of emotional, physical, and sexual IPV in pregnancy can adversely impact the health and safety of mother and fetus. Furthermore, IPV is associated with increased risk of HIV, exacerbating the public health impact of violence among pregnant women in this HIV endemic setting. In-depth understanding of cultural and contextual drivers of experiences of IPV is a critical precursor to development of interventions effectively addressing this issue among pregnant women in South Africa. The present study examines factors contributing to IPV among pregnant women to identify potential points of intervention. We conducted twenty in-depth interviews with postpartum women who used oral pre-exposure prophylaxis (PrEP) in pregnancy and reported recent experiences of IPV and/or ongoing alcohol use in a township near Cape Town, South Africa that experiences a heavy burden of both HIV and IPV. Interpretive thematic analysis was used. Several patterns of IPV during pregnancy were identified and violence was frequently described as co-occurring with male partner alcohol use. A majority of women referenced oral PrEP as their preferred method for HIV prevention, highlighting the agency and discretion it provided as beneficial attributes for women experiencing IPV. Fear of judgement from peers for remaining with an abusive partner and a lack of clear community messaging around IPV were identified as barriers to disclosure and support-seeking. Addressing the lack of social support received by women experiencing IPV during pregnancy in South Africa is essential to comprehensive IPV programming., (© 2024. The Author(s).)

Objective: Therapeutic exercises are a core treatment for low back pain (LBP), but it is uncertain how rehabilitative exercise facilitates change in outcomes. Realist reviews explore how the context (C) of certain settings or populations and underlying mechanisms (M) create intended or unintended outcomes (O). Our objective was to explore and understand the behavioural mechanisms by which therapeutic exercise creates change in outcomes of adherence, engagement and clinical outcomes for patients with LBP., Methods: This was a realist review reported following the Realist and Meta-narrative Evidence Syntheses: Evolving Standards guidance. We developed initial programme theories, modified with input from a steering group (experts, n=5), stakeholder group (patients and clinicians, n=10) and a scoping search of the published literature (n=37). Subsequently, an information specialist designed and undertook an iterative search strategy, and we refined and tested CMO configurations., Results: Of 522 initial papers identified, 75 papers were included to modify and test CMO configurations. We found that the patient-clinician therapeutic consultation builds a foundation of trust and was associated with improved adherence, engagement and clinical outcomes, and that individualised exercise prescription increases motivation to adhere to exercise and thus also impacts clinical outcomes. Provision of support such as timely follow-up and supervision can further facilitate motivation and confidence to improve adherence to therapeutic exercises for LBP., Conclusions: Engagement in and adherence to therapeutic exercises for LBP, as well as clinical outcomes, may be optimised using mechanisms of trust, motivation and confidence. These CMO configurations provide a deeper understanding of ways to optimise exercise prescription for patients with LBP., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Persistent low back pain (LBP) is the leading cause of disability worldwide, and therapeutic exercise is recommended as a first-line treatment in international guidelines. The effects of exercise on clinical outcomes of pain and physical function are small to moderate, despite broader impacts on cardiovascular systems, biological health, mood, and emotional well-being. Therapeutic exercise prescription is defined as exercise that is prescribed by a clinician for a health-related treatment. It is unknown how therapeutic exercise prescription creates effects on outcomes of importance. Realist reviews explore how underlying mechanisms (M) may be active in the context (C) of certain situations, settings, or populations to create an intended or unintended outcome (O). Our objective is to explore and understand the mechanisms by which therapeutic exercise prescription changes outcomes for people with persistent LBP., Methods: We will develop initial programme theories based on preliminary data from a previous systematic review and consensus workshop. These theories will be modified with input from a steering group (experts), a stakeholder group (people with lived experience of exercise for persistent LBP and clinicians), and a scoping search of the published literature. An information specialist will design and undertake an iterative search strategy. These will be used to create CMO configurations, which will be refined and tested using the literature. The realist review will be reported following RAMESES guidance., Discussion: Realist reviews are uncommon in LBP research to date, yet those offer an opportunity to contrast with traditional methods of randomised controlled trials and systematic reviews and provide additional information regarding the contexts and mechanisms that may trigger certain outcomes. This can aid our understanding of the contextual features that may influence exercise prescription, such as for whom they are most effective, in what setting, how they are implemented and why. This realist synthesis will enhance our understanding of therapeutic exercise prescription to improve adherence and engagement and ultimately will provide clinically relevant recommendations regarding exercise prescription for those with persistent LBP., Systematic Review Registration: The review has been registered with PROSPERO (CRD42017072023)., (© 2024. The Author(s).)

Objective: To compare pregnancy outcomes using self-reported and objective levels of intracellular tenofovir diphosphate (TFV-DP) in pregnant women using preexposure prophylaxis (PrEP)., Design: We enrolled pregnant women >15 years without HIV at first antenatal care visit in an observational cohort study to compare pregnancy outcomes by PrEP use., Methods: Exposure defined as: any PrEP use [tenofovir disoproxil and emtricitabine (TDF/FTC]) prescription + reported taking PrEP], or objectively-measured TFV-DP in dried blood spots in PrEP-using pregnant women. The primary outcome was a composite of pregnancy loss, preterm birth (<37weeks), low birthweight (<2500 g), small for gestational age ([SGA] ≤ tenth percentile), or neonatal death. Multivariable logistic regression models evaluated individual and composite adverse outcomes by self-reported or objectively measured PrEP use adjusting for age, gestational age, gravidity and socio-economic status., Results: Between August 19 and February 23, we followed 1195 pregnant women and ascertained 1145 pregnancy outcomes (96%); 72% ( n  = 826) reported taking PrEP while pregnant, 16% did not take PrEP ( n  = 178), 12% were unconfirmed ( n  = 141). Overall, 94.5% ( n  = 1082) had singleton live births with a median birthweight of 3.2 kg [interquartile range (IQR) = 2.9-3.5], with no difference in pregnancy loss between self-reported PrEP exposed vs. unexposed [4.0 vs. 5.6%; adjusted odds ratio (aOR) = 0.65, 95% confidence interval (CI) = 0.32-1.47]. Composite adverse outcomes did not differ by reported PrEP use (20% for both groups; aOR = 1.07, 95% CI = 0.71-1.63). Comparing objective PrEP use (any TFV-DP vs. no TFV-DP or not on PrEP), adverse outcomes did not differ (aOR = 0.64, 95% CI = 0.39-1.04), nor did other outcomes including preterm birth nor SGA., Conclusions: Pregnancy outcomes did not differ by PrEP exposure (self-reported or objective), suggesting real-world efficacy that TDF/FTC as PrEP is safe in pregnancy., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Knee osteoarthritis (OA) negatively impacts the health outcomes and equity, social and employment participation, and socio-economic wellbeing of those affected. Little community-based support is offered to people with knee OA in Aotearoa New Zealand. Identifying Māori and non-Māori with knee OA in community pharmacy and providing co-ordinated, evidence- and community-based care may be a scalable, sustainable, equitable, effective and cost-effective approach to improve health and wellbeing., Aim: Assess whether the Knee Care for Arthritis through Pharmacy Service (KneeCAPS) intervention improves knee-related physical function and pain (co-primary outcomes). Secondary aims assess impacts on health-related quality of life, employment participation, medication use, secondary health care utilisation, and relative effectiveness for Māori., Methods and Analysis: A pragmatic randomised controlled trial will compare the KneeCAPS intervention to the Pharmaceutical Society of New Zealand Arthritis Fact Sheet and usual care (active control) at 12 months for Māori and non-Māori who have knee OA. Participants will be recruited in community pharmacies. Knee-related physical function will be measured using the function subscale of the Short Form of the Western Ontario and McMaster Universities Osteoarthritis Index. Knee-related pain will be measured using an 11-point numeric pain rating scale. Primary outcome analyses will be conducted on an intention-to-treat basis using linear mixed models. Parallel within-trial health economic analysis and process evaluation will also be conducted., Ethics and Trial Dissemination: Ethical approval was obtained from the Central Health and Ethics Committee (2022-EXP-11725). The trial is registered with ANZCTR (ACTRN12622000469718). Findings will be submitted for publication and shared with participants., (© 2023 The Authors. Musculoskeletal Care published by John Wiley & Sons Ltd.)

