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.

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.

Valvular heart disease (VHD) has become an epidemic and nearly two million people in the UK suffer from it. This number is expected to double by 2040. About half of those affected by VHD are unaware of their condition. Early diagnosis is the key to providing essential treatment and preventing untimely death. We are developing an intelligent stethoscope to automatically detect heart murmurs and the underlying pathology, which would help provide early diagnosis of VHD. Currently, heart murmurs are picked up as a part of a physical exam by GP using a stethoscope. However, VHD can often become severe before symptoms develop, meaning many patients may only be picked up when they have already developed irreversible complications, such as heart failure, or post-mortem. The AI-enabled stethoscope proposed could provide a much higher accuracy than could be achieved by trained practitioners via auscultation. It could also be used by less-skilled healthcare professionals in a screening program for those at risk or by patients for at-home monitoring. This would reduce the number of missed diagnoses, reduce the burden on GPs of detection, and support early intervention to minimise morbidity and mortality.

Although an increasing number of people survive heart attacks, the scar left in their heart muscle leaves them at an increased risk of developing lethal cardiac 'arrhythmias' (abnormal beating of the heart) following the initial attack. Little is known about the underlying processes linking the presence of scars to increased death from cardiac arrhythmias. Specifically, it is not well understood whether the scar is involved in the actual generation of the arrhythmia, or whether it just helps to stabilise an arrhythmic episode generated by another mechanism, unrelated to the scar itself. As a result, diagnosis and therapy planning is non-optimal for these patients, and the rate of sudden death due to arrhythmic events is still high within this population. Current clinical tools can provide useful information regarding scars within patients who have suffered prior heart attacks. Clinical magnetic resonance (MR) imaging gives an important non-invasive means of analysing the location and shape of scars in patients. In addition, analysis of clinical electrocardiogram (ECG) recordings during arrhythmia can suggest not only the type of arrhythmia, but also the role the scar may play in such episodes. In particular, careful analysis of the shape of the ECG trace in the first few arrhythmic beats has suggested that, in many cases, the scar itself is highly likely to be the actual source of the ectopic activity responsible for generating the arrhythmia. Basic science investigations have shown that the structure of the tissue in and around the scar is highly diverse, and that the functional electrical properties are also changed from that of the normal, healthy cardiac tissue. As such, how the scar may act to generate lethal arrhythmia is thought to involve highly complex processes, which are not yet well understood. Our goal is to use computer modelling alongside high-resolution animal and clinical images to gain an in-depth understanding of the underlying processes involved in the generation of lethal arrhythmias directly from within cardiac scars. By using high-resolution animal images of scars, we will generate exceptionally-detailed computational models to investigate how the interaction between structural and functional diversity within a scar may encourage the generation of arrhythmia. This will allow us to understand how the fine-scaled properties of the scar and surrounding tissue make it susceptible to arrhythmias, identifying key 'hot spot' regions which represent the most dangerous potential sources of arrhythmic activity. We will then use this knowledge in comparison with patient MR and arrhythmia incidence data to make an important step towards translating these findings into the clinic, helping provide a mechanistic explanation of the underlying observed relationships uncovered in the clinical data. Overall, the findings from this research will pave the way for improved of risk stratification in patients with cardiac scars, and the development of novel clinically-useful therapies targeting the scar as a source of arrhythmia generation. The potential beneficiaries from this research will be extensive due to the high incidence of heart attacks annually in the UK (124,000), and the significant risk posed by arrhythmia to individuals following a heart attack. Consequently, this work also has the potential to reduce the health and economic costs of associated death and illness.