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Kennedy Institute researchers Alex Clarke and Thomas Riffelmacher have been awarded prestigious Wellcome Trust Fellowships to further develop their research in autoimmune diseases.
Clinical and cost-effectiveness of individualised (early) patient-directed rehabilitation versus standard rehabilitation after surgical repair of the rotator cuff of the shoulder: protocol for a multicentre, randomised controlled trial with integrated Quintet Recruitment Intervention (RaCeR 2).
INTRODUCTION: Despite the high number of operations and surgical advancement, rehabilitation after rotator cuff repair has not progressed for over 20 years. The traditional cautious approach might be contributing to suboptimal outcomes. Our aim is to assess whether individualised (early) patient-directed rehabilitation results in less shoulder pain and disability at 12 weeks after surgical repair of full-thickness tears of the rotator cuff compared with current standard (delayed) rehabilitation. METHODS AND ANALYSIS: The rehabilitation after rotator cuff repair (RaCeR 2) study is a pragmatic multicentre, open-label, randomised controlled trial with internal pilot phase. It has a parallel group design with 1:1 allocation ratio, full health economic evaluation and quintet recruitment intervention. Adults awaiting arthroscopic surgical repair of a full-thickness tear are eligible to participate. On completion of surgery, 638 participants will be randomised. The intervention (individualised early patient-directed rehabilitation) includes advice to the patient to remove their sling as soon as they feel able, gradually begin using their arm as they feel able and a specific exercise programme. Sling removal and movement is progressed by the patient over time according to agreed goals and within their own pain and tolerance. The comparator (standard rehabilitation) includes advice to the patient to wear the sling for at least 4 weeks and only to remove while eating, washing, dressing or performing specific exercises. Progression is according to specific timeframes rather than as the patient feels able. The primary outcome measure is the Shoulder Pain and Disability Index total score at 12-week postrandomisation. The trial timeline is 56 months in total, from September 2022. TRIAL REGISTRATION NUMBER: ISRCTN11499185.
Early-life exposure to tobacco, genetic susceptibility, and accelerated biological aging in adulthood.
Early-life tobacco exposure serves as a non-negligible risk factor for aging-related diseases. To understand the underlying mechanisms, we explored the associations of early-life tobacco exposure with accelerated biological aging and further assessed the joint effects of tobacco exposure and genetic susceptibility. Compared with those without in utero exposure, participants with in utero tobacco exposure had an increase in Klemera-Doubal biological age (KDM-BA) and PhenoAge acceleration of 0.26 and 0.49 years, respectively, but a decrease in telomere length of 5.34% among 276,259 participants. We also found significant dose-response associations between the age of smoking initiation and accelerated biological aging. Furthermore, the joint effects revealed that high-polygenic risk score participants with in utero exposure and smoking initiation in childhood had the highest accelerated biological aging. There were interactions between early-life tobacco exposure and age, sex, deprivation, and diet on KDM-BA and PhenoAge acceleration. These findings highlight the importance of reducing early-life tobacco exposure to improve healthy aging.
The Outcomes of Isolated Tibiocalcaneal Arthrodesis: A Systematic Review.
BACKGROUND: Tibiocalcaneal arthrodesis (TCA) can be achieved by internal fixation (intramedullary nail or plate), external fixation, or a combination. Evidence for the optimal approach is limited. This systematic review examines the outcomes of these different approaches to guide surgical management. METHODS: A MEDLINE and Oxford SOLO search was performed using "tibiocalcaneal," "ankle," "fusion OR arthrodesis." The primary outcome was union. Secondary outcomes included rates of postoperative complications, weightbearing status, rates of revision surgery, and PROMs. We included any studies with follow-up greater than 6 months that contained our primary outcome and at least 1 secondary outcome. RESULTS: The initial search yielded 164 articles, of which 9 studies totaling 53 cases met the criteria. The majority of articles were excluded because they were nonsurgical studies, or were not about isolated TCA but were for tibiotalocalcaneal arthrodesis, more complex reconstructions (eg, Charcot), case reports, and/or did not include the predetermined outcome measures.TCA union rate was 86.2% following external fixation, 82.4% for intramedullary nail fixation, and 83.3% for plate fixation. One patient underwent a hybrid of external and internal fixation, and the outcome was nonunion. The rate of complications following TCA was 69.8%. CONCLUSION: There is limited evidence on the best operative approach for isolated tibiocalcaneal arthrodesis. Both external and internal fixation methods had comparable union rates. External fixation had frequent complications and a more challenging postoperative protocol. Novel techniques such as 3D-printed cages and talus replacement may become a promising alternative but require further investigation.