Real-time fMRI neurofeedback (rt-fMRI-NF) is a technique in which information about an individual's neural state is given back to them, typically to enable and reinforce neuromodulation. Its clinical potential has been demonstrated in several applications, but lack of evidence on optimal parameters limits clinical utility of the technique. This study aimed to identify optimal parameters for rt-fMRI-NF-aided craving regulation training in alcohol use disorder (AUD). Adults with AUD (n = 30) participated in a single-session study of four runs of rt-fMRI-NF where they downregulated "craving-related" brain activity. They received one of three types of neurofeedback: multi-region of interest (ROI), support vector machine with continuous feedback (cSVM), and support vector machine with intermittent feedback (iSVM). Performance was assessed on the success rate, change in neural downregulation, and change in self-reported craving for alcohol. Participants had more successful trials in run 4 versus 1, as well as improved downregulation of the insula, anterior cingulate, and dorsolateral prefrontal cortex (dlPFC). Greater downregulation of the latter two regions predicted greater reduction in craving. iSVM performed significantly worse than the other two methods. Downregulation of the striatum and dlPFC, enabled by ROI but not cSVM neurofeedback, was correlated with a greater reduction in craving. rt-fMRI-NF training for downregulation of alcohol craving in individuals with AUD shows potential for clinical use, though this pilot study should be followed with a larger randomized-control trial before clinical meaningfulness can be established. Preliminary results suggest an advantage of multi-ROI over SVM and intermittent feedback approaches., (Published 2023. This article is a U.S. Government work and is in the public domain in the USA.)

Background: Addressing the increasing prevalence of obesity is a global public health priority. Severe obesity (body mass index > 40) reduces life expectancy, due to its association with people developing complications (e.g. diabetes, cancer, cardiovascular disease), and greatly impairs quality of life. The National Health Service (NHS) in the UK provides specialist weight management services (SWMS) for people with severe obesity, but key uncertainties remain around patient access to and engagement with weight management services, as well as pathways beyond the service., Methods: In this multiple methods study, using online forum data and semi-structured interviews, stakeholders' experiences of delivering and receiving SWMS were explored. Using the web search engine Google with keywords and web address (URL) identifiers, relevant public online platforms were sourced with snowball sampling and search strings used to identify threads related to people's experiences of accessing SWMS (n = 57). Interviews were conducted with 24 participants (nine patients, 15 staff), and data from all sources were analysed thematically using the framework approach., Results: Six themes related to access to and engagement with SWMS emerged during data analysis: (1) making the first move, (2) uncertainty and confusion, (3) resource issues, (4) respect and understanding, (5) mode of delivery, and (6) desire for ongoing support., Conclusion: There is a mixed and varied picture of SWMS provision across the UK. The service offered is based on local clinical decision making and available resources, resulting in a range of patient experiences and perspectives. Whilst service capacity issues and patient anxiety were seen as barriers to accessing care, peer support and positive clinical and group interactions (connectedness between individuals) were considered to increase engagement., (© 2023. The Author(s).)

Background: Cardiovascular disease is the most common cause of death globally. Traditionally, centre-based cardiac rehabilitation programmes are offered to individuals after cardiac events to aid recovery and prevent further cardiac illness. Home-based and technology-supported cardiac rehabilitation programmes have been introduced in an attempt to widen access and participation, especially during the SARS-CoV-2 pandemic. This is an update of a review previously published in 2009, 2015, and 2017., Objectives: To compare the effect of home-based (which may include digital/telehealth interventions) and supervised centre-based cardiac rehabilitation on mortality and morbidity, exercise-capacity, health-related quality of life, and modifiable cardiac risk factors in patients with heart disease SEARCH METHODS: We updated searches from the previous Cochrane Review by searching the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid), Embase (Ovid), PsycINFO (Ovid) and CINAHL (EBSCO) on 16 September 2022. We also searched two clinical trials registers as well as previous systematic reviews and reference lists of included studies. No language restrictions were applied., Selection Criteria: We included randomised controlled trials that compared centre-based cardiac rehabilitation (e.g. hospital, sports/community centre) with home-based programmes (± digital/telehealth platforms) in adults with myocardial infarction, angina, heart failure, or who had undergone revascularisation., Data Collection and Analysis: Two review authors independently screened all identified references for inclusion based on predefined inclusion criteria. Disagreements were resolved through discussion or by involving a third review author. Two authors independently extracted outcome data and study characteristics and assessed risk of bias. Certainty of evidence was assessed using GRADE., Main Results: We included three new trials in this update, bringing a total of 24 trials that have randomised a total of 3046 participants undergoing cardiac rehabilitation. A further nine studies were identified and are awaiting classification. Manual searching of trial registers until 16 September 2022 revealed a further 14 clinical trial registrations - these are ongoing. Participants had a history of acute myocardial infarction, revascularisation, or heart failure. Although there was little evidence of high risk of bias, a number of studies provided insufficient detail to enable assessment of potential risk of bias; in particular, details of generation and concealment of random allocation sequencing and blinding of outcome assessment were poorly reported. No evidence of a difference was seen between home- and centre-based cardiac rehabilitation in our primary outcomes up to 12 months of follow-up: total mortality (risk ratio [RR] = 1.19, 95% confidence interval [CI] 0.65 to 2.16; participants = 1647; studies = 12/comparisons = 14; low-certainty evidence) or exercise capacity (standardised mean difference (SMD) = -0.10, 95% CI -0.24 to 0.04; participants = 2343; studies = 24/comparisons = 28; low-certainty evidence). The majority of evidence (N=71 / 77 comparisons of either total or domain scores) showed no significant difference in health-related quality of life up to 24 months follow-up between home- and centre-based cardiac rehabilitation. Trials were generally of short duration, with only three studies reporting outcomes beyond 12 months (exercise capacity: SMD 0.11, 95% CI -0.01 to 0.23; participants = 1074; studies = 3; moderate-certainty evidence). There was a similar level of trial completion (RR 1.03, 95% CI 0.99 to 1.08; participants = 2638; studies = 22/comparisons = 26; low-certainty evidence) between home-based and centre-based participants. The cost per patient of centre- and home-based programmes was similar., Authors' Conclusions: This update supports previous conclusions that home- (± digital/telehealth platforms) and centre-based forms of cardiac rehabilitation formally supported by healthcare staff seem to be similarly effective in improving clinical and health-related quality of life outcomes in patients after myocardial infarction, or revascularisation, or with heart failure. This finding supports the continued expansion of healthcare professional supervised home-based cardiac rehabilitation programmes (± digital/telehealth platforms), especially important in the context of the ongoing global SARS-CoV-2 pandemic that has much limited patients in face-to-face access of hospital and community health services. Where settings are able to provide both supervised centre- and home-based programmes, consideration of the preference of the individual patient would seem appropriate. Although not included in the scope of this review, there is an increasing evidence base supporting the use of hybrid models that combine elements of both centre-based and home-based cardiac rehabilitation delivery. Further data are needed to determine: (1) whether the short-term effects of home/digital-telehealth and centre-based cardiac rehabilitation models of delivery can be confirmed in the longer term; (2) the relative clinical effectiveness and safety of home-based programmes for other heart patients, e.g. post-valve surgery and atrial fibrillation., (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Objective: Accurate knowledge is central to effective self-care of osteoarthritis (OA). This study aimed to assess the measurement properties of the Osteoarthritis Knowledge Scale (OAKS) with versions for the hip and knee., Methods: Participants with hip OA (n = 144), knee OA (n = 327), and no OA (n = 735) were recruited. Rasch analysis was conducted to assess psychometric properties using data from all participants with hip OA and 144 randomly selected participants with either knee OA or no OA. Test-retest reliability and measurement error were estimated among those with hip (n = 51) and knee (n = 142) OA., Results: Four items from the draft scales were deleted following Rasch analysis. The final 11-item OAKS was unidimensional. Item functioning was not affected by gender, age, educational level, or scale version (hip or knee). Person separation index was 0.75. Test-retest intraclass correlation coefficient was 0.81 (95% CI 0.74, 0.86; hip version 0.66 [0.47, 0.79]; knee version 0.85 (0.79, 0.90)). Smallest detectable change was 9 points (scale range 11-55; hip OA version 11 points; knee OA version 8 points)., Conclusion: The OAKS is a psychometrically adequate, unidimensional measure of important OA knowledge that can be used in populations with and without hip and knee OA. Caution is needed when using with populations with only hip OA as test-retest reliability of the hip version did not surpass the acceptable range., (© 2022 The Authors. Musculoskeletal Care published by John Wiley & Sons Ltd.)

Purpose/objective: Early powered mobility (PM) experiences can be essential facilitators of self-initiated mobility, socialization, and exploration for young children with disabilities. Cerebral palsy (CP) and developmental delay are two of the most common diagnoses associated with motor disability in young children with 1 in 345 children diagnosed with CP and 1 in 6 with developmental delay in the US. The purpose of this study was to explore the longitudinal experiences and caregiver perceptions of socio-emotional development in particular, in young children with disabilities during modified ride-on car (ROC) use., Research Method/design: A qualitative, grounded theory approach was used. Semi-structured interviews were conducted with 15 families (children ages 1-4 with CP or developmental delay) at baseline, 6 months (as able due to COVID), and 1 year following ROC introduction. Data were coded independently by three researchers using constant comparison until data saturation occurred and themes emerged., Results: Four themes emerged from the data: "Leveling the Playing Field," "Breaking Down Barriers," "Fun and Work: ROC as Toy and Therapy Device," and "Mobility is a Pathway to Autonomy." Conclusions/Implication: Children and caregivers viewed ROCs as both fun and therapeutic, consistently identifying perceived benefits for children's socio-emotional development. This qualitative study provides a better understanding of the complexities and impact of ROCs on children and their families in the socio-emotional domain and may help facilitate clinical decision-making when introducing PM to young children with disabilities as part of a multimodal approach to early intervention. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Introduction: The UK has worse cancer outcomes than most comparable countries, with a large contribution attributed to diagnostic delay. Electronic risk assessment tools (eRATs) have been developed to identify primary care patients with a ≥2% risk of cancer using features recorded in the electronic record., Methods and Analysis: This is a pragmatic cluster randomised controlled trial in English primary care. Individual general practices will be randomised in a 1:1 ratio to intervention (provision of eRATs for six common cancer sites) or to usual care. The primary outcome is cancer stage at diagnosis, dichotomised to stage 1 or 2 (early) or stage 3 or 4 (advanced) for these six cancers, assessed from National Cancer Registry data. Secondary outcomes include stage at diagnosis for a further six cancers without eRATs, use of urgent referral cancer pathways, total practice cancer diagnoses, routes to cancer diagnosis and 30-day and 1-year cancer survival. Economic and process evaluations will be performed along with service delivery modelling. The primary analysis explores the proportion of patients with early-stage cancer at diagnosis. The sample size calculation used an OR of 0.8 for a cancer being diagnosed at an advanced stage in the intervention arm compared with the control arm, equating to an absolute reduction of 4.8% as an incidence-weighted figure across the six cancers. This requires 530 practices overall, with the intervention active from April 2022 for 2 years., Ethics and Dissemination: The trial has approval from London City and East Research Ethics Committee, reference number 19/LO/0615; protocol version 5.0, 9 May 2022. It is sponsored by the University of Exeter. Dissemination will be by journal publication, conferences, use of appropriate social media and direct sharing with cancer policymakers., Trial Registration Number: ISRCTN22560297., Competing Interests: Competing interests: WH owns background IP for the eRATs but will not use this for personal finacial benefit from any NHS use. All other authors declare no competing interests., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Introduction: Using tele-rehabilitation methods to deliver exercise, physical activity (PA) and behaviour change interventions for people with multiple sclerosis (pwMS) has increased in recent years, especially since the SARS-CoV-2 pandemic. This scoping review aims to provide an overview of the literature regarding adherence to therapeutic exercise and PA delivered via tele-rehabilitation for pwMS., Methods and Analysis: Frameworks described by Arksey and O'Malley and Levac et al underpin the methods. The following databases will be searched from 1998 to the present: Medline (Ovid), Embase (Ovid), CINAHL (EBSCOhost), Health Management Information Consortium Database, ProQuest Dissertations and Theses Global, Pedro, Cochrane Central Register of Controlled Trials, US National Library of Medicine Registry of Clinical Trials, WHO International Clinical Trials Registry Platform portal and The Cochrane Database of Systematic Reviews. To identify papers not included in databases, relevant websites will be searched. Searches are planned for 2023. With the exception of study protocols, papers on any study design will be included. Papers reporting information regarding adherence in the context of prescribed therapeutic exercise and PA delivered via tele-rehabilitation for pwMS will be included. Information relating to adherence may comprise; methods of reporting adherence, adherence levels (eg, exercise diaries, pedometers), investigation of pwMS' and therapists' experiences of adherence or a discussion of adherence. Eligibility criteria and a custom data extraction form will be piloted on a sample of papers. Quality assessment of included studies will use Critical Appraisal Skills Programme checklists. Data analysis will involve categorisation, enabling findings relating to study characteristics and research questions to be presented in narrative and tabular format., Ethics and Dissemination: Ethical approval was not required for this protocol. Findings will be submitted to a peer-reviewed journal and presented at conferences. Consultation with pwMS and clinicians will help to identify other dissemination methods., Competing Interests: Competing interests: GG received funding through an HEE/NIHR ICA Internship (November 2020–April 2021)., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Background: Real-world adherence to clinical practice guidelines is often poor, resulting in sub-standard patient care and unnecessary healthcare costs. This study evaluates the effect of a guideline-implementation intervention for the management of low back pain (LBP) in general practice-the Fear Reduction Exercised Early (FREE) approach-on LBP-related injury insurance claims, healthcare utilisation, and costs of treatment., Design: Data were extracted from comprehensive nationwide New Zealand injury insurance claims records. Data were analysed using a 'triple-difference' (difference-in-difference-in-differences) method to isolate the causal effect of FREE training on LBP claims activity, comparing the difference in general practitioner (GP) LBP claims and associated activity before and after training with their non-musculoskeletal injury claims for the same periods (assumed to be unaffected by training), relative to the same comparisons for GPs not trained in the FREE approach., Results: Training GPs in the FREE approach resulted in significant reductions in the number of LBP injury claims lodged (- 19%, 95% CI -34 to -5), the use of physiotherapy (-30%, 95% CI - 42 to - 18) and imaging (- 27%, 95% CI - 46 to - 8%), and the healthcare costs (- 21%, 95% CI - 41 to - 1) of LBP injury. Changes in claims for earnings' compensation (- 10%, 95% CI - 34 to 13) were not significant., Conclusions: A brief guideline-implementation intervention following best-practice LBP management and guideline-implementation strategies achieved significant reductions, persisting over at least 6 to18 months, in healthcare utilisation consistent with improved delivery of guideline-concordant care., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Community-based peer support groups for stroke survivors are common in the United Kingdom and aim to support rehabilitation. This study of 260 stroke survivors across 118 groups nationally used an online survey format, completed on average 3 months into the pandemic. Analysis of both quantitative and open-ended responses provided insights into how stroke group members maintained contact during the COVID-19 pandemic and how the group processes of shared social identity and perceived social support related to psychosocial outcomes (self-esteem, well-being and loneliness). Group members adapted to the pandemic early through telephone calls (61.6% of participants) and internet-based contact (>70% of participants), although also showed a desire for greater contact with their groups. A stronger sense of shared social identity and perceptions of social support from the stroke groups were weakly associated with reductions in loneliness among members, and greater perceived social support was associated with higher self-esteem. However, having poor health and living alone were more strongly associated with more negative psychosocial outcomes. The discussion considers how barriers to contact during pandemics can be managed, including access and use of online communication, limitations imposed by stroke-related disability, and how the experience of feeling supported and social identification can be better nurtured within remote contexts., (© 2022 The Authors. Applied Psychology: Health and Well-Being published by John Wiley & Sons Ltd on behalf of International Association of Applied Psychology.)

Purpose: Hemiparesis and physical deconditioning following stroke lead to an increase in falls, which many individuals cannot get up from. Teaching stroke survivors to independently get off the floor (IGO) might mitigate long-lie complications. IGO was taught as part of a community-based, functional rehabilitation training programme (ReTrain). We explore the feasibility of teaching IGO and assess participant's level of mastery, adherence, and injury risk., Materials and Methods: Videos of participants ( n  = 17) performing IGO at early, middle, and late stages of the ReTrain programme were compared to a manualised standard. A visual, qualitative analysis was used to assess technique mastery, adherence, and injury risk., Results: Most participants (64%) achieved independent, safe practice of IGO. A good (73%) level of adherence to IGO and low incidence of risk of injury (6.8%) were observed. Deviations were made to accommodate for non-stroke related comorbidities., Conclusions: IGO was successfully and safely practised by stroke survivors including those with hemiparesis. Trainers should be aware of comorbidities that may impede completion of IGO and modify teaching to accommodate individual need. Further research should assess if IGO can be utilised by individuals who have other disabilities with unilateral impairments and whether IGO has physical, functional and economic benefit.Implications for rehabilitationFalls are common in stroke survivors, and many are unable to get up despite being uninjured, leading to long-lie complications or ambulance call-outs but non-conveyance to hospital.Teaching the independently getting up off the floor (IGO) technique to stroke survivors was possible for those with or without hemiparesis, and remained safe despite modifications to accommodate an individual's needs.Individual assessment is needed to check if a stroke survivor is suitable for learning IGO including, but not limited to, their ability to safely get to the floor and to temporarily stand (without support) at the end of the technique.

Background: The e-coachER trial aimed to determine whether adding web-based behavioural support to exercise referral schemes (ERS) increased long-term device-measured physical activity (PA) for patients with chronic conditions, compared to ERS alone, within a randomised controlled trial. This study explores the mechanisms of action of the e-coachER intervention using measures of the behaviour change processes integral to the intervention's logic model., Methods: Four hundred fifty adults with obesity, diabetes, hypertension, osteoarthritis or history of depression referred to an ERS were recruited in Plymouth, Birmingham and Glasgow. The e-coachER intervention comprising 7-Steps to Health was aligned with Self-Determination Theory and mapped against evidence-based behaviour change techniques (BCTs). Participants completed questionnaires at 0, 4, and 12 months to assess PA and self-reported offline engagement with core BCTs in day-to-day life (including action planning and self-monitoring) and beliefs relating to PA (including perceived importance, confidence, competence, autonomy and support). We compared groups at 4 and 12 months, controlling for baseline measures and other covariates. Mediation analysis using the product of coefficients method was used to determine if changes in process variables mediated intervention effects on moderate to vigorous physical activity (MVPA) recorded by accelerometer and self-report at 4- and 12-months., Results: The internal reliability (Cronbach's alpha) for all multi-item scales was > 0.77. At 4-months, those randomised to e-coachER reported higher levels of PA beliefs relating to importance (1.01, 95% confidence interval (CI): 0.42 to 1.61, p = 0.001), confidence (1.28, 95% CI: 0.57 to 1.98, p < 0.001), competence (1.61, 95% CI: .68 to 2.54, p = 0.001), availability of support (0.77, 95% CI: 0.07 to 1.48, p = 0.031), use of action planning (1.54, 95% CI: 0.23 to 2.85, p = 0.021) and use of self-monitoring (0.76, 95% CI: 0.19 to 1.32, p = 0.009) compared to ERS alone. There were no intervention effects on autonomous beliefs or perceived frequency of support, compared to ERS alone. At the 12-month follow-up, participants belief in the importance of PA was the only process measure to remain significantly higher in the e-coachER group when compared to ERS alone (0.75, 95% CI: 0.05 to 1.45). Intervention effects on perceived importance (2.52, 95% CI: 0.45 to 5.39), action planning (1.56, 95% CI: 0.10 to 3.54) and self-monitoring (1.92, 95% CI: 0.21 to 4.33) at 4-months significantly mediated change in accelerometer measured MVPA at 12-months (recorded in ≥ 10-min bouts)., Conclusions: e-coachER led to some short-term changes in most process outcomes. Some of these processes also appeared to mediate e-coachER effects on changes in accelerometer measured MVPA. Further work should be carried out to understand how best to design and implement theoretically underpinned web-based physical activity promotion interventions within ERS., Trial Registration: ISRCTN, ISRCTN15644451 . Registered 12 February 2015., (© 2022. The Author(s).)

Background: Approximately 15 million people in the UK live with obesity, around 5 million of whom have severe obesity (body mass index (BMI) ≥35kg/m 2 ). Having severe obesity markedly compromises health, well-being and quality of life, and substantially reduces life expectancy. These adverse outcomes are prevented or ameliorated by weight loss, for which sustained behavioural change is the cornerstone of treatment. Although NHS specialist 'Tier 3' Weight Management Services (T3WMS) support people with severe obesity, using individual and group-based treatment, the current evidence on optimal intervention design and outcomes is limited. Due to heterogeneity of severe obesity, there is a need to tailor treatment to address individual needs. Despite this heterogeneity, there are good reasons to suspect that a structured group-based behavioural intervention may be more effective and cost-effective for the treatment of severe obesity compared to usual care. The aims of this study are to test the feasibility of establishing and delivering a multi-centre randomised controlled clinical trial to compare a group-based behavioural intervention versus usual care in people with severe obesity., Methods: This feasibility randomised controlled study is a partially clustered multi-centre trial of PROGROUP (a novel group-based behavioural intervention) versus usual care. Adults ≥18 years of age who have been newly referred to and accepted by NHS T3WMS will be eligible if they have a BMI ≥40, or ≥35 kg/m 2 with comorbidity, are suitable for group-based care and are willing to be randomised. Exclusion criteria are participation in another weight management study, planned bariatric surgery during the trial, and unwillingness or inability to attend group sessions. Outcome assessors will be blinded to treatment allocation and success of blinding will be evaluated. Clinical measures will be collected at baseline, 6 and 12 months post-randomisation. Secondary outcome measures will be self-reported and collected remotely. Process and economic evaluations will be conducted., Discussion: This randomised feasibility study has been designed to test all the required research procedures and additionally explore three key issues; the feasibility of implementing a complex trial at participating NHS T3WMS, training the multidisciplinary healthcare teams in a standard intervention, and the acceptability of a group intervention for these particularly complex patients., Trial Registration: ISRCTN number 22088800., (© 2022. The Author(s).)

Objectives: To conduct a systematic review and synthesise qualitative research of electronic risk assessment tools (eRATs) in primary care, examining how they affect the communication and understanding of diagnostic risk and uncertainty. eRATs are computer-based algorithms designed to help clinicians avoid missing important diagnoses, pick up possible symptoms early and facilitate shared decision-making., Design: Systematic search, using predefined criteria of the published literature and synthesis of the qualitative data, using Thematic Synthesis. Database searches on 27 November 2019 were of MEDLINE, Embase, CINAHL and Web of Science, and a secondary search of the references of included articles. Included studies were those involving electronic risk assessment or decision support, pertaining to diagnosis in primary care, where qualitative data were presented. Non-empirical studies and non-English language studies were excluded. 5971 unique studies were identified of which 441 underwent full-text review. 26 studies were included for data extraction. A further two were found from citation searches. Quality appraisal was via the CASP (Critical Appraisal Skills Program) tool. Data extraction was via line by line coding. A thematic synthesis was performed., Setting: Primary care., Results: eRATs included differential diagnosis suggestion tools, tools which produce a future risk of disease development or recurrence or calculate a risk of current undiagnosed disease. Analytical themes were developed to describe separate aspects of the clinical consultation where risk and uncertainty are both central and altered via the use of an eRAT: 'Novel risk', 'Risk refinement', 'Autonomy', 'Communication', 'Fear' and 'Mistrust'., Conclusion: eRATs may improve the understanding and communication of risk in the primary care consultation. The themes of 'Fear' and 'Mistrust' could represent potential challenges with eRATs., Trial Registration Number: CRD219446., 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: Foods prepared outside the home (e.g., fast-food chains, restaurants) represent increasing proportions of diets worldwide, and have been associated with higher energy intakes and BMIs. To improve the healthiness of population diets, it is important to understand patterns of consumption of these foods, and whether related policy measures are effective., Objectives: This study aimed to identify the frequency and sources of consumption of foods prepared outside the home in Australia, and to understand the impact of nutrition information in restaurants on related food choices., Methods: Data were from a web-based survey (the International Food Policy Study) completed in 2018 by Australian adults aged ≥18 years (n = 4103). The number of meals prepared outside the home, their purchase locations, and the extent to which nutrition information was noticed and influenced purchasing decisions were each analyzed by sociodemographic characteristics and BMI, with linear models also adjusted for sex, age group, education, ethnicity, and BMI., Results: An average of 2.73 (95% CI, 2.61-2.86) meals per week were prepared outside the home, with higher frequencies among men, younger ages, and more highly educated participants. A wide variety of sources for these foods was observed, with fast-food outlets being most common. Around one-quarter of all foods prepared outside the home were delivered. A small percentage (14.9%; 95% CI, 13.3%-16.7%) of participants reported noticing nutrition information, but among those who did, around half reported that it influenced their behavior., Conclusions: Foods prepared outside the home are commonly purchased in Australia, particularly by young adults, from a variety of outlet types. While current menu energy labeling regulations may provide some population health benefit, a broader policy focus on foods prepared outside the home is needed as part of efforts to improve population diets., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Context: As psychosocial factors have been recognised as significant predictors of the recovery trajectory from chronic back pain, the 34-item Back Pain Attitudes Questionnaire (Back-PAQ) was developed based on themes obtained from patient interviews, but previous psychometric analyses with a general population sample revealed uncertainty around the factor structure of the instrument., Objectives: To provide more detailed information about the psychometric properties of the Back-PAQ when used with participants from the general population and also to test the internal validity of the tool for use with General Practitioners (GPs)., Methods: After applying partial-credit Rasch analysis with a sample of participants from the general population ( n  = 600), a replication analysis was conducted with a sample of GPs ( n  = 184). This approach permitted examination of sample-specific personal factors for differential item functioning. Subtests were used to differentiate between local dependency due to underlying dimensionality from local dependency due to method effects., Results: A unidimensional fit to the Rasch model was achieved after 14 misfitting items had been deleted. The final 20-item solution also fit with a sample of 184 GPs. In both cases, the Back-PAQ-20 demonstrated good reliability (PSI ≥ 0.80), with no evidence of differential item functioning by personal factors., Conclusion: The ordinal-to-interval conversion algorithms presented here further enhance the precision of the scale and permit analysis of Back-PAQ-20 scores using parametric statistics. The present study provided evidence for valid and reliable assessment of the back pain recovery beliefs of both users as well as providers of health services.IMPLICATIONS FOR REHABILITATIONPsychosocial factors have been recognised as significant predictors of the recovery trajectory from chronic back pain.The 34-item Back Pain Attitudes Questionnaire (Back-PAQ) was developed based on themes obtained from patient interviews, but previous psychometric analyses with a general population sample revealed uncertainty around the factor structure of the instrument.The 20-item version of the Back Pain Attitudes Questionnaire (Back-PAQ) is shown here to have strong psychometric properties for administration with users and providers of health services.

Introduction: Ornithine transcarbamylase (OTC) deficiency is the most common urea cycle disorder, inherited in an X-linked manner. Males are severely affected. Female phenotypes vary from asymptomatic to severe, and symptoms may be triggered by high metabolic states like childbirth. Literature on OTC deficiency in pregnancy and placental pathology is limited., Methods: Pathology records were searched at a single referral center from 2000-2020 and identified three placental cases from two mothers heterozygous for OTC deficiency. Placental pathology and maternal and neonatal history were reviewed in detail., Results: The placenta from one symptomatic mother carrying an affected male fetus showed widespread high-grade fetal vascular malperfusion (FVM) lesions of varying age. These lesions were not seen in the two placentas from the asymptomatic mother., Discussion: In cases of symptomatic maternal OTC deficiency, our findings highlight the need for placental examination. Since thrombotic events in the placenta have the potential to associate with fetal and neonatal endothelial damage, a high index of suspicion for neonatal thrombosis may be warranted.

We explore the views of managers' knowledge needs and use to optimise care practices and enhance the life experience for older people living, and staff working, in long-term care homes (with and without nursing). This paper contributes to previous research by offering insights into the knowledge types drawn upon and used by managers to inform efforts to better support gaining and mobilising knowledge. Using a pragmatic qualitative approach, we undertook 19 semi-structured interviews with managers and leaders in 15 care homes in the South West of England, varying in geographical location, size and type of ownership. We did a thematic analysis of the data using Framework Analysis. Our interpretations were informed by the existing literature on knowledge types. We identified three themes from our analysis as to managers' knowledge needs and use when implementing changes. First, views about training and formal reports or "explicit knowledge" consisting of the two sub-themes "gaining explicit knowledge" and "research knowledge". Second, perspectives relating to practical experience or "tacit knowledge" and judging the use of knowledge in particular cases or "phronesis". Third, the role of emotion in managers' knowledge needs and use. We found that having knowledge was positively valued by managers and leaders for improving care practices and enhancing the lives of people residing in care homes. Tacit knowledge and phronesis were particularly highly valued and we note challenges with the perceived applicability, relevance and use of research evidence. We identify that emotions are an important component within knowledge use and a need to further understand how to support the emotional wellbeing of managers so they can support care staff and residents. Greater consideration is needed as to how to optimise gaining and mobilising all knowledge types - "know-what," "know-how," "know-when" and "know-feel" - to benefit people living, and staff working, in care homes., (© 2020 The Authors. Health and Social Care in the Community published by John Wiley & Sons Ltd.)

