National Health Service Lothian

Simpson A., Sartania N., Haque E., Merriman A.

Yule S., Yule J., Arthur C.

Leong I.U., Cabrera C.P., Cipriani V., Ross P.J., Turner R.M., Stuckey A., Sanghvi S., Pasko D., Moutsianas L., Odhams C.A., Elgar G.S., Chan G., Giess A., Walker S., Foulger R.E., et. al.

PURPOSE As part of the 100,000 Genomes Project, we set out to assess the potential viability and clinical impact of reporting genetic variants associated with drug-induced toxicity for patients with cancer recruited for whole-genome sequencing (WGS) as part of a genomic medicine service. METHODS Germline WGS from 76,805 participants was analyzed for pharmacogenetic (PGx) variants in four genes ( DPYD , NUDT15 , TPMT , UGT1A1 ) associated with toxicity induced by five drugs used in cancer treatment (capecitabine, fluorouracil, mercaptopurine, thioguanine, irinotecan). Linking genomic data with prescribing and hospital incidence records, a phenome-wide association study (PheWAS) was performed to identify whether phenotypes indicative of adverse drug reactions (ADRs) were enriched in drug-exposed individuals with the relevant PGx variants. In a subset of 7,081 patients with cancer, DPYD variants were reported back to clinicians and outcomes were collected. RESULTS We identified clinically relevant PGx variants across the four genes in 62.7% of participants in our cohort. Extending this to annual prescription numbers in England for the drugs affected by these PGx variants, approximately 14,540 patients per year could potentially benefit from a reduced dose or alternative drug to reduce the risk of ADRs. Validating PGx associations in a real-world data set, we found a significant association between PGx variants in DPYD and toxicity-related phenotypes in patients treated with capecitabine or fluorouracil. Reported DPYD variants were deemed informative for clinical decision making in a majority of cases. CONCLUSION Reporting PGx variants from germline WGS relevant to patients with cancer alongside primary findings related to their cancer can be clinically informative, informing prescribing to reduce the risk of ADRs. Extending the range of actionable variants to those found in patients of non-European ancestry is important and will extend the potential clinical impact.

Dick L., Livingstone M., Hughes K.

Westwood H., Mandy W., Brewer R.

Abstract This study investigated the mechanisms underlying disordered eating of autistic adults, by investigating associations between eating disorder (ED) symptoms and autistic traits; autism-specific atypical eating; alexithymia; interoception; and body image in autistic and non-autistic participants. Autistic adults (n = 196) and non-autistic adults (n = 206) completed online self-report measures assessing ED pathology, atypical eating, body image dissatisfaction, interoception, alexithymia, and autistic traits. Structural Equation Modelling tested a theoretical model of the relationships between these variables, and whether these relationships were moderated by autism diagnosis. Autistic adults self-reported higher ED pathology than non-autistic adults. The proposed model and the strength of the relationship between body image and ED pathology did not differ between the autistic and non-autistic groups. Atypical eating (not related to over-evaluation of weight/shape), however, was only associated with ED pathology in the autistic group. Both traditional and additional factors, including eating disturbances not driven by weight/shape concern, appear to contribute to ED pathology in autism.

Sheppard R., Evanson B., Campbell I., Shand A.

In conjunction with BMJ Case Reports, DTB will feature occasional drug-related cases that are likely to be of interest to readers. These will include cases that involve recently marketed drugs for which there is limited knowledge of adverse effects and cases that highlight unusual reactions to drugs that have been marketed for several years. Olmesartan is an angiotensin II receptor blocker licensed for the treatment of hypertension. It can cause a sprue-like enteropathy (SLE), characterised by chronic diarrhoea, weight loss and villous atrophy. Transiently raised anti-tissue transglutaminase (ATTG) antibody has also been rarely reported in the literature. We describe the case of a woman in her mid-50s, who presented with a history of intermittent loose stools over 1 year, associated with significant weight loss. She had two marginally raised serum ATTG antibody tests during her work-up. After extensive investigations, she was diagnosed with olmesartan-induced enteropathy. On subsequent follow-up, her symptoms had resolved with cessation of her olmesartan therapy. This case adds to existing literature, highlighting the importance of considering olmesartan as a possible differential diagnosis for SLE. It also reports the presence of a raised ATTG antibody which is infrequently reported in this context. Olmesartan is an angiotensin II receptor blocker (ARB), first licensed for hypertension in 2002. The association between olmesartan and enteropathy was first described by Rubio-Tapia et al , with the Food and Drug Administration subsequently issuing a safety alert in 2013.1 Several large retrospective cohort studies found diagnoses of malabsorption following olmesartan therapy ranging between 0.02 and 12.49 per 100 000.2–6 While open to significant selection and information biases, we can infer from these studies that the incidence is likely to be low. There are case reports of enteropathy associated with other ARBs, but systematic reviews have shown olmesartan to cause 90–94% of ARB-associated …

Megaw R.

To ensure that normal vision is maintained, the photoreceptor must continually renew its outer segment, a massive expanse of ciliary membrane extending from the tip of its connecting cilium. The outer segment is organised into hundreds of flattened discs, the formation of which is highly regulated. Disc morphogenesis requires the metronomic assembly of an actin cytoskeletal network to initiate the necessary membrane deformation and subsequent network disassembly to allow disc completion. Disruption of disc turnover, due to human mutations, results in an inherited retinal dystrophy (IRD), a leading cause of visual loss in children and working adults. This chapter will describe the structural evidence that disc formation is actin-driven and discuss what is known of the molecular mechanisms that govern the process.

Clement N.D., Scott C.E., Macpherson G.J., Simpson P.M., Leitch G., Patton J.T.

AimsUnicompartmental knee arthroplasty (UKA) is associated with an accelerated recovery, improved functional outcomes, and retention of anatomical knee kinematics when compared to manual total knee arthroplasty (mTKA). UKA is not universally employed by all surgeons as there is a higher revision risk when compared to mTKA. Robotic arm-assisted (ra) UKA enables the surgeon to position the prosthesis more accurately when compared to manual UKA, and is associated with improved functional outcomes and a lower early revision risk. Non-randomized data suggests that, when compared to mTKA, raUKA has a clinically meaningful greater functional benefit. This protocol describes a randomized controlled trial that aims to evaluate the clinical and cost-effectiveness of raUKA compared to mTKA for individuals with isolated medial compartment osteoarthritis (OA).MethodsThe total versus robotic-assisted unicompartmental knee arthroplasty (TRAKER) trial is a patient- and assessor-blinded, pragmatic parallel two-arm randomized superiority trial of adults undergoing elective primary knee arthroplasty for primary medial compartment OA at a single NHS hospital (ClinicalTrials.gov NCT05290818). Participants will be randomly allocated on a 1:2 basis to either raUKA or mTKA, respectively. The primary analysis will compare the Oxford Knee Score (OKS) six months after surgery. Secondary outcomes measured at three, six, and 12 months include the OKS, Forgotten Joint Score, patient expectations, EuroQol five-dimension questionnaire (EQ-5D), and EQ-visual analogue scale (EQ-VAS), patient satisfaction, range of motion, postoperative complications, need for further surgery, resource use, and financial costs. Cost-effectiveness will be measured over a ten-year time span. A total of 159 patients will be randomized (n = 53 raUKA vs n = 106 mTKA) to obtain 80% power to detect a five-point difference in OKS between the groups six months after surgery.ConclusionThe trial findings will provide evidence about the clinical and cost-effectiveness of raUKA compared to mTKA in patients with isolated medial compartment OA. This will inform future National Institute for Health and Care Excellence guidelines on primary knee arthroplasty in the UK.Cite this article: Bone Jt Open 2025;6(2):164–177.

Tochel C., Engelmann J., Giarratano Y., Dhillon B., Megaw R., Bernabeu M.O.

Carnegie R., Livingstone M.

Davies S.M., Hodder A., Walker S., Bale N., Vincent H., Dasgupta T., Birch A., Piper K., Silverio S.A.

