Using evidence-based co-design to develop a hybrid delivered exercise intervention that aims to increase confidence to exercise in people with haemophilia.

INTRODUCTION: Due to advances in treatments, people with haemophilia (PWH) are living longer. They are not as active as the general population due to joint damage and lack confidence to be active due to concerns about further bleeds and pain. There is a need to facilitate healthy aging through promotion of physical activity (PA) and exercise. Changing patient beliefs and increasing physical literacy and confidence to move are thought to be key to helping PWH become more active. AIM: This paper describes the development of an exercise and behaviour change intervention to improve confidence to exercise in PWH. METHODS: The 4-stage Medical Research Council framework for complex intervention development was used. RESULTS: Stakeholders included 17 PWH and 7 physiotherapists working in haemophilia. Seven online focus group meetings were held. The final intervention is a hybrid 12-week physiotherapist led progressive exercise programme. Classes are 45 min including Pilates, High intensity interval training and balance elements, together with discussion sessions focusing on PA recommendations, the types and benefits of different exercise styles and the effects of PA, together with the effects of aging for PWH. The COM-B model of behaviour change was used to develop the intervention. CONCLUSION: Co-design helps to produce an intervention that understands the stakeholders needs. Through this process the intervention developed to incorporate not only increasing PA but also confidence to exercise. The use of behaviour change theory identified the behaviour techniques included in the intervention and aims to increase physical literacy in this population.

Do baseline patient reported outcome measures predict changes in self-reported function, following a chronic pain rehabilitation programme?

Background: Interdisciplinary pain management programmes, based on cognitive-behavioural principles, aim to improve physical and psychological functioning and enhance self-management in people living with chronic pain. Currently there is insufficient evidence about whether psychological, biological or social factors are predictive of positive outcomes following pain rehabilitation. This study aims to evaluate predictors of change in Brief Pain Inventory - pain interference score (BPI) in a clinical data set to determine whether age, sex and baseline outcome measures are predictive of improvement in pain interference following pain rehabilitation. Methods: A retrospective, pragmatic observational analysis of routinely collected clinical data in two pain rehabilitation programmes, Balanced Life Programme (BLP) and Get Back Active (GBA) was conducted. Standard regression and hierarchical regression analyses were used to identify predictors of change to assess temporal changes in BPI. Responder analysis was also conducted. Results: Standard regression analyses of 208 (BLP) and 310 (GBA) patients showed that higher baseline BPI and better physical performance measures predicted better improvement in BPI across both programmes. Hierarchical regression showed that age and sex accounted for 2.7% (BLP) and 0.002% (GBA) of the variance in change in BPI. After controlling for age and sex, the other measures explained an additional 23% (BLP) and 19% (GBA) of the variance, p = < .001 where BPI and physical performance measures were consistently statistically significant predictors, p < .05. Responder analysis also showed that pain interference and physical performance were significantly associated with improvement (p = < .0005). Conclusions: The combination of high self-reported pain interference and better physical performance measures may be a useful indicator of who would benefit from interdisciplinary rehabilitation. Further validation of the results is required.

A Comparison of the Periprosthetic Fracture Rate of Unicompartmental and Total Knee Replacements: An Analysis of Data of >100,000 Knee Replacements from the National Joint Registry for England, Wales, Northern Ireland and the Isle of Man and Hospital Episode Statistics.