Purpose of Review: To investigate the type and effectiveness of health promotion programs designed to improve nutrition for people with intellectual disability. This review also sought to highlight gaps in the evidence by mapping interventions to the socio-ecological model., Recent Findings: To date, reviews on health promotion programs for people with intellectual disability have focused on individualised weight management interventions and behaviour change techniques. No reviews have focused solely on nutrition or considered a broader range of interventions and policies targeted beyond the individual. This review found that health promotion interventions to date were predominantly at the individual level of the socio-ecological model and of varying effectiveness. Of the non-individually focused interventions, those targeting the physical environment or considering multiple socio-ecological levels achieved the greatest improvements in nutrition outcomes. Nutrition and obesity prevention research and policy need to include intellectual disability as part of equity considerations, while intellectual disability policy needs to consider the broader food environment., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Abstract: Repeated presentations of a rare symptom in a patient should make a physician stop and evaluate for rare conditions. This is a report of a teenager with multiple episodes of rhabdomyolysis and weakness. He was eventually diagnosed as having McArdle muscular dystrophy, or glycogen storage disease type V. His rhabdomyolysis has been severe, with a creatinine kinase level of >320,000 U/L, myoglobinuria, transaminitis, and elevated bilirubin. He has a low threshold for triggering rhabdomyolysis, such as doing an hour of aerobic exercise 2 days in a row. McArdle disease is a glycogen storage disorder in which the skeletal muscle cannot convert glycogen to glucose. Unlike other glycogen storage disorders, McArdle muscular dystrophy only affects the skeletal muscle, sparing the brain and visceral organs, leading to a vague phenotype. These patients have exercise intolerance, muscle cramps, and rhabdomyolysis. Many patients report loading with simple carbohydrates before exercise, as they have learned that this can increase their stamina. The vague symptoms can lead to decades of delay in diagnosis and significant mismanagement. Rhabdomyolysis is the most dangerous sign of McArdle disease, and it can lead to acute kidney injury, resulting in renal failure requiring dialysis in the severest cases.Rhabdomyolysis has numerous causes, but when it is recurrent, especially with seemingly insignificant triggers, one needs to develop a broader differential and pursue advanced testing. This testing can include specific exercise tests, genetic sequencing, and muscle biopsy. This case report will guide the clinician through the process of evaluating recurrent rhabdomyolysis, working through the differential diagnosis and testing options.1., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Strong evidence supports beginning stroke rehabilitation as soon as the patient's medical status has stabilized and continuing following discharge from acute care. However, adherence to rehabilitation treatments over the rehabilitation phase has been shown to be suboptimal., Objective: The aim of this study is to assess the impact of a telerehabilitation platform on stroke patients' adherence to a rehabilitation plan and on their level of reintegration into normal social activities, in comparison with usual care. The primary outcome is patient adherence to stroke rehabilitation (up to 12 weeks), which is hypothesized to influence reintegration into normal living. Secondary outcomes for patients include functional recovery and independence, depression, adverse events related to telerehabilitation, use of services (up to 6 months), perception of interprofessional shared decision making, and quality of services received. Interprofessional collaboration as well as quality of interprofessional shared decision making will be measured with clinicians., Methods: In this interrupted time series with a convergent qualitative component, rehabilitation teams will be trained to develop rehabilitation treatment plans that engage the patient and family, while taking advantage of a telerehabilitation platform to deliver the treatment. The intervention will be comprised of 220 patients who will take part in stroke telerehabilitation with an interdisciplinary group of clinicians (telerehabilitation group) versus face-to-face standard of care (control group: n=110 patients)., Results: Our Research Ethics Board approved the study in June 2020. Data collection for the control group is underway, with another year planned before we begin the intervention phase., Conclusions: This study will contribute to the minimization of both knowledge and practice gaps, while producing robust, in-depth data on the factors related to the effectiveness of telerehabilitation in a stroke rehabilitation continuum. Findings will inform best practice guidelines regarding telecare services and the provision of telerehabilitation, including recommendations for effective interdisciplinary collaboration regarding stroke rehabilitation., Trial Registration: ClinicalTrials.gov NCT04440215; https://clinicaltrials.gov/ct2/show/NCT04440215., International Registered Report Identifier (irrid): DERR1-10.2196/32134., (©Isabelle Gaboury, Michel Tousignant, Hélène Corriveau, Matthew Menear, Guylaine Le Dorze, Christian Rochefort, Brigitte Vachon, Annie Rochette, Sylvie Gosselin, François Michaud, Jessica Bollen, Sarah Dean. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 28.10.2021.)

Community groups are commonly used as a mode of delivery of interventions for promoting health and well-being. Research has demonstrated that developing a sense of shared social identity with other group members is a key mechanism through which the health benefits of group membership are realized. However, there is little understanding of how shared social identity emerges within these therapeutic settings. Understanding the emergence of shared social identity may help researchers optimize interventions and improve health outcomes. Group-based singing activities encourage coordination and a shared experience, and are a potential platform for the development of shared social identity. We use the " Singing for People with Aphasia " (SPA) group intervention to explore whether group cohesiveness, as a behavioral proxy for shared social identity, can be observed and tracked across the intervention. Video recordings of group sessions from three separate programmes were rated according to the degree of cohesiveness exhibited by the group. For all treatment groups, the final group session evidenced reliably higher levels of cohesiveness than the first session ( t values ranged from 4.27 to 7.07; all p values < 0.003). As well as providing confidence in the design and fidelity of this group-based singing intervention in terms of its capacity to build shared social identity, this evaluation highlighted the value of observational methods for the analysis of shared social identity in the context of group-based singing interventions., Competing Interests: All authors report the Stroke Association funding for the work under consideration but no other conflicts of interest., (Copyright © 2021 Tarrant, Lamont, Carter, Dean, Spicer, Sanders and Calitri.)

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.

Background: Biological characterisation of breast cancer subtypes is essential as it informs treatment regimens especially as different subtypes have distinct locoregional patterns. This is related to metabolic phenotype, where altered cellular metabolism is a fundamental adaptation of cancer cells during rapid proliferation. In this context, the metabolism of the essential branched-chain amino acids (BCAAs), catalysed by the human branched-chain aminotransferase proteins (hBCAT), offers multiple benefits for tumour growth. Upregulation of the cytosolic isoform of hBCAT (hBCATc), regulated by c-Myc, has been demonstrated to increase cell migration, tumour aggressiveness and proliferation in gliomas, ovarian and colorectal cancer but the importance of the mitochondrial isoform, hBCATm has not been fully investigated., Methods: Using immunohistochemistry, the expression profile of metabolic proteins (hBCAT, IDH) was assessed between breast cancer subtypes, HER2 + , luminal A, luminal B and TNBC. Correlations between the percentage and the intensity of protein expression/co-expression with clinical parameters, such as hormone receptor status, tumour stage, lymph-node metastasis and survival, were determined., Results: We show that hBCATc expression was found to be significantly associated with the more aggressive HER2 + and luminal B subtypes, whilst hBCATm and IDH1 associated with luminal A subtype. This was concomitant with better prognosis indicating a differential metabolic reliance between these two subtypes, in which enhanced expression of IDH1 may replenish the α-ketoglutarate pool in cells with increased hBCATm expression., Conclusion: The cytosolic isoform of BCAT is associated with tumours that express HER2 receptors, whereas the mitochondrial isoform is highly expressed in tumours that are ER + , indicating that the BCAT proteins are regulated through different signalling pathways, which may lead to the identification of novel targets for therapeutic applications targeting dysregulated cancer metabolism.

Objectives: 1) Develop unidimensional instruments to measure osteoarthritis (OA) knowledge among people with hip or knee OA, and 2) assess the structural validity, internal consistency, cross-cultural validity/measurement invariance, test-retest reliability, and measurement error of the Hip Osteoarthritis Knowledge Scale (HOAKS) and the Knee Osteoarthritis Knowledge Scale (KOAKS)., Methods: Draft HOAKS and KOAKS were developed and refined following best-practice (COSMIN) guidelines with involvement of consumer research partners. Measurement properties of the HOAKS and KOAKS will be assessed through an online survey. The survey will include the novel HOAKS or KOAKS, the current short form of the Hip or Knee injury and Osteoarthritis Outcome Score (HOOS-12/KOOS-12), and items that gather demographic and OA characteristics and explore self-rated OA knowledge. People will be eligible to participate if aged 18 years and older, can communicate in English, and have either hip or knee OA as diagnosed by a health professional or by meeting diagnostic criteria. We aim to obtain 400 complete HOAKS or KOAKS responses and 100 complete HOAKS or KOAKS retest responses one week after initial completion. Rasch analysis will estimate structural validity, internal consistency and cross-cultural validity/measurement invariance. Assessment will include test-retest reliability (intraclass correlation coefficient) and absolute measurement error (standard error of measurement; smallest detectable change)., Conclusion: This study will produce robust unidimensional instruments to measure hip and knee OA knowledge. We anticipate that the HOAKS and KOAKS scales will be useful in clinical and research settings to identify knowledge gaps or evaluate interventions designed to improve knowledge., Competing Interests: All authors attest that there are no conflicts of interest., (© 2021 The Authors.)