Reporting guideline for the early stage clinical evaluation of decision support systems driven by artificial intelligence: DECIDE-AI.
A growing number of artificial intelligence (AI)-based clinical decision support systems are showing promising performance in preclinical, in silico, evaluation, but few have yet demonstrated real benefit to patient care. Early stage clinical evaluation is important to assess an AI system’s actual clinical performance at small scale, ensure its safety, evaluate the human factors surrounding its use, and pave the way to further large scale trials. However, the reporting of these early studies remains inadequate. The present statement provides a multistakeholder, consensus-based reporting guideline for the Developmental and Exploratory Clinical Investigations of DEcision support systems driven by Artificial Intelligence (DECIDE-AI). We conducted a two round, modified Delphi process to collect and analyse expert opinion on the reporting of early clinical evaluation of AI systems. Experts were recruited from 20 predefined stakeholder categories. The final composition and wording of the guideline was determined at a virtual consensus meeting. The checklist and the Explanation & Elaboration (E&E) sections were refined based on feedback from a qualitative evaluation process. 123 experts participated in the first round of Delphi, 138 in the second, 16 in the consensus meeting, and 16 in the qualitative evaluation. The DECIDE-AI reporting guideline comprises 17 AI specific reporting items (made of 28 subitems) and 10 generic reporting items, with an E&E paragraph provided for each. Through consultation and consensus with a range of stakeholders, we have developed a guideline comprising key items that should be reported in early stage clinical studies of AI-based decision support systems in healthcare. By providing an actionable checklist of minimal reporting items, the DECIDE-AI guideline will facilitate the appraisal of these studies and replicability of their findings.
Implementing a shared decision-making intervention to support treatment decisions for patients following an anterior cruciate ligament rupture - a protocol for the POP-ACLR feasibility study.
BACKGROUND: Treatment for anterior cruciate ligament (ACL) rupture may follow a surgical or nonsurgical pathway. At present, there is uncertainty around treatment choice. Two shared decision-making tools have been codesigned to support patients to make a decision about treatment following an ACL rupture. The shared decision-making tools include a patient information leaflet and an option grid. We report the protocol for a mixed-methods feasibility study, with nested qualitative interviews, to understand feasibility, acceptability, indicators of effectiveness and implementation factors of these shared decision-making tools (combined to form one shared decision-making intervention). METHODS: A single-centre non-randomised feasibility study will be conducted with 20 patients. Patients diagnosed with an ACL rupture following magnetic resonance imaging will be identified from an orthopaedic clinic. The shared decision-making intervention will be delivered during a clinical consultation with a physiotherapist. The primary feasibility outcomes include the following: recruitment rate, fidelity, acceptability and follow-up questionnaire completion. The secondary outcome is the satisfaction with decision scale. The nested qualitative interview will explore experience of using the shared decision-making intervention to understand acceptability, implementation factors and areas for further refinement. DISCUSSION: This study will determine the feasibility of using a newly developed shared decision-making intervention designed to support patients to make a decision about treatment of their ACL rupture. The acceptability and indicators of effectiveness will also be explored. In the long term, the shared decision-making intervention may improve service and patient outcomes and ensure cost-effectiveness for the NHS; ensuring those most likely to benefit from surgical treatment proceed along this pathway. TRIAL REGISTRATION: Pending registration on ISRCTN.