BACKGROUND: Periprosthetic fractures are rare but devastating complications of knee replacement, often requiring complex surgery with substantial morbidity and mortality. It is not known how the fracture rates after total knee replacement (TKR) and unicompartmental knee replacement (UKR) compare. We performed the first matched study comparing TKR and UKR periprosthetic fracture rates. METHODS: This study involved 54,215 UKRs and 54,215 TKRs, identified in the National Joint Registry and Hospital Episodes Statistics database, which were propensity score-matched on patient and surgical factors. The International Classification of Diseases, Tenth Revision, (ICD-10) code M96.6 was used to identify periprosthetic fractures at ≤3 and >3 months postoperatively, as well as estimate rates at up to 10 years. Subgroup analyses were performed in different age groups (<55, 55 to 64, 65 to 74, and ≥75 years), body mass index (BMI) categories (normal, 18.5 to <25 kg/m 2 ; overweight, 25 to <30 kg/m 2 ; obese, 30 to <40 kg/m 2 ; and morbidly obese, ≥40 kg/m 2 ), and sexes. RESULTS: The 3-month fracture rate was 0.09% (n = 50) in the UKR group and 0.05% (n = 25) in the TKR group, with this difference being significant (odds ratio [OR], 2.0; p = 0.004). The rate of fractures occurring at >3 months was 0.32% (n = 171) in the UKR group and 0.61% (n = 329) in the TKR group (OR, 0.51; p < 0.001). At 10 years, the cumulative incidence of fractures was 0.6% after UKR versus 1% after TKR (OR, 0.68; p < 0.001). Fracture rates increased with increasing age, decreasing BMI, and female sex for both UKRs and TKRs. CONCLUSIONS: The fracture risk was small after both UKR and TKR, with small absolute differences between implant types. During the first 3 postoperative months, the fracture rate after UKR was 0.1% and was about twice as high as that after TKR. However, over the first 10 years, the cumulative fracture rate after TKR was 1% and was almost twice as high as that after UKR. Fracture rates after both UKR and TKR were higher in women, patients ≥75 years of age, and patients with normal weight. LEVEL OF EVIDENCE: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

Less pain reported 5 years after cementless compared to cemented unicompartmental knee replacement: an analysis of pain, neuropathy, and co-morbidity scores.

PURPOSE: To compare patient-reported pain scores and assess the influence of neuropathy and co-morbidity, on knee pain following cemented and cementless medial unicompartmental knee replacement (UKR) 5 years after surgery. METHOD: In this longitudinal study, 262 cemented and 262 cementless Oxford UKR performed for the same indications and with the same techniques were recruited. Patients were reviewed at five years, evaluating patient-reported pain and association with clinical outcomes. Intermittent and Constant Osteoarthritis Pain (ICOAP), PainDETECT (PD), Charnley score, Oxford Knee Score (OKS) and American Knee Society Score (AKSS) were compared. RESULTS: In both cohorts, intermittent pain was more common than constant pain (47% vs 21%). Cementless knees reported significantly less pain than cemented (ICOAP-Total 5/100 vs 11/100, p < 0.0001). A greater proportion of cementless knees experienced no pain at all (ICOAP = 0/100, 61% vs 43%, p < 0.0001) and 75% fewer experienced severe or extreme pain. Pain sub-scores in PD, OKS and AKSS follow this trend. Pain was unlikely to be neuropathic (PD positive: 5.26%), but patients reporting high levels of 'strongest' pain were three times more likely to be neuropathic. Patients with co-morbidities (Charnley C) experienced greater pain than those without (Charnley A+B) across all knee-specific scores, despite scores being knee specific. CONCLUSION: Both cemented and cementless UKR in this study had substantially less pain than that reported in literature following TKR. Cementless UKR had significantly less pain than cemented UKR in all scores. Two-thirds of patients with a cementless UKR had no pain at all at 5 years, and pain experienced was most likely to be mild and intermittent with no patients in severe or extreme pain. Patients with cementless UKR that had higher levels of pain were more likely to have co-morbidity or evidence or neuropathic pain. It is unclear why cementless UKR have less pain than cemented; further study is necessary.

The experience of living with adolescent idiopathic scoliosis: a qualitative evidence synthesis using meta-ethnography.

BACKGROUND: Adolescent idiopathic scoliosis (AIS) is a common spinal deformity with physical and psychosocial implications for adolescents. The aim of this qualitative evidence synthesis (QES) was to systematically search for, identify, and synthesise qualitative research in order to improve our understanding of what it is like to live with AIS and to facilitate empathetic and effective healthcare. METHODS: We systematically searched 4 databases (Medline, EMBASE, PsycINFO and CINAHL) and used the 7 phases of meta-ethnography to synthesise qualitative evidence including studies with children and adolescents, and additional viewpoints from parents about the experience of AIS. RESULTS: We distilled 7 themes. (1) Diagnosis turned time on its head revolves around the AIS diagnosis and the uncertainty of the future that accompanied it. (2) Usual activities no longer the same explores how activities and participation in everyday life are impacted by AIS. (3) Hiding my body describes the pervasive struggle with self-image and appearance. (4) I want to feel normal again explores adolescents' desire to return to 'normality' and challenges of feeling different. (5) Balancing isolation and support considers the relationships in the adolescents' lives alongside their feelings of isolation. (6) Trying to keep control of treatment decisions explores how adolescents and their parents strive to feel in control. (7) Fearing surgery yet feeling hopeful focused on the apprehension and fear around spinal surgery and the beacon of hope it represented. CONCLUSIONS: Our QES contributes to the understanding of the adolescent experience of living with AIS. From our findings, clinicians can better understand the physical and psychosocial obstacles and the challenges faced throughout the journey of AIS to inform their clinical interactions with these patients.

'Will I wear purple?'-a school arts-based research project in the UK to disseminate findings from a qualitative evidence synthesis about living to an extreme age.

BACKGROUND: a change in attitude towards ageing is needed. Arts-based research (ABR) refers to the use of any creative art in research. ABR can provide an environment to reflect on challenging social issues and has the potential to make lasting impressions. OBJECTIVE: we aimed to explore the use of ABR to disseminate findings from a qualitative evidence synthesis exploring what it means to live well beyond the age of 80. DESIGN: ABR using art as a stimulus for recorded discussions and written annotations. SETTING: a mixed catchment state secondary school in the UK. SUBJECTS: fifty-four secondary school pupils aged 14-15. The majority identified as female (ratio 5:1). METHODS: school pupils created artwork to represent themes about ageing drawn from a qualitative evidence synthesis. The artwork was a stimulus for recorded discussions. We used thematic analysis to develop themes about children's response to ageing. RESULTS: we developed six themes. Pupils found comfort in recognising that old age can be lived well; they began to see themselves in the older person; they explored the ambiguous nature of memory; they highlighted the dangers of disconnection; they affirmed a need to restore connection with elders and they recognised the need to cherish time and live meaningfully. CONCLUSIONS: this project encouraged pupils to think about what it means to grow old. ABR has the potential to contribute to a more positive relationship with older people and towards ageing. Research stakeholders should not undervalue the potential power of shifts in perspective for powering social change.

The experience of women reporting damage from vaginal mesh: a reflexive thematic analysis.

Background: The UK's 'First do no harm' report highlighted missed opportunities to prevent harm and emphasised the need to incorporate patient voices into healthcare. Due to concerns about, and the subsequent suspension, of vaginal mesh for urinary incontinence thousands of women face the decision about mesh removal surgery. The aim of this study was to explore and understand the experience of living with complications attributed to vaginal mesh surgery so that this knowledge can contribute to improvements in care for those considering mesh, or mesh removal, surgery. Methods: This study was embedded in the 'PURSUE' study which explored the experiences of 74 people with urogynaecological conditions in the UK (30th April 2021-17th December 2021). Of these 74 people, fifteen women reported complications that they attributed to vaginal mesh surgery. We used the six stages of reflexive thematic analysis to conceptualise these fifteen accounts. Findings: Our conceptual model anchors eight themes around two dualities: (1) body parts versus body whole, (2) dominant discourse versus marginal discourse. Our themes indicate that trust can be established through: (1) embodied healthcare that focuses on connecting with patients' lived experience, (2) dialectic communication that recognises patient experiences and remains open to alternative perspectives. Interpretation: This study raises some important issues for education and practice. Our findings can translate to other health settings where treatments aimed to provide care have caused harm. Funding: NIHR Policy Research Programme (NIHR202450).

A synthesis of qualitative research to understand the complexity behind treatment decision-making for osteoarthritis.

Objective: Osteoarthritis is the most common joint disease with treatment involving a multidisciplinary approach with pharmacological, physical therapies and surgery as options. Qualitative research can help us to understand the complexity of managing health conditions and this understanding plays a role in good clinical practice. We aimed to systematically search for, identify, and synthesise qualitative research exploring the experience of living with osteoarthritis, including decision making about joint replacement. Methods: We comprehensively searched 4 bibliographic databases and used the methods of meta-ethnography to synthesise qualitative research findings. We screened 10 â€‹123 titles, 548 abstracts, and 139 full texts. We included findings from 118 reports (105 unique samples) of at least 2534 adults living with osteoarthritis around the world. Results: We developed 7 themes: Becoming your own expert can be hard work; Living has become a careful balancing act; Medication is a double-edged sword; I have other things in my life to consider; You have to weigh up the odds of surgery; Surgery is the only effective option; and Surgery will give me a chance to live now. These findings have been drawn into a conceptual model reflecting a complex balancing act with tensions underpinning treatment decision making. Conclusions: Osteoarthritis is framed as a world where patients become their own expert about their management and healthcare choices. Our conceptual model highlights key tensions underpinning treatment decision-making. These findings provide clinicians with insight of the complex nature of these decisions and how they can help patients through shared decision making.

Associations Between Physical Activity and Adolescent Idiopathic Scoliosis: A Systematic Review and Meta-analysis.

OBJECTIVE: To investigate the associations between adolescent idiopathic scoliosis (AIS) and physical activity (PA). DATA SOURCES: MEDLINE, EMBASE, AMED, SPORTDiscus, Cochrane Library, and CINAHL electronic databases were searched from inception to August 2022/plus citation tracking. STUDY SELECTION: Observational studies of participants with radiographically confirmed AIS with ≥10° lateral spinal curvature (Cobb method) and comparator groups without AIS that measured PA were selected by 2 reviewers. DATA EXTRACTION: Data were extracted independently and cross-checked by 2 reviewers. Risk of bias was evaluated using Newcastle Ottawa Scales and overall confidence in the evidence using the GRADE approach. DATA SYNTHESIS: Sixteen studies with 9627 participants (9162, 95% women) were included. A history of vigorous PA significantly reduced the odds of being newly diagnosed with AIS by 24% (odds ratio [OR] 0.76, 95% confidence interval [CI] 0.65-0.89) (high certainty). Moderate PA reduced odds by 13% (moderate certainty) and light PA increased odds by 9% (low certainty), but neither analysis was statistically significant. Ballet or gymnastics (OR 1.47, 95% CI 3.08 (1.90, 5.00) were the only individual sports significantly associated with AIS diagnosis (moderate certainty). Case-control studies of people with and without AIS provided greater evidence that having AIS reduces vigorous PA and sports participation, and less evidence light PA and walking are affected. CONCLUSION: Adolescents who participate in more vigorous PA are less likely to be diagnosed with AIS. Ballet and gymnastics are associated with AIS diagnosis, but the direction of this association is uncertain. People with AIS are likely to do less vigorous physical and sporting activity compared with those without AIS, which could negatively affect health and quality of life. Further research is warranted into the inter-relations between PA and AIS, studies need to be of sufficient size, include men, and evaluate vigorous including higher-impact PA compared with moderate or light PA.

Combination Therapies Targeting ALK-aberrant Neuroblastoma in Preclinical Models.

PURPOSE: ALK-activating mutations are identified in approximately 10% of newly diagnosed neuroblastomas and ALK amplifications in a further 1%-2% of cases. Lorlatinib, a third-generation anaplastic lymphoma kinase (ALK) inhibitor, will soon be given alongside induction chemotherapy for children with ALK-aberrant neuroblastoma. However, resistance to single-agent treatment has been reported and therapies that improve the response duration are urgently required. We studied the preclinical combination of lorlatinib with chemotherapy, or with the MDM2 inhibitor, idasanutlin, as recent data have suggested that ALK inhibitor resistance can be overcome through activation of the p53-MDM2 pathway. EXPERIMENTAL DESIGN: We compared different ALK inhibitors in preclinical models prior to evaluating lorlatinib in combination with chemotherapy or idasanutlin. We developed a triple chemotherapy (CAV: cyclophosphamide, doxorubicin, and vincristine) in vivo dosing schedule and applied this to both neuroblastoma genetically engineered mouse models (GEMM) and patient-derived xenografts (PDX). RESULTS: Lorlatinib in combination with chemotherapy was synergistic in immunocompetent neuroblastoma GEMM. Significant growth inhibition in response to lorlatinib was only observed in the ALK-amplified PDX model with high ALK expression. In this PDX, lorlatinib combined with idasanutlin resulted in complete tumor regression and significantly delayed tumor regrowth. CONCLUSIONS: In our preclinical neuroblastoma models, high ALK expression was associated with lorlatinib response alone or in combination with either chemotherapy or idasanutlin. The synergy between MDM2 and ALK inhibition warrants further evaluation of this combination as a potential clinical approach for children with neuroblastoma.

An investigation into the relationship between nutritional status, dietary intake, symptoms and health-related quality of life in children and young people with juvenile idiopathic arthritis: a systematic review and meta-analysis.