BackgroundThe safety of vaginal breech birth is associated with the skill and experience of professionals in attendance, but minimal training opportunities exist. OptiBreech collaborative care is an evidence‐based care bundle, based on previous research. This care pathway is designed to improve access to care and the safety of vaginal breech births, when they occur, through dedicated breech clinics and intrapartum support. This improved process also enhances professional training. Care coordination is accomplished in most cases by a key breech specialist midwife on the team. The goal of this qualitative inventory was to describe the roles and tasks undertaken by specialist midwives in the OptiBreech care implementation feasibility study.MethodsSemistructured interviews were conducted with OptiBreech team members (17 midwives and 4 obstetricians; N = 21), via video conferencing software. Template analysis was used to code, analyze, and interpret data relating to the roles of the midwives delivering breech services. Tasks identified through initial coding were organized into 5 key themes in a template, following reflective discussion at weekly staff meetings and stakeholder events. This template was then applied to all interviews to structure the analysis.ResultsBreech specialist midwives functioned as change agents. In each setting, they fulfilled similar roles to support their teams, whether this role was formally recognized or not. We report an inventory of tasks performed by breech specialist midwives, organized into 5 themes: care coordination and planning, service development, clinical care delivery, education and training, and research.DiscussionBreech specialist midwives perform a consistent set of roles and responsibilities to co‐ordinate care throughout the OptiBreech pathway. The inventory has been formally incorporated into the OptiBreech collaborative care logic model. This detailed description can be used by employers and professional organizations who wish to formalize similar roles to meet consistent standards and improve care.

Croft J., Ainsworth G., Corrigan N., Gordon K., Perry A., Twiddy M., Strachan M., Wadsley J., Mehanna H., Sharma N., Glenister E., Stocken D.D., Balasubramanian S.P.

Introduction Postsurgical hypoparathyroidism (PoSH) is an iatrogenic condition that occurs as a complication of several different procedures with thyroid surgery being the most common. PoSH has significant short- and long-term morbidities. The volume of thyroid surgery is increasing, and PoSH is therefore likely to increase. Some studies have shown promising results using near-infrared fluorescence (NIRF) imaging in reducing the risk of PoSH which has the potential to significantly reduce morbidity and costs associated with monitoring and treatment. Methods and analysis NIFTy is an unblinded, parallel group, multicentre, seamless phase II/III randomised controlled trial in patients undergoing total or completion thyroidectomy. The trial incorporates a process evaluation (IDEAL (Idea, Development, Exploration, Assessment and Long-term follow-up framework) 2a) to inform the trial protocol, a phase II (IDEAL 2b) analysis using a surrogate primary outcome of 1 day transient hypocalcaemia to determine early futility and phase III (IDEAL 3) assessment of the primary outcome of PoSH at 6 months after surgery. 454 participants will be randomised on a 1:1 basis to evaluate thyroid surgery with NIRF and indocyanine green against standard thyroid surgery in reducing PoSH at 6 months after surgery, with the phase II analysis occurring once data are available for 200 participants. Analysis in both phases will be using multilevel logistic regression incorporating random effects with respect to surgeon and adjusting for minimisation factors. Phase III secondary outcomes include protracted hypoparathyroidism, hypercalcaemia, complications, length of stay, readmissions and patient reported quality of life using the Short Form 36 Health Survey Questionnaire and Hypoparathyroid Patient Questionnaire instruments. Ethics and dissemination NIFTy is funded by National Institute for Health and Care Research Efficacy and Mechanism Evaluation Programme (Grant Ref: 17/11/27) and approved by a Research Ethics Committee (reference: 21/WA/0375) and Health Research Authority (HRA). Trial results will be disseminated through conference presentations, peer-reviewed publication and through relevant patient groups. Trial registration number NCT59074092 .

Chin K., Watson G., Paveley A., Dulson H., Thompson L., Schiff R.