Aim: To report on the acceptability of virtual reality (VR) nature environments for people with memory loss at memory cafes, and explore the experiences and perceptions of carers and staff. Methods: A qualitative study was conducted between January and March 2019. Ten adults with memory loss, eight carers and six volunteer staff were recruited from two memory cafes, located in Cornwall, UK. There were 19 VR sessions which were audio recorded and all participants were interviewed at the end of the sessions. Framework analysis was used to identify patterns and themes in the data. Results: During the VR experience, participants were engaged to varying degrees, with engagement facilitated by the researcher, and in some cases, with the help of a carer. Participants responded positively to the nature scenes, finding them soothing and evoking memories. The VR experience was positive; many felt immersed in nature and saw it as an opportunity to 'go somewhere'. However, it was not always positive and for a few, it could be 'strange'. Participants reflected on their experience of the VR equipment, and volunteer staff and carers also shared their perceptions of VR for people with dementia in long-term care settings. Conclusions: The VR nature experience was an opportunity for people with memory loss to be immersed in nature and offered the potential to enhance their quality of life. Future work should build on lessons learned and continue to work with people with dementia in developing and implementing VR technology in long-term care settings.

Introduction: Persistent non-cancer pain affects one in five adults and is more common in Māori-the Indigenous population of New Zealand (NZ), adults over 65 years, and people living in areas of high deprivation. Despite the evidence supporting multidisciplinary pain management programmes (PMPs), access to PMPs is poor due to long waiting lists. Although online-delivered PMPs enhance access, none have been codesigned with patients or compared with group-based, in-person PMPs. This non-inferiority trial aims to evaluate the clinical and cost-effectiveness of a cocreated, culturally appropriate, online-delivered PMP (iSelf-help) compared with in-person PMP in reducing pain-related disability., Methods and Analysis: Mixed-methods, using a modified participatory action research (PAR) framework, involving three phases. Phase I involved cocreation and cultural appropriateness of iSelf-help by PAR team members. Phase II: The proposed iSelf-help trial is a pragmatic, multicentred, assessor-blinded, two-arm, parallel group, non-inferiority randomised controlled trial. Adults (n=180, age ≥18 years) with persistent non-cancer pain eligible for a PMP will be recruited and block randomised (with equal probabilities) to intervention (iSelf-help) and control groups (in-person PMP). The iSelf-help participants will participate in two 60-minute video-conferencing sessions weekly for 12 weeks with access to cocreated resources via smartphone application and a password-protected website. The control participants will receive group-based, in-person delivered PMP. Primary outcome is pain-related disability assessed via modified Roland Morris Disability Questionnaire at 6 months post intervention. Secondary outcomes include anxiety, depression, stress, pain severity, quality of life, acceptance, self-efficacy, catastrophising and fear avoidance. Data will be collected at baseline, after the 12-week intervention, and at 3 and 6 months post intervention. We will conduct economic analyses and mixed-method process evaluations (Phase IIA)., Ethics and Dissemination: The Health and Disability Ethics Committee approved the study protocol (HDEC18/CEN/162). Phase III involves dissemination of findings guided by the PAR team as outcomes become apparent., Trial Registration Number: ACTRN 12619000771156., 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.)

Objectives: Pilot feasibility randomised controlled trial (RCT) for the singing groups for people with aphasia (SPA) intervention to assess: (1) the acceptability and feasibility of participant recruitment, randomisation and allocation concealment; (2) retention rates; (3) variance of continuous outcome measures; (4) outcome measure completion and participant burden; (5) fidelity of intervention delivery; (6) SPA intervention costs; (7) acceptability and feasibility of trial and intervention to participants and others involved., Design: A two-group, assessor-blinded, randomised controlled external pilot trial with parallel mixed methods process evaluation and economic evaluation., Setting: Three community-based cohorts in the South-West of England., Participants: Eligible participants with post-stroke aphasia were randomised 1:1 to SPA or control., Intervention: The manualised SPA intervention was delivered over 10 weekly singing group sessions, led by a music facilitator and assisted by an individual with post-stroke aphasia. The intervention was developed using the Information-Motivation-Behavioural skills model of behaviour change and targeted psychosocial outcomes. Control and intervention participants all received an aphasia information resource pack., Outcome Measures: Collected at baseline, 3 and 6 months post-randomisation, candidate primary outcomes were measured (well-being, quality of life and social participation) as well as additional clinical outcomes. Feasibility, acceptability and process outcomes included recruitment and retention rates, and measurement burden; and trial experiences were explored in qualitative interviews., Results: Of 87 individuals screened, 42 participants were recruited and 41 randomised (SPA=20, control=21); 36 participants (SPA=17, control=19) completed 3-month follow-up, 34 (SPA=18, control=16) completed 6-month follow-up. Recruitment and retention (83%) were acceptable for a definitive RCT, and participants did not find the study requirements burdensome. High fidelity of the intervention delivery was shown by high attendance rates and facilitator adherence to the manual, and participants found SPA acceptable. Sample size estimates for a definitive RCT and primary/secondary outcomes were identified., Conclusions: The SPA pilot RCT fulfilled its objectives, and demonstrated that a definitive RCT of the intervention would be both feasible and acceptable., Trial Registration Number: NCT03076736., Competing Interests: Competing interests: All authors report the Stroke Association funding for the work under consideration., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Insulin-like growth factor binding protein 3 (IGFBP-3) plays a key role in breast cancer progression and was recently shown to bind to the chaperone protein glucose-regulated protein 78 (GRP78); however, the clinical significance of this association remains poorly investigated. Here we report a direct correlation between the expression of GRP78 and IGFBP-3 in breast cancer cell lines and tumour sections. Kaplan-Meier survival plots revealed that patients with low GRP78 expression that are positive for IGFBP-3 had poorer survival rates than those with low IGFBP-3 levels, and we observed a similar trend in the publicly available METABRIC gene expression database. With breast cancer cells, in vitro IGFBP-3 enhanced induced apoptosis, however when GRP78 expression was silenced the actions of IGFBP-3 were switched from increasing to inhibiting ceramide (C2)-induced cell death and promoted cell invasion. Using immunofluorescence and cell surface biotinylation, we showed that knock-down of GRP78 negated the entry of IGFBP-3 into the cells. Together, our clinical and experimental results suggest that loss of GRP78 reduces IGFBP-3 entry into cells switching its actions to promote tumorigenesis and predicts a poor prognosis in breast cancer patients.

Introduction: There is emerging evidence that food industry involvement in nutrition research may bias research findings and/or research agendas. However, the extent of food industry involvement in nutrition research has not been systematically explored. This study aimed to identify the extent of food industry involvement in peer-reviewed articles from a sample of leading nutrition-related journals, and to examine the extent to which findings from research involving the food industry support industry interests., Methods: All original research articles published in 2018 in the top 10 most-cited nutrition- and dietetics-related journals were analysed. We evaluated the proportion of articles that disclosed involvement from the food industry, including through author affiliations, funding sources, declarations of interest or other acknowledgments. Principal research findings from articles with food industry involvement, and a random sample of articles without food industry involvement, were categorised according to the extent to which they supported relevant food industry interests., Results: 196/1,461 (13.4%) articles reported food industry involvement. The extent of food industry involvement varied by journal, with The Journal of Nutrition (28.3%) having the highest and Paediatric Obesity (3.8%) having the lowest proportion of industry involvement. Processed food manufacturers were involved in the most articles (77/196, 39.3%). Of articles with food industry involvement, 55.6% reported findings favourable to relevant food industry interests, compared to 9.7% of articles without food industry involvement., Conclusion: Food industry involvement in peer-reviewed research in leading nutrition-related journals is commonplace. In line with previous literature, this study has shown that a greater proportion of peer-reviewed studies involving the food industry have results that favour relevant food industry interests than peer-reviewed studies without food industry involvement. Given the potential competing interests of the food industry, it is important to explore mechanisms that can safeguard the integrity and public relevance of nutrition research., Competing Interests: GS and AJC are academic partners on a publicly funded healthy supermarket intervention trial that includes Australian local government and supermarket retail (IGA) collaborators. GS has been involved in studies to benchmark the policies and commitments of food companies related to obesity prevention and nutrition in Australia, New Zealand, Canada, Malaysia and Europe. The authors have not received funding from any organization in the food industry. The authors have no other potential competing interests to declare. The competing interests of the authors do not alter our adherence to PLOS ONE policies on sharing data and materials.