BACKGROUND: The association between diet, symptoms and health related quality of life in children and young people with Juvenile idiopathic arthritis (JIA) is not clearly understood. The objectives of this systematic review and meta-analysis were to explore the evidence for a relationship between nutritional status, dietary intake, arthritis symptoms, disease activity and health-related quality of life in children and young people with JIA considering both observational and interventional studies separately. METHOD: The databases PubMed, CINAHL, PsycINFO, Web of Science and Cochrane were searched in October 2019, updated in September 2020 and October 2021. Searches were restricted to English language, human and age (2-18 years old). Studies were included if they measured the effect of dietary supplements, vitamins or minerals, or diet in general, on quality of life and/ or arthritis symptom management. Two researchers independently screened titles and abstracts. Full texts were sourced for relevant articles. PRISMA guidelines were used for extracting data. For variables (vitamin D and disease activity), a random-effects meta-analysis model was performed. Two authors using a standardized data extraction form, extracted data independently. RESULTS: 11,793 papers were identified through database searching, 26 studies met our inclusion criteria with 1621 participants. Overall studies quality were fair to good. Results from controlled trial and case control studies with total 146 JIA patients, found that Ɯ-3 PUFA improved the mean active joint count (p < 0.001), Juvenile Arthritis Disease Activity Score (JADAS-27) (p < 0.001) and immune system (≤ 0.05). Furthermore, n-3 and n-6 PUFAs have a negative correlation with CRP (C-reactive protein) and ESR (erythrocyte sedimentation rate) (p < 0.05). Improvement in JIA symptoms were observed in one case, one pilot and one exploratory study with overall 9 JIA patients after receiving Exclusive Enteral Nutrition (EEN) which contains protein and what is required for a complete nutrition, A clinical trial study found Kre-Celazine nutrition (composed of a proprietary alkali buffered, creatine monohydrate and fatty acids mixture) in 16 JIA patients improved symptoms of JIA. No association was found between vitamin D and disease activity from three studies. Height and weight values in relation to healthy controls varied across studies (p = 0.029). CONCLUSIONS: We were only able to include small studies, of lower design hierarchy, mainly pilot studies. We found some evidence of lower height and weight across studies in JIA, but were unable to confirm an association between diet, symptoms and health-related quality of life in children and young people with JIA. Well-designed, carefully measured and controlled interventional studies of dietary patterns in combination with important contributing factors such as medication and lifestyle behaviours, including physical activity, are required to determine the impact of diet in improving symptoms and growth patterns in children and young people with JIA, with an aim to improve the quality of their life. TRIAL REGISTRATION: PROSPERO [CRD42019145587].

Early post-operative physiotherapy rehabilitation after primary unilateral unicompartmental knee replacement: a systematic review.

BACKGROUND: Unicompartmental Knee Replacement (UKR) is an established treatment for end stage arthritis affecting one compartment of the knee. UKR lends itself to rapid recovery and early discharge. The content, type, timing and dose of early post-operative physiotherapy treatment has yet to be reviewed. OBJECTIVE: To review the content of early physiotherapy in the first eight weeks following unilateral UKR. DATA SOURCES: A literature search of Medline, CINAHL, AMED and PubMed and the Physiotherapy Evidence Database (PEDRo) plus citation searching. ELIGIBILITY CRITERIA: Randomised controlled trials (RCTs) and observational studies reporting a physiotherapy intervention for UKR involving a form of post-operative exercise/education/advice delivered within the first eight weeks of surgery and commencing as an in-patient. Two reviewers independently performed screening, data extraction and risk of bias assessment. DATA SYNTHESIS: Narrative syntheses were undertaken due to the heterogeneity of the primary outcomes. RESULTS: Eleven studies were included (n = 1293 participants), three RCTs and eight observational studies. The dose and content of post-operative physiotherapy was highly variable with a move in recent years to rapid recovery and same day discharge with more self-directed rehabilitation. No studies had a low risk of bias. LIMITATIONS: Small sample sizes and high heterogeneity limit our findings CONCLUSIONS: This review highlights the range of post-operative physiotherapy provision following UKR with a recent move to minimal physiotherapy input. Further research is required to identify those patients who may need additional physiotherapy above that now routinely provided, along with the most effective timing, type, and dosage of the intervention. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42021243238. CONTRIBUTION OF THE PAPER.