What recovery domains are important following a total knee replacement? A qualitative, interview-based study
ObjectivesTo explore people’s views of recovery from total knee replacement (TKR) and which recovery domains they felt were important.DesignSemi-structured interviews exploring the views of individuals about to undergo or who have undergone TKR. A constant-comparative approach with thematic analysis was used to identify themes. The process of sampling, collecting data and analysis were continuous and iterative throughout the study, with interviews ceasing once thematic saturation was achieved.SettingTertiary care centre.ParticipantsA purposive sample was used to account for variables including pre, early or late postoperative status.Results12 participants were interviewed, 4 who were preoperative, 4 early postoperative and 4 late postoperative. Themes of pain, function, fear of complications, awareness of the artificial knee joint and return to work were identified. Subthemes of balancing acute and chronic pain were identified.ConclusionsThe results of this interview-based study identify pain and function, in particular mobility, that were universally important to those undergoing TKR. Surgeons should consider exploring these domains when taking informed consent to enhance shared decision-making. Researchers should consider these recovery domains when designing interventional studies.
Loss of p53 and MCT-1 Overexpression Synergistically Promote Chromosome Instability and Tumorigenicity
Abstract MCT-1 oncoprotein accelerates p53 degradation by means of the ubiquitin-dependent proteolysis. Our present data show that induction of MCT-1 increases chromosomal translocations and deregulated G2-M checkpoint in response to chemotherapeutic genotoxin. Remarkably, increases in chromosome copy number, multinucleation, and cytokinesis failure are also promoted while MCT-1 is induced in p53-deficient cells. In such a circumstance, the Ras–mitogen-activated protein kinase/extracellular signal-regulated kinase kinase–mitogen-activated protein kinase signaling activity and the expression of metastatic molecules are amplified. Given a p53-silencing background, MCT-1 malignantly transforms normal breast epithelial cells that are satisfactory for stimulating cell migration/adhesion and tumorigenesis. Detailed analyses of MCT-1 oncogenicity in H1299 p53-null lung cancer cells have shown that ectopically expressed MCT-1 advances xenograft tumorigenicity and angiogenesis, which cannot be completely suppressed by induction of p53. MCT-1 counteracts mutually with p53 at transcriptional levels. Clinical validations confirm that MCT-1 mRNA levels are differentially enriched in comparison between human lung cancer and nontumorigenic tissues. The levels of p53 mRNA are comparatively reduced in a subset of cancer specimens, which highly present MCT-1 mRNA. Our results indicate that synergistic promotions of chromosomal imbalances and oncogenic potency as a result of MCT-1 expression and p53 loss play important roles in tumor development. (Mol Cancer Res 2009;7(4):536–48)
The antagonism between MCT-1 and p53 affects the tumorigenic outcomes
Abstract Background MCT-1 oncoprotein accelerates p53 protein degradation via a proteosome pathway. Synergistic promotion of the xenograft tumorigenicity has been demonstrated in circumstance of p53 loss alongside MCT-1 overexpression. However, the molecular regulation between MCT-1 and p53 in tumor development remains ambiguous. We speculate that MCT-1 may counteract p53 through the diverse mechanisms that determine the tumorigenic outcomes. Results MCT-1 has now identified as a novel target gene of p53 transcriptional regulation. MCT-1 promoter region contains the response elements reactive with wild-type p53 but not mutant p53. Functional p53 suppresses MCT-1 promoter activity and MCT-1 mRNA stability. In a negative feedback regulation, constitutively expressed MCT-1 decreases p53 promoter function and p53 mRNA stability. The apoptotic events are also significantly prevented by oncogenic MCT-1 in a p53-dependent or a p53-independent fashion, according to the genotoxic mechanism. Moreover, oncogenic MCT-1 promotes the tumorigenicity in mice xenografts of p53-null and p53-positive lung cancer cells. In support of the tumor growth are irrepressible by p53 reactivation in vivo, the inhibitors of p53 (MDM2, Pirh2, and Cop1) are constantly stimulated by MCT-1 oncoprotein. Conclusions The oppositions between MCT-1 and p53 are firstly confirmed at multistage processes that include transcription control, mRNA metabolism, and protein expression. MCT-1 oncogenicity can overcome p53 function that persistently advances the tumor development.
Research prioritization in paediatric orthopaedics and the impact on funding
In 2017, the British Society for Children’s Orthopaedic Surgery engaged the profession and all relevant stakeholders in two formal research prioritization processes. In this editorial, we describe the impact of this prioritization on funding, and how research in children’s orthopaedics, which was until very recently a largely unfunded and under-investigated area, is now flourishing. Establishing research priorities was a crucial step in this process.Cite this article: Bone Joint J 2024;106-B(5):422–424.
Current state-of-the-art and gaps in platform trials: 10 things you should know, insights from EU-PEARL
Platform trials bring the promise of making clinical research more efficient and more patient centric. While their use has become more widespread, including their prominent role during the COVID-19 pandemic response, broader adoption of platform trials has been limited by the lack of experience and tools to navigate the critical upfront planning required to launch such collaborative studies. The European Union-Patient-cEntric clinicAl tRial pLatform (EU-PEARL) initiative has produced new methodologies to expand the use of platform trials with an overarching infrastructure and services embedded into Integrated Research Platforms (IRPs), in collaboration with patient representatives and through consultation with U.S. Food and Drug Administration and European Medicines Agency stakeholders. In this narrative review, we discuss the outlook for platform trials in Europe, including challenges related to infrastructure, design, adaptations, data sharing and regulation. Documents derived from the EU-PEARL project, alongside a literature search including PubMed and relevant grey literature (e.g., guidance from regulatory agencies and health technology agencies) were used as sources for a multi-stage collaborative process through which the 10 more important points based on lessons drawn from the EU-PEARL project were developed and summarised as guidance for the setup of platform trials. We conclude that early involvement of critical stakeholder such as regulatory agencies or patients are critical steps in the implementation and later acceptance of platform trials. Addressing these gaps will be critical for attaining the full potential of platform trials for patients. Funding: Innovative Medicines Initiative 2 Joint Undertaking with support from the European Union's Horizon 2020 research and innovation programme and EFPIA.
Reverse total shoulder replacement versus anatomical total shoulder replacement for osteoarthritis: population based cohort study using data from the National Joint Registry and Hospital Episode Statistics for England.
OBJECTIVES: To answer a national research priority by comparing the risk-benefit and costs associated with reverse total shoulder replacement (RTSR) and anatomical total shoulder replacement (TSR) in patients having elective primary shoulder replacement for osteoarthritis. DESIGN: Population based cohort study using data from the National Joint Registry and Hospital Episode Statistics for England. SETTING: Public hospitals and publicly funded procedures at private hospitals in England, 2012-20. PARTICIPANTS: Adults aged 60 years or older who underwent RTSR or TSR for osteoarthritis with intact rotator cuff tendons. Patients were identified from the National Joint Registry and linked to NHS Hospital Episode Statistics and civil registration mortality data. Propensity score matching and inverse probability of treatment weighting were used to balance the study groups. MAIN OUTCOME MEASURES: The main outcome measure was revision surgery. Secondary outcome measures included serious adverse events within 90 days, reoperations within 12 months, prolonged hospital stay (more than three nights), change in Oxford Shoulder Score (preoperative to six month postoperative), and lifetime costs to the healthcare service. RESULTS: The propensity score matched population comprised 7124 RTSR or TSR procedures (126 were revised), and the inverse probability of treatment weighted population comprised 12 968 procedures (294 were revised) with a maximum follow-up of 8.75 years. RTSR had a reduced hazard ratio of revision in the first three years (hazard ratio local minimum 0.33, 95% confidence interval 0.18 to 0.59) with no clinically important difference in revision-free restricted mean survival time, and a reduced relative risk of reoperations at 12 months (odds ratio 0.45, 95% confidence interval 0.25 to 0.83) with an absolute risk difference of -0.51% (95% confidence interval -0.89 to -0.13). Serious adverse events and prolonged hospital stay risks, change in Oxford Shoulder Score, and modelled mean lifetime costs were similar. Outcomes remained consistent after weighting. CONCLUSIONS: This study's findings provide reassurance that RTSR is an acceptable alternative to TSR for patients aged 60 years or older with osteoarthritis and intact rotator cuff tendons. Despite a significant difference in the risk profiles of revision surgery over time, no statistically significant and clinically important differences between RTSR and TSR were found in terms of long term revision surgery, serious adverse events, reoperations, prolonged hospital stay, or lifetime healthcare costs.