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Geraint Thomas, DPhil student and Academic Clinical Fellow, was named as one of the 2014 Scientific Award Winners at The Hip Society meeting in March 2014.
Assessing early postoperative recovery following lower limb joint replacement
Improving perioperative recovery is critical to enhance patient care, ensure timely discharge from the patient, clinician and hospital perspective and improve short and long-term outcomes after surgery. A systematic review was performed examining tools for early post-operative recovery after elective lower limb joint replacement. It showed that no fully-validated, patient-reported tools existed. Currently used measures included pain scores, opioid usage, length of stay and surgical satisfaction. In order to address this need, a patient-reported outcome measure (PROM) and change measure for use in the first six weeks following surgery have been developed. A five-phased, best practice, iterative approach was used. Planning Phase - Qualitative interviews (n=22) were performed with orthopaedic healthcare professionals, ascertaining if and how clinicians would use such a PROM. These helped determine the views of potential users, and guide structure and layout. Phase One - Qualitative patient-interviews (n=30) from the day of surgery to nine weeks postoperatively were completed. Analysis of these interviews identified important patient-reported factors in early recovery. Phase Two - The factors provided from Phase One interviews were used to find questionnaire themes. Items were then generated and pilot questionnaires developed. Items were tested and refined in the context of cognitive debrief interviews (n=34) for potential inclusion in the final tools. Phase Three - Final testing of questionnaire properties with item reduction (n=168). The Oxford Arthroplasty Early Recovery Score (OARS) is a 14-item PROM measuring health status at the time of testing. The Oxford Arthroplasty Early Change Score (OACS) is a 14-item measure to assess change. Phase Four - Validation: The OARS and OACS were administered to consecutive patients (n=155) in an independent cohort. Validity and reliability were assessed. Psychometric testing showed positive results, good validity and sensitivity to change. The OARS and OACS were then utilised in a pilot study to assess the feasibility of day case treatment. Inpatient (n=29) and day-case (n=26) unicompartmental knee arthroplasty (UKA) patients completed the two measures, and the results confirmed that day case treatment and discharge is a valid option. The work completed in this thesis will now enable these newly developed scores to be used to define and assess an optimal-recovery protocol for lower limb joint replacement.
Reframing pain: the power of individual and societal factors to enhance pain treatment.
The effectiveness of analgesics can be increased if synergistic behavioural, psychological, and pharmacological interventions are provided within a supportive environment.
Relationship between HLA genetic variations, COVID-19 vaccine antibody response, and risk of breakthrough outcomes.
The rapid global distribution of COVID-19 vaccines, with over a billion doses administered, has been unprecedented. However, in comparison to most identified clinical determinants, the implications of individual genetic factors on antibody responses post-COVID-19 vaccination for breakthrough outcomes remain elusive. Here, we conducted a population-based study including 357,806 vaccinated participants with high-resolution HLA genotyping data, and a subset of 175,000 with antibody serology test results. We confirmed prior findings that single nucleotide polymorphisms associated with antibody response are predominantly located in the Major Histocompatibility Complex region, with the expansive HLA-DQB1*06 gene alleles linked to improved antibody responses. However, our results did not support the claim that this mutation alone can significantly reduce COVID-19 risk in the general population. In addition, we discovered and validated six HLA alleles (A*03:01, C*16:01, DQA1*01:02, DQA1*01:01, DRB3*01:01, and DPB1*10:01) that independently influence antibody responses and demonstrated a combined effect across HLA genes on the risk of breakthrough COVID-19 outcomes. Lastly, we estimated that COVID-19 vaccine-induced antibody positivity provides approximately 20% protection against infection and 50% protection against severity. These findings have immediate implications for functional studies on HLA molecules and can inform future personalised vaccination strategies.
Characterising the immune response to combined skin and solid organ transplants
Transplantation offers a life-saving solution for patients with end-stage organ failure. Despite advances in recent years, managing acute rejection episodes remains challenging. This is partly due to difficulties in recognising when acute rejection is taking place. The concept of a sentinel skin flap for monitoring of organ transplantation has recently been introduced as a potential solution for this. The advent of abdominal wall transplants for the reconstruction of large defects in patients undergoing small bowel transplantation has further highlighted the usefulness of skin for monitoring, particularly in differentiating organ rejection from infections. Sentinel skin flaps also provide a site that is easy to biopsy, and which patients can be trained to review. There are limited data in the literature on the alloresponse to a combined skin and solid organ transplant. The aim of this thesis is to characterise in depth this immune response. In chapter 3 the systemic immune response is examined using a combination of flow cytometry and gene expression analysis to analyse blood samples. Chapters 4 and 5 investigate the local immune response in small bowel and skin samples respectively, using the multiplexed gene expression and spatial proteomic techniques. Finally in Chapter 6 a human transgenic mouse model is used to explore the role of Langerhans cell related pathways in skin transplant rejection. This is the first study to characterise both the systemic and local immune response in a combined skin and solid organ transplant, offering unique insights into the dynamic changes in immune phenotype post-transplantation and during rejection. The data provide support for the use of a sentinel skin flap for immune monitoring in solid organ transplantation and will be used to guide future clinical trials.
Effect of bimekizumab on patient-reported disease impact in patients with psoriatic arthritis: 1 year results from two phase 3 studies
Objectives: To evaluate 1-year bimekizumab efficacy in psoriatic arthritis (PsA) from the patient perspective using the 12-item PsA Impact of Disease (PsAID-12) questionnaire. Methods: BE OPTIMAL (NCT03895203; biologic disease-modifying antirheumatic drug [bDMARD]-naïve), BE COMPLETE (NCT03896581; inadequate response/intolerance to tumour necrosis factor inhibitors [TNFi-IR]) and BE VITAL (NCT04009499; open-label extension) assessed bimekizumab 160 mg every 4 weeks in patients with PsA. Post hoc analyses of patientreported disease impact, assessed by the PsAID-12 questionnaire, are reported to 1 year (collected to Week 40 in BE COMPLETE). Results: Overall, 1,112 total patients were included (698 bimekizumab, 414 placebo). Rapid improvements observed with bimekizumab treatment at Week 4 continued to Week 16 and were sustained to 1 year. At 1 year, mean (standard error) change from baseline in PsAID-12 total score was comparable between bimekizumab-randomized patients and patients who switched to bimekizumab at Week 16 (bDMARD-naïve bimekizumab –2.3 [0.1], placebo/bimekizumab –2.2 [0.1]; TNFi-IR bimekizumab –2.5 [0.1], placebo/bimekizumab –2.2 [0.2]). Proportions of bimekizumab-randomized patients achieving clinically meaningful within-patient improvement (≥3- point decrease from baseline) at Week 16 were sustained to 1 year (bDMARD-naïve 49.0%; TNFi-IR 48.5%) and were similar for placebo/bimekizumab patients (bDMARD-naïve 44.4%; TNFi-IR 40.6%). Across studies and arms, 35.3% to 47.8% of patients had minimal or no symptom impact at 1 year. Improvements were observed to 1 year across all single-item domains, including pain, fatigue and skin problems. Conclusion: Bimekizumab treatment resulted in rapid and sustained clinically meaningful improvements in disease impact up to 1 year in bDMARD-naïve and TNFi-IR patients with PsA.