The AERO study: A feasibility randomised controlled trial of individually tailored exercise adherence strategies based on a brief behavioural assessment for older people with musculoskeletal conditions.

INTRODUCTION: Exercise is a widely used treatment modality for older people with musculoskeletal conditions. The effectiveness of exercise programmes is limited by adherence. The aims of this study were to examine the acceptability and feasibility of the AERO intervention in facilitating exercise adherence in older people with musculoskeletal conditions, and to inform the design of a future randomised controlled trial. METHODS: A two arm feasibility randomised controlled trial with an embedded qualitative study conducted at one orthopaedic hospital in the South of England. Older adults referred to physiotherapy with musculoskeletal conditions were randomised to receive either usual care consisting of standard physiotherapy only, or the AERO intervention, consisting of usual care with the addition of tailored exercise adherence approaches based on a brief behavioural assessment. Feasibility outcomes included recruitment, randomisation, retention, acceptability, and fidelity to trial protocol. Secondary outcomes included exercise adherence, physical activity, and behavioural regulation. RESULTS: 48 participants were recruited to the study with 27 randomised to usual care and 21 to AERO and usual care. On the basis of recruitment, retention, the acceptability to participants and physiotherapists and fidelity, the AERO intervention was determined to be feasible. CONCLUSION: The AERO intervention in which participants received tailored adherence strategies based on a behavioural assessment plus standard physiotherapy is feasible and acceptable. It is now ready to be tested in an adequately powered randomised controlled trial. CONTRIBUTION OF THE PAPER: CLINICAL TRIAL REGISTRATION NUMBER: This study was registered at clinicaltrials.gov REF: NCT03643432.

Hormone replacement therapy (conjugated oestrogens plus bazedoxifene) for post-menopausal women with symptomatic hand osteoarthritis: primary report from the HOPE-e randomised, placebo-controlled, feasibility study.

Background: Symptomatic hand osteoarthritis is more common in women than in men, and its incidence increases around the age of menopause, implicating oestrogen deficiency. No randomised controlled trials of hormone replacement therapy (HRT) have been done in people with hand osteoarthritis. We aimed to determine the feasibility and acceptability of a form of HRT (conjugated oestrogens plus bazedoxifene) in post-menopausal women with painful hand osteoarthritis. Methods: The HOPE-e feasibility study was a randomised, double-blind, placebo-controlled trial, for which we recruited women aged 40-65 years, for whom 1-10 years had passed after their final menstrual period, with definite hand osteoarthritis and at least two painful hand joints. Participants were recruited across three primary or secondary care sites and from the community and were randomly assigned (1:1) to receive conjugated oestrogens plus bazedoxifene or placebo, orally once every day for 24 weeks, before weaning for 4 weeks until the end of the study. The primary feasibility outcomes were rates of identification, recruitment, randomisation, retention, and compliance of eligible participants, and the likelihood of unmasking. The secondary objective was to generate proof-of-concept quantitative and qualitative data on the acceptability of proposed clinical outcomes for a full trial and adverse events. We used an intention-to-treat analysis, and criteria for progression to a full trial were pre-defined as recruitment of at least 30 participants across all sites in 18 months; a dropout rate of less than or equal to 30% of randomised individuals; and acceptability to the majority of participants, including acceptable rates of adverse events. Due to the COVID-19 pandemic, the recruitment window was reduced to 12-15 months. A proportionately reduced minimum sample size of 22 was judged to be sufficient to test feasibility. This trial was registered at ISRCTN, ISRCTN12196200. Findings: From May 9, 2019 to Dec 31, 2020, 434 enquiries or referrals were received. We did 96 telephone pre-screens; of the 35 eligible participants, seven were excluded as ineligible at the telephone or face-to-face screening and 28 (80% [95% CI 63-92]) were randomly assigned. Of the 406 who were not randomly assigned, 250 (62%) were ineligible (with contraindicated medications accounting for 50 [20%] of these), 101 (25%) did not respond to further enquiries, and 55 (14%) chose not to proceed (with the most common reason being not wanting to take a hormone-based drug). All 28 randomised participants completed all follow-up assessments with high compliance and outcome measure completeness. All three adverse event-related treatment withdrawals were in the placebo group. No serious adverse events were reported. Participants and investigators were successfully masked (participant Bang's blinding index placebo group 0·50 [95% CI 0·25-0·75]). The trial met the prespecified criteria for progression to a full trial. Interpretation: This first-ever feasibility study of a randomised controlled trial of HRT for post-menopausal women with painful hand osteoarthritis met its progression criteria, although it was not powered to detect a clinical effect. This outcome indicates that a full trial of an HRT in this population is feasible and acceptable and identifies potential refinements with regard to the design of such a trial. Funding: Research for Patient Benefit programme, National Institute for Health Research.