Importance: Data on the efficacy of hydroxychloroquine for the treatment of coronavirus disease 2019 (COVID-19) are needed., Objective: To determine whether hydroxychloroquine is an efficacious treatment for adults hospitalized with COVID-19., Design, Setting, and Participants: This was a multicenter, blinded, placebo-controlled randomized trial conducted at 34 hospitals in the US. Adults hospitalized with respiratory symptoms from severe acute respiratory syndrome coronavirus 2 infection were enrolled between April 2 and June 19, 2020, with the last outcome assessment on July 17, 2020. The planned sample size was 510 patients, with interim analyses planned after every 102 patients were enrolled. The trial was stopped at the fourth interim analysis for futility with a sample size of 479 patients., Interventions: Patients were randomly assigned to hydroxychloroquine (400 mg twice daily for 2 doses, then 200 mg twice daily for 8 doses) (n = 242) or placebo (n = 237)., Main Outcomes and Measures: The primary outcome was clinical status 14 days after randomization as assessed with a 7-category ordinal scale ranging from 1 (death) to 7 (discharged from the hospital and able to perform normal activities). The primary outcome was analyzed with a multivariable proportional odds model, with an adjusted odds ratio (aOR) greater than 1.0 indicating more favorable outcomes with hydroxychloroquine than placebo. The trial included 12 secondary outcomes, including 28-day mortality., Results: Among 479 patients who were randomized (median age, 57 years; 44.3% female; 37.2% Hispanic/Latinx; 23.4% Black; 20.1% in the intensive care unit; 46.8% receiving supplemental oxygen without positive pressure; 11.5% receiving noninvasive ventilation or nasal high-flow oxygen; and 6.7% receiving invasive mechanical ventilation or extracorporeal membrane oxygenation), 433 (90.4%) completed the primary outcome assessment at 14 days and the remainder had clinical status imputed. The median duration of symptoms prior to randomization was 5 days (interquartile range [IQR], 3 to 7 days). Clinical status on the ordinal outcome scale at 14 days did not significantly differ between the hydroxychloroquine and placebo groups (median [IQR] score, 6 [4-7] vs 6 [4-7]; aOR, 1.02 [95% CI, 0.73 to 1.42]). None of the 12 secondary outcomes were significantly different between groups. At 28 days after randomization, 25 of 241 patients (10.4%) in the hydroxychloroquine group and 25 of 236 (10.6%) in the placebo group had died (absolute difference, -0.2% [95% CI, -5.7% to 5.3%]; aOR, 1.07 [95% CI, 0.54 to 2.09])., Conclusions and Relevance: Among adults hospitalized with respiratory illness from COVID-19, treatment with hydroxychloroquine, compared with placebo, did not significantly improve clinical status at day 14. These findings do not support the use of hydroxychloroquine for treatment of COVID-19 among hospitalized adults., Trial Registration: ClinicalTrials.gov: NCT04332991.

Background: Urinary incontinence affects one in three women worldwide. Pelvic floor muscle training is an effective treatment. Electromyography biofeedback (providing visual or auditory feedback of internal muscle movement) is an adjunct that may improve outcomes., Objectives: To determine the clinical effectiveness and cost-effectiveness of biofeedback-mediated intensive pelvic floor muscle training (biofeedback pelvic floor muscle training) compared with basic pelvic floor muscle training for treating female stress urinary incontinence or mixed urinary incontinence., Design: A multicentre, parallel-group randomised controlled trial of the clinical effectiveness and cost-effectiveness of biofeedback pelvic floor muscle training compared with basic pelvic floor muscle training, with a mixed-methods process evaluation and a longitudinal qualitative case study. Group allocation was by web-based application, with minimisation by urinary incontinence type, centre, age and baseline urinary incontinence severity. Participants, therapy providers and researchers were not blinded to group allocation. Six-month pelvic floor muscle assessments were conducted by a blinded assessor., Setting: This trial was set in UK community and outpatient care settings., Participants: Women aged ≥ 18 years, with new stress urinary incontinence or mixed urinary incontinence. The following women were excluded: those with urgency urinary incontinence alone, those who had received formal instruction in pelvic floor muscle training in the previous year, those unable to contract their pelvic floor muscles, those pregnant or < 6 months postnatal, those with prolapse greater than stage II, those currently having treatment for pelvic cancer, those with cognitive impairment affecting capacity to give informed consent, those with neurological disease, those with a known nickel allergy or sensitivity and those currently participating in other research relating to their urinary incontinence., Interventions: Both groups were offered six appointments over 16 weeks to receive biofeedback pelvic floor muscle training or basic pelvic floor muscle training. Home biofeedback units were provided to the biofeedback pelvic floor muscle training group. Behaviour change techniques were built in to both interventions., Main Outcome Measures: The primary outcome was urinary incontinence severity at 24 months (measured using the International Consultation on Incontinence Questionnaire Urinary Incontinence Short Form score, range 0-21, with a higher score indicating greater severity). The secondary outcomes were urinary incontinence cure/improvement, other urinary and pelvic floor symptoms, urinary incontinence-specific quality of life, self-efficacy for pelvic floor muscle training, global impression of improvement in urinary incontinence, adherence to the exercise, uptake of other urinary incontinence treatment and pelvic floor muscle function. The primary health economic outcome was incremental cost per quality-adjusted-life-year gained at 24 months., Results: A total of 300 participants were randomised per group. The primary analysis included 225 and 235 participants (biofeedback and basic pelvic floor muscle training, respectively). The mean 24-month International Consultation on Incontinence Questionnaire Urinary Incontinence Short Form score was 8.2 (standard deviation 5.1) for biofeedback pelvic floor muscle training and 8.5 (standard deviation 4.9) for basic pelvic floor muscle training (adjusted mean difference -0.09, 95% confidence interval -0.92 to 0.75; p  = 0.84). A total of 48 participants had a non-serious adverse event (34 in the biofeedback pelvic floor muscle training group and 14 in the basic pelvic floor muscle training group), of whom 23 (21 in the biofeedback pelvic floor muscle training group and 2 in the basic pelvic floor muscle training group) had an event related/possibly related to the interventions. In addition, there were eight serious adverse events (six in the biofeedback pelvic floor muscle training group and two in the basic pelvic floor muscle training group), all unrelated to the interventions. At 24 months, biofeedback pelvic floor muscle training was not significantly more expensive than basic pelvic floor muscle training, but neither was it associated with significantly more quality-adjusted life-years. The probability that biofeedback pelvic floor muscle training would be cost-effective was 48% at a £20,000 willingness to pay for a quality-adjusted life-year threshold. The process evaluation confirmed that the biofeedback pelvic floor muscle training group received an intensified intervention and both groups received basic pelvic floor muscle training core components. Women were positive about both interventions, adherence to both interventions was similar and both interventions were facilitated by desire to improve their urinary incontinence and hindered by lack of time., Limitations: Women unable to contract their muscles were excluded, as biofeedback is recommended for these women., Conclusions: There was no evidence of a difference between biofeedback pelvic floor muscle training and basic pelvic floor muscle training., Future Work: Research should investigate other ways to intensify pelvic floor muscle training to improve continence outcomes., Trial Registration: Current Controlled Trial ISRCTN57746448., Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 24, No. 70. See the NIHR Journals Library website for further project information.