BMA Foundation for Medical Research – grant winners 2023

Dr Ben Kasstan MSc, PhD

London School of Hygiene and Tropical Medicine

& Dr Tehseen Khan MBChB, MPH, MECGP 
Spring Hill Practice

Addressing vaccine deferral: an implementation study

Childhood vaccination coverage rates in England have been declining over the past decade, resulting in the transmission of preventable diseases such as measles and poliovirus. Distinguishing between vaccine deferral and refusal is important when interpreting this decline. Vaccine deferral is an acute public health challenge because children who are not vaccinated to schedule are vulnerable to illness in the intervening period and can expose immuno-compromised people to infection. Vaccine deferral also presents operational challenges for primary care teams.

Vaccine deferral is more common in families with larger numbers of children than the national average. This study will implement a qualitative methodology to compare the reasons that underlie vaccine deferral among Haredi Jewish families in London, Salford, and Gateshead, and to investigate whether and how regional health systems and services have the operational flexibility to respond through tailored delivery strategies. Understanding the parental decision-making process through which deferral leads to acceptance may help immunisation services to achieve timeliness in vaccination. A comparative approach will help to identify models of best practice and data information sharing between local authorities. The study will produce implementation guidance to help address vaccine deferral among underserved communities and
to achieve sustainably higher vaccination coverage levels.

Miss Paramita Baruah, MBBS, PhD, FRC(ORL-HNS)

University Hospital of Leicester

A single-cell atlas of endolymphatic sac and vestibular neuroepithelium: unlocking the pathophysiology of Ménière’s and Autoimmune inner ear disease

Ménière’s disease (MD) and autoimmune inner ear disease (AIED) have a signifi cant impact on quality of life due to dizzy spells and associated hearing loss, and may have common underlying tissue changes in the inner ear. Patients whose symptoms continue despite medical therapy, including steroids, are left with tissue destructive treatment options (MD) which result in permanent hearing and balance defi cits or immunosuppressive medications (AIED) with signifi cant side effects. Therefore, there is a significant need for newer, safer organ and function preserving treatment modalities. MD and AIED result in expansion of the fluid system of the inner ear (hydrops) which may link to the function of the cellular lining of the inner ear (vestibular tissue) and the endolymphatic sac (a structure of the inner ear that potentially regulates immune function of the inner ear). This project aims to chart the individual cells in vestibular tissue and the endolymphatic sac based on the gene function of the individual cells (single cell RNA sequencing). Emphasis will be on support cells and immune cells and how these cells ‘speak’ with each other and maintain inner ear health. This work will potentially unveil new treatment targets to prevent inner ear damage with MD and AIED.

Mrs Samantha Downie, MBChB, FRCS (Tr & Orth)

Ninewells Hospital and Medical School

Epidemiological study investigating the lifetime risk of a career in orthopaedic surgery (LiROS): a national data linkage project

A career in orthopaedic surgery is thought to increase the risk of some cancers by up to three times compared to the nonmedical population. This is thought to be related to the use of intraoperative x-ray imaging for common orthopaedic surgical procedures on a cumulative basis over an individual’s career. In addition, as increasing numbers of women pursue a career in orthopaedics, there are reports of pregnancy-related complications including increased miscarriage rate and a threefold higher risk of breast cancer. Lead aprons, used to protect staff during operative x-ray exposure, are designed for men and may not provide adequate protection to the outer breast region in women, the most common site for breast cancer.

This will be a study of all individuals on the General Medical Council (GMC) specialist register for orthopaedic surgery (current and retired) between 1950 and 2022 cross-linked with the Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics (HES) databases (for UK general practice and hospital admissions).

The project aims to describe the rate of all-cancer diagnosis in orthopaedic surgeons in comparison to a group of age and gender-matched plastic surgeons, a surgical specialty which does not routinely use operative x-rays, and radiologists, a medical specialty which involves similar rates of x-ray exposure.

Professor Jonathan Koffman, BA (Hons), MSc, PhD

Hull York Medicial School

& Dr Matthew Allsop BSc, PhD

University of Leeds

The Association of Social Determinants of Health in Decision Making at the End of Life: A Retrospective Observation Cohort Study

Over 600,000 people die each year in the UK, with most dying in hospitals instead of at home. This is not what many want. Electronic palliative care coordination systems (EPaCCS) are a solution, which can allow individuals to make decisions about their end-of-life care and where they want to die. This information is electronically shared with healthcare providers during crises. Social determinants of health, including gender, age, ethnicity and socioeconomic position, play a role in the experiences and outcomes of end-of-life care. Despite the NHS recommending the rollout of EPaCCS, it remains unclear how social determinants of health are associated with the creation of EPaCCS records or their content to support end-of-life care decisions. A retrospective observational cