BACKGROUND Globally, an estimated 4.5 million people will fracture their hip in 2050. Even with surgery, 30% of patients die within a year. Among survivors, 25% never walk again and 22% change from living at home to a nursing home. Rehabilitation assists patients 'to achieve and maintain optimal functioning'. Yet, there is limited evidence to guide effective rehabilitation after hip fracture. This uncertainty may be due to between patient differences. A stratified approach could improve outcomes by tailoring rehabilitation to patient needs. Hip fracture survivors describe a tailored approach as key to recovery. Further, the NHS recommends a stratified approach as central to healthcare progress. AIMS We aim to improve patient and carer outcomes of rehabilitation after hip fracture. Supported by patients and carers at each step, the objectives are to: 1. identify patient groups with different risk of poor outcomes 2. design an intervention which matches these groups to rehabilitation tailored to their needs 3. feasibility test the intervention in acute hospital 4. create a collaborative group with patients, carers, and the public in older adult trauma rehabilitation research INVESTIGATION PLAN Identify patient groups: We completed a systematic review and interviewed 20 patients and carers to identify 4 factors that influence patients risk of poor outcome after rehabilitation for hip fracture- age, sex, cognition, and mobility. We will analyse of National Hip Fracture Database (NHFD) and Physiotherapy Hip Fracture Sprint Audit (PHFSA) to estimate the prediction accuracy of poor outcome following rehabilitation according to combinations of these factors. Analyses will be supported by the National Institute for Health Research (NIHR) Statistics Group at Kings College London. We will use results to classify multifactorial strata as low-, medium-, or high- risk of poor outcome. We will discuss classification acceptability with patient, carers, and allied health professionals. Intervention development and testing: Supported by patients and carers, we will design and feasibility test the intervention per the MRC framework for the development of complex interventions. We will update the Cochrane systematic review of rehabilitation after hip fracture. We will complete an overview of reviews on acute rehabilitation for adults with frailty. We will use NHFD and PHFSA to quantify current rehabilitation provision for patients classified as low-, medium-, and high- risk. We will interview allied health professionals to obtain their views on this provision. These interviews will complement completed patient interviews. We will hold stakeholder workshops to assess patient, carer, and allied health professional views on reviews, current provision, and interviews, and to design an intervention which matches low-, medium-, and high- risk strata to rehabilitation tailored to their needs. The intervention will include behaviour change techniques and allied health care. There will be a decreasing emphasis on behaviour change from low- to high- risk strata. We will obtain approvals prior to intervention testing in acute hospital to determine 1. the number of eligible, recruited, and retained patients 2. the acceptability of randomization, assessments, and intervention to patients, carers, and allied health professionals 3. compliance with the intervention and fidelity of its delivery 4. adverse events 5. estimate of an effect size for a future definitive trial Sackley (KCL mentor, NIHR Senior Investigator, £50,000,000 awarded for complex intervention trials) will support intervention development. Create a collaborative group: We will create a group, website, and strategy for sustained collaboration with patients, carers, and the public in older adult trauma rehabilitation research. The group will be modeled on the Stroke Research Patient and Family Group at KCL which has sustained public engagement since 2005.

Ornithine transcarbamylase deficiency (OTCD) is a rare X-linked genetic disorder characterized by complete or partial lack of the enzyme ornithine transcarbamylase (OTC). OTC is a key element of the urea cycle, whereby the liver breaks down and removes surplus nitrogen from the body. OTCD patients accumulate nitrogen in the form of excess ammonia (hyperammonemia) in the blood. Ammonia is toxic and patients suffer 'hyperammonaemic decompensations' with symptoms including vomiting, impaired voluntary movement, and progressive lethargy. If left untreated these may progress to coma and life-threatening complications. Symptoms present within a few days of birth of males with severe OTCD. As well as significant risk of mortality, the neurotoxic effects of excess ammonia result in longer-term neurological abnormalities such as intellectual disability, developmental delays, and cerebral palsy. As with milder forms of this disease (which may present later in both male and female children and adults), infants are managed with ammonia-scavenging drugs and dietary intervention, however hyperammonaemic decompensations still occur. Neonatal-onset OTCD patients require liver transplantation (LT) for long-term survival. Whilst LT can be life-saving, opportunity for this intervention remains limited and not without risk of mortality and morbidity. Advances have been made in surgical practices to facilitate access to donor liver tissue, including 'living-donor partial liver grafts' and 'reduced-liver transplantation' whereby infants and children receive a portion of an adult liver. However, both the patient and their family still remain with the challenge of life-long immunosuppression and medical follow-up. European guidelines recommend LT for those patients with severe phenotype, aged between 3 and 12 months as neonatal transplant in such metabolically unstable patients is considered too great a risk. Of 15 paediatric OTCD patients transplanted in the UK this past decade, there were only 4 of this age. All others were over 3 years old and all had long-term neurological impairment. We have developed an Adeno associated virus (AAV)-based gene therapy (AAV-LK03-OTC) to specifically target the liver and restore functional expression of OTC. Our approach encompasses the single administration of gene therapy to OTCD infants to provide immediate normalisation of liver metabolism, thereby reducing acute risk of mortality from hyperammonaemic decompensations. Such treatment would serve as a 'bridge-to-transplant' enabling paediatric patients to continue to grow in a metabolically stable condition until such time that transplantation is possible, also minimising longer-term neurological morbidity associated with hyperammonaemia. Our laboratory experiments have demonstrated the enhanced ability of AAV-LK03-OTC to target liver cells over other AAV, and to elicit elevated expression of functional OTC. We have demonstrated that AAV-LK03-OTC restores liver function in experimental mouse models of this genetic disease and are currently testing the safety of AAV-LK03-OTC in animal studies. Recent success with other viral gene therapies advanced to early clinical trials (e.g. AAV8 for Haemophilia B) and the increased targeting to liver cells (AAV-LK03 >10-fold more transformation of liver cells than AAV8) reinforce confidence in this approach as being safe. We will now translate our pre-clinical findings to conduct a Phase I/II dose-finding clinical trial assessing the safety and efficacy of AAV-LK03-OTC. As children are the OTCD population with greatest unmet need, we aim to recruit 12 paediatric patients in the UK to provide early clinical data for later stage development and commercialisation of this transformative advanced therapy. This project aims to deliver a step-change in the clinical management of paediatric OTCD patients and provide critical gene therapy evidence applicable to many other liver-inherited metabolic diseases.

Our EPSRC CDT in Advanced Engineering for Personalised Surgery & Intervention will train a new generation of researchers for diverse engineering careers that deliver patient and economic impact through innovation in surgery & intervention. We will achieve this through cohort training that implements the strategy of the EPSRC by working across sectors (academia, industry, and NHS) to stimulate innovations by generating and exchanging knowledge. Surgery is recognised as an "indivisible, indispensable part of health care" but the NHS struggles to meet its rising demand. More than 10m UK patients underwent a surgical procedure in 2021, with a further 5m patients still requiring treatment due to the COVID-19 backlog. This level of activity, encompassing procedures such as tumour resection, reconstructive surgery, orthopaedics, assisted fertilisation, thrombectomy, and cardiovascular interventions, accounts for a staggering 10% of the healthcare budget, yet it is not always curative. Unfortunately, one third of all country-wide deaths occur within 90 days of surgery. The Department of Health and Social Care urges for "innovation and new technology", echoing the NHS Long Term Plan on digital transformation and personalised care. Our proposed CDT will contribute to this mission and deliver mission-inspired training in the EPSRC's Research Priority "Transforming Health and Healthcare". In addition to patient impact, engineering innovation in surgery and intervention has substantial economic potential. The UK is a leader in the development of such technology and the 3rd biggest contributor to Europe's c.150bn euros MedTech market (2021). The market's growth rate is substantial, e.g., an 11.4% (2021 - 2026) compound annual growth rate is predicted just for the submarket of interventional robotics. The engineering scientists required to enhance the UK's societal, scientific, and economic capacity must be expert researchers with the skills to create innovative solutions to surgical challenges, by carrying out research, for example, on micro-surgical robots for tumour resection, AI-assisted surgical training, novel materials and theranostic agents for "surgery without the knife", and predictive computational models to develop patient-specific surgical procedures. Crucially, they should be comfortable and effective in crossing disciplines while being deeply engaged with surgical teams to co-create technology solutions. They should understand the pathway from bench-to-bedside and possess an entrepreneurial mindset to bring their innovations to the market. Such researchers are currently scarce, making their training a key contributor to the success of the UK Government's "Build Back Better - our plan for growth" and UKRI's "five-year strategy". The cross-discipline collaboration of King's School of Biomedical Engineering & Imaging Sciences (BMEIS, host), Department of Engineering, and King's Health Partners (KHP), our Academic Health Science Centre, will create an engineering focused CDT that embeds students within three acute NHS Trusts. Our CDT brings together 50+ world-class supervisors whose grant portfolio (c.£150m) underpins the full spectrum of the CDT's activity, i.e., Smart Instruments & Active Implants, Surgical Data Science, and Patient-specific Modelling & Simulation. We will offer MRes/PhD training pathway (1+3), and direct PhD training pathway (0+4). All students, regardless of pathway, will benefit from continuous education modules which cover aspects of clinical translation and entrepreneurship (with King's Entrepreneurship Institute), as well as core value modules to foster a positive research culture. Our graduates will acquire an entrepreneurial mindset with skills in data science, fundamental AI, computational modelling, and surgical instrumentation and implants. Career paths will range from creating next generation medical innovators within academia and/or industry to MedTech start-up entrepreneurs.