Physiotherapy exercise rehabilitation with tailored exercise adherence support for people with osteoporosis and vertebral fractures: protocol for a randomised controlled trial - the OsteoPorosis Tailored exercise adherence INtervention (OPTIN) study.

INTRODUCTION: Vertebral fragility fractures affect at least 20% of the older population in the UK. Best practice guidelines recommend the use of exercise to slow the rate of bone loss, to maintain muscle strength and physical function, and to prevent falls and further fractures. However, treatment effects are often small and difficult to sustain and adherence, or the extent to which patients engage in treatment, has been identified as an important issue by many studies. Our hypothesis is that integrating adherence intervention strategies with an exercise intervention will be beneficial. We will compare physiotherapy exercise rehabilitation with adherence support versus physiotherapy exercise rehabilitation alone in terms of effects on (A) physical function, quality of life and fear of falling and (B) exercise self-efficacy and adherence. METHODS AND ANALYSIS: A multicentre, two-arm, parallel group, superiority randomised controlled trial with blinded assessments at baseline (0) and 4, 8 and 12 months, with a nested qualitative study and health economic analysis. 116 participants will be allocated to either (1) outpatient physiotherapy which will include a musculoskeletal assessment and treatment including balance, posture, strength training and low impact weight-bearing exercises over 16 weeks or (2) OsteoPorosis Tailored exercise adherence INtervention intervention. This includes standard physiotherapy as above plus an additional, integrated assessment interview (30 min) and 60 min of adherence support spread over the subsequent 16 weeks. ETHICS AND DISSEMINATION: The study protocol was approved by West of Scotland Research Ethics Committee 4 (21/WS/0071). Trial registration number ISRCTN 14465704. The paper is based on Protocol V.4. TRIAL REGISTRATION NUMBER: ISRCTN 14465704.

The challenges and gains of delivering a home-exercise intervention: a qualitative study of physiotherapists and physiotherapy assistants.

OBJECTIVES: The paper presents insights from the Community based Rehabilitation after Knee Arthroplasty (CORKA) trial. We aimed to explore physiotherapists and physiotherapy assistants' experiences of delivering a home-base exercise intervention following knee replacement surgery. We were particularly interested in the feasibility, potential benefits and barriers of a community-based exercise programme from the perspective of physiotherapists and physiotherapy assistants and to understand any constraints or training needs that arose.  DESIGN: Qualitative thematic analysis of semi-structured interviews.  SETTING: The Community based Rehabilitation after Knee Arthroplasty (CORKA) trial. PARTICIPANTS: Five physiotherapists and six physiotherapy assistants with a range of clinical experience. METHODS: Interviews were digitally recorded and transcribed verbatim. We used the stages of reflexive thematic analysis suggested by Braun and Clarke. One researcher conducted the interviewers whilst three researchers with experience in qualitative research methods contributed to the coding and analysis of data. RESULTS: We developed seven themes that help to understand the benefits and challenges of delivering treatment interventions in a person's home: seeing the person in their own world; thinking outside the cubicle;developing people skills; enjoying the above and beyond; treading a fine line between patient and friend; feeling outside my comfort zone; needing a support network. CONCLUSIONS: Treating people in their own homes facilitates a holistic approach. Our findings highlight areas for clinical education: (1) how do we help clinicians to tread the fine line between friend and professional (2) how do we balance the need to provide support and structure with the freedom to work creatively and independently?

Rehabilitation versus surgical reconstruction for non-acute anterior cruciate ligament injury (ACL SNNAP): a pragmatic randomised controlled trial.