Arthritis complicating inflammatory bowel disease – the future is now
Fundamental advances are occurring across immune-mediated inflammatory diseases (IMIDs). Recent therapeutic developments include strategies to prevent rheumatoid arthritis (RA) in high-risk individuals, using baseline cellular immunophenotypes to predict biologic response in psoriatic arthritis (PsA), and employing biologicals in a ‘top-down’ approach in Crohn’s disease (CD). However, meaningful progress has not occurred in the management of patients with spondyloarthropathy (SpA) complicating inflammatory bowel disease (IBD). Currently, the pathophysiology of IBD-related SpA is poorly understood, moreover, there remain no accepted or disease-specific screening tools, diagnostic criteria, or licenced treatment(s). Furthermore, current approaches to clinical care from rheumatologists and gastroenterologists largely involve the extrapolation of SpA and IBD clinical guidelines respectively, despite increasing recognition of IBDrelated SpA being its own entity, with a unique phenotype. There is an obvious contrast with the management of arthropathy complicating psoriasis, a disease area where defined diagnostic criteria and dedicated clinical trials allow clear management guidelines. We argue that the time has come for a parallel approach and dedicated focus of IBD-related SpA.
Multi-cancer early detection test in symptomatic patients referred for cancer investigation in England and Wales (SYMPLIFY): a large-scale, observational cohort study.
BACKGROUND: Analysis of circulating tumour DNA could stratify cancer risk in symptomatic patients. We aimed to evaluate the performance of a methylation-based multicancer early detection (MCED) diagnostic test in symptomatic patients referred from primary care. METHODS: We did a multicentre, prospective, observational study at National Health Service (NHS) hospital sites in England and Wales. Participants aged 18 or older referred with non-specific symptoms or symptoms potentially due to gynaecological, lung, or upper or lower gastrointestinal cancers were included and gave a blood sample when they attended for urgent investigation. Participants were excluded if they had a history of or had received treatment for an invasive or haematological malignancy diagnosed within the preceding 3 years, were taking cytotoxic or demethylating agents that might interfere with the test, or had participated in another study of a GRAIL MCED test. Patients were followed until diagnostic resolution or up to 9 months. Cell-free DNA was isolated and the MCED test performed blinded to the clinical outcome. MCED predictions were compared with the diagnosis obtained by standard care to establish the primary outcomes of overall positive and negative predictive value, sensitivity, and specificity. Outcomes were assessed in participants with a valid MCED test result and diagnostic resolution. SYMPLIFY is registered with ISRCTN (ISRCTN10226380) and has completed follow-up at all sites. FINDINGS: 6238 participants were recruited between July 7 and Nov 30, 2021, across 44 hospital sites. 387 were excluded due to staff being unable to draw blood, sample errors, participant withdrawal, or identification of ineligibility after enrolment. Of 5851 clinically evaluable participants, 376 had no MCED test result and 14 had no information as to final diagnosis, resulting in 5461 included in the final cohort for analysis with an evaluable MCED test result and diagnostic outcome (368 [6·7%] with a cancer diagnosis and 5093 [93·3%] without a cancer diagnosis). The median age of participants was 61·9 years (IQR 53·4-73·0), 3609 (66·1%) were female and 1852 (33·9%) were male. The MCED test detected a cancer signal in 323 cases, in whom 244 cancer was diagnosed, yielding a positive predictive value of 75·5% (95% CI 70·5-80·1), negative predictive value of 97·6% (97·1-98·0), sensitivity of 66·3% (61·2-71·1), and specificity of 98·4% (98·1-98·8). Sensitivity increased with increasing age and cancer stage, from 24·2% (95% CI 16·0-34·1) in stage I to 95·3% (88·5-98·7) in stage IV. For cases in which a cancer signal was detected among patients with cancer, the MCED test's prediction of the site of origin was accurate in 85·2% (95% CI 79·8-89·3) of cases. Sensitivity 80·4% (95% CI 66·1-90·6) and negative predictive value 99·1% (98·2-99·6) were highest for patients with symptoms mandating investigation for upper gastrointestinal cancer. INTERPRETATION: This first large-scale prospective evaluation of an MCED diagnostic test in a symptomatic population demonstrates the feasibility of using an MCED test to assist clinicians with decisions regarding urgency and route of referral from primary care. Our data provide the basis for a prospective, interventional study in patients presenting to primary care with non-specific signs and symptoms. FUNDING: GRAIL Bio UK.
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.