Effective, clear and compassionate verbal and non-verbal communication has been shown to be essential to good patient care, as well as part of an efficient and cost-effective healthcare system (McDonald, 2016). Since the Covid-19 outbreak, communication between patients and healthcare professionals has altered, with healthcare professionals facing new challenges: adapting to the introduction of widespread use of Personal Protective Equipment (PPE), video-call consultations, social distancing and limited physical touch. Healthcare professionals have described the impact of wearing PPE as isolating, exhausting and impeding communication, articulating the urgent need for research in this area which has been reiterated by proactive requests for support from institutions such as University College of London Hospitals (UCLH). Through Clod Ensemble's Performing Medicine programme WILLSON (Principal Investigator) provides sector-leading interventions in healthcare education using performative techniques from non-verbal artistic disciplines, such as dance and physical theatre, to enable healthcare professionals to gain a deeper understanding of how they communicate non-verbally. These techniques have been proven to enhance self-care and communication with patients and colleagues (Osman et al., 2018). This proposed research programme of interviews and workshops will investigate the impact of arts-based interventions on the training and support of healthcare professionals and medical students with regard to the non-verbal communication challenges presented by Covid-19. Undertaken by a unique, multidisciplinary partnership between arts organisations, NHS trusts and academics who have been collaborating for decades, this project will create, test, scale and disseminate online and in-person resources to support healthcare professionals and medical students.

B cells are cells of the immune system. B cells fight infections by identifying infectious particles via very specific receptors on the B cell surface, called the B cell receptors. B cell receptors recognise infectious agents by their individual shape and they bind to them in a lock-and-key way. Millions of B cells circulate through the blood and tissues of the body and each B cell has a B cell receptor that is unique to that B cell. As a consequence, no matter what infectious agent finds its way into the body, there will be a B cell with a receptor of the complementary shape to bind it. If a B cell binds to an infectious particle via its B cell receptor, the B cell may become activated and secrete its B cell receptor that will bind to and fight the infectious agent. When the B cell receptor is secreted it is referred to as antibody. The process that generates the huge and diverse set of B cells with unique receptors has a major associated hazard. B cells can be produced that bind to the body's own cells and tissues and can attack them. Other cells of the immune system called T cells have the capacity to regulate B cells and they themselves can discriminate well between self and non-self. However, many B cells can make T cell independent responses and these are particularly dangerous if not properly regulated for specificity. The infectious agents that activate B cells in a T-cell independent way include those that cause some types of pneumonia. B cells have an additional trick to recognise these agents because they have a repeating pattern of shapes on the surface. B cells may be able to recognise the shape through the B cell receptor, but also the regularity with which the shape is presented. Experiments in our lab suggest that B cell selection that would prevent self-reactivity and promote responsiveness to particles that activate B cells independent of T cells happens in the gut. The gut contains a lot of 'friendly' bacteria that constantly stimulate the immune system it contains. Our experiments suggest that this environment supports stages in B cell development that are largely ignored in models of human B cell immunology or assessment of human disease. We call this a 'checkpoint' because it is a stage of B cell development where only cells that have a required set of properties are allowed to pass. The gut is involved in the development of B cells in different ways in many species, including chickens, mice, sheep and rabbits. Therefore an influence of the gut on human B cell development is important and highly likely to occur, but as yet totally mysterious. The aims of experiments described in this application are to understand how B cells mature in the gut and how this is regulated.