BACKGROUND: Anterior cruciate ligament (ACL) rupture is a common debilitating injury that can cause instability of the knee. We aimed to investigate the best management strategy between reconstructive surgery and non-surgical treatment for patients with a non-acute ACL injury and persistent symptoms of instability. METHODS: We did a pragmatic, multicentre, superiority, randomised controlled trial in 29 secondary care National Health Service orthopaedic units in the UK. Patients with symptomatic knee problems (instability) consistent with an ACL injury were eligible. We excluded patients with meniscal pathology with characteristics that indicate immediate surgery. Patients were randomly assigned (1:1) by computer to either surgery (reconstruction) or rehabilitation (physiotherapy but with subsequent reconstruction permitted if instability persisted after treatment), stratified by site and baseline Knee Injury and Osteoarthritis Outcome Score-4 domain version (KOOS4). This management design represented normal practice. The primary outcome was KOOS4 at 18 months after randomisation. The principal analyses were intention-to-treat based, with KOOS4 results analysed using linear regression. This trial is registered with ISRCTN, ISRCTN10110685, and ClinicalTrials.gov, NCT02980367. FINDINGS: Between Feb 1, 2017, and April 12, 2020, we recruited 316 patients. 156 (49%) participants were randomly assigned to the surgical reconstruction group and 160 (51%) to the rehabilitation group. Mean KOOS4 at 18 months was 73·0 (SD 18·3) in the surgical group and 64·6 (21·6) in the rehabilitation group. The adjusted mean difference was 7·9 (95% CI 2·5-13·2; p=0·0053) in favour of surgical management. 65 (41%) of 160 patients allocated to rehabilitation underwent subsequent surgery according to protocol within 18 months. 43 (28%) of 156 patients allocated to surgery did not receive their allocated treatment. We found no differences between groups in the proportion of intervention-related complications. INTERPRETATION: Surgical reconstruction as a management strategy for patients with non-acute ACL injury with persistent symptoms of instability was clinically superior and more cost-effective in comparison with rehabilitation management. FUNDING: The UK National Institute for Health Research Health Technology Assessment Programme.

Validity of sagittal thoracolumbar curvature measurement using a non-radiographic surface topography method.

PURPOSE: To estimate the criterion validity of sagittal thoracolumbar spine measurement using a surface topography method in a clinical population against the gold standard and to estimate concurrent validity against two non-radiographic clinical tools. METHODS: In this cross-sectional validity study, thoracolumbar curvature was measured in adults with spinal conditions recruited from a specialist orthopaedic hospital. A surface topography method using a Kinect sensor was compared to three other measurement methods: spinal radiograph (gold standard), flexicurve and digital inclinometer. Correlation coefficients and agreement between the measurement tools were analysed. RESULTS: Twenty-nine participants (79% female) were included in criterion validity analyses and 38 (76% female) in concurrent validity analyses. The surface topography method was moderately correlated with the radiograph (r = .70, p < .001) in the thoracic spine, yet there was no significant correlation with the radiograph in the lumbar spine (r = .32, p = .89). The surface topography method was highly correlated with the flexicurve (rs = .91, p < .001) and digital inclinometer (r = .82, p < .001) in the thoracic spine, and highly correlated with the flexicurve (r = .74, p < .001) and digital inclinometer (r = .74, p < .001) in the lumbar spine. CONCLUSIONS: The surface topography method showed moderate correlation and agreement in thoracic spine with the radiograph (criterion validity) and high correlation with the flexicurve and digital inclinometer (concurrent validity). Compared with other non-radiographic tools, this surface topography method displayed similar criterion validity for kyphosis curvature measurement.

Establishment of In Vivo Acquired Resistance to Chemotherapy Via Individual Dose Escalation Treatment Regime.

The vast majority of cancer deaths are the result of drug resistance. The lack of superior preclinical models that better reflect the complexity of relapsed disease hinders the development of novel therapeutics. 2D and 3D in vitro cell-based assays have provided some information, but this is limited and does not consider the role of the tumor microenvironment. The development of an in vivo assay can allow to generate resistance, while taking into account the role of the tumor microenvironment and the tumor structure. To achieve this, we have developed an in vivo dose-escalation protocol that models the acquisition of resistance. This model of chemo-resistant neuroblastoma presented with metastases and a genetic signature characteristic of clinical relapsed tumors (Yogev et al. Cancer Res. 79:5382-5393, 2019). We believe that this protocol can be used to generate faithful models for other types of relapse disease; these could serve as reliable tools while developing novel therapies.