Abstract Introduction CGA is the gold-standard intervention for older adults living with frailty. A challenge is providing person-centred, time-efficient CGA. The CGA-questionnaire (CGA-Q) aims to facilitate person-centred CGA, allowing patients/carers to highlight concerns. We describe a two-site multi-cycle QIP implementing the CGA-Q. Methods CGA-Q is a 19-item questionnaire covering seven CGA domains. It was adapted from the validated CGA-GOLD questionnaire. Between March 2023–June 2024, CGA-Q was established in a London and Scottish NHS Trust using ‘Plan-Do-Study-Act’ methodology. Cycle 1–3 involved designing and establishing CGA-Q at one London geriatric clinic. Cycle 4 assessed feasibility in multiple London geriatric clinics. Cycle 5 examined implementation of CGA-Q in a Scottish day-hospital. Person-centredness refers to inclusion of person-selected concerns in clinic letters, and not including person-excluded concerns. Results Across cycles, cohorts were comparable in age, sex, frailty and cognitive status. In cycles 1–3 (n = 174), CGA-Q completion rates improved from 39% to 83%. More CGA-Q questions were addressed especially cognition, mood, continence and falls. Inclusion of person-selected concerns increased from 60% to 70%; exclusion of person-excluded concerns remained ~70%. In cycle 4, completion rates varied by clinic: renal-CGA 100% (12/12); CGA 42% (13/31); bone-health 14% (10/60). >50% of questionnaires were completed by patients, except in bone-health where two-thirds were completed by staff. Staff feedback highlights CGA-Q is a useful discussion prompt. In cycle 5 (n = 41), a similar breadth of CGA-Q questions was addressed among respondents compared to baseline. With CGA-Q, continence and pain were addressed more frequently. Inclusion of person-selected concerns was 62%; exclusion of person-excluded concerns was 71%. Conclusion CGA-Q has been successfully implemented across multiple sites and clinics. It can improve person-centeredness and breadth of CGA, but early results vary across subspecialty geriatric medicine clinics with their unique processes. Ongoing work will determine the experience of patients and carers of this approach.

De Silva N., Quinton R., De Silva N.L., Jayasena C.N., Barbar B., Boot C., Wright R.J., Shipley T.W., Kanagasundaram N.S.

Przybylska M., Philips C., Jones L., Kalima P., Henderson N., Dewar S.

Abstract Background Regularly reviewing local guidelines is essential to ensure that clinical practice aligns with national standards and incorporates the latest evidence-based recommendations. To optimize patient care and strengthen antimicrobial stewardship, antimicrobial guidelines need to account for evolving microbial resistance patterns, including regional trends; consider the latest evidence on drug efficacy, side effects and new antimicrobial options; account for changing disease patterns; and provide specific guidance for at risk populations that may require tailored treatment advice. Objectives The primary objective was to update our local paediatric antimicrobial guidelines to ensure alignment with the UK Paediatric Antimicrobial Stewardship (UKPAS) Network recommendations. Methods A multidisciplinary guideline review committee was established, consisting of consultant microbiologists, a consultant in paediatric infectious diseases, a clinical development fellow and a pharmacist. Local antimicrobial guidelines were reviewed and updated, aligning them with UKPAS recommendations. The revised guidelines were subsequently submitted to the Antimicrobial Committee for further review and approval. Results The review process highlighted the importance of regularly updating guidelines to reflect emerging evidence, new drug recommendation (e.g. from MHRA), and evolving microbial resistance patterns. It also provided an opportunity to reassess and strengthen local antimicrobial stewardship initiatives. Key changes included recommendations aimed at reducing unnecessary antibiotic use e.g. shortening antibiotic course durations where clinically appropriate, enhancing antimicrobial education for clinicians, and improving the dissemination of information to staff. IV to oral switch guidance was updated, adopting recent UKSHA guidance. Additionally, a review of current practices revealed the potential need for further education to bridge gaps between existing practices and new recommendations, ensuring successful implementation and adherence to the updated guidelines. Interdisciplinary collaboration was crucial in achieving a comprehensive and balanced update of the guidelines. Involvement of the pharmacy team ensured considerations related to drug availability and resource management were considered. This helped ensure the proposed changes were feasible. Conclusions Interdisciplinary approach to updating local antimicrobial guidelines not only ensures clinical practice is aligned with national standards but also provides a valuable opportunity to maintain effective antimicrobial stewardship, optimize resource management, and improve staff education and engagement with the guidelines. There are ongoing challenges in incorporating increased antibiotic dosing guidelines in paediatrics (to comply with EUCAST reporting of ‘I’) and paediatric-specific guidance for MHRA warnings (e.g. fluoroquinolones) to local policies. Through ongoing dialogue and guidance from national initiatives like UKPAS, these challenges are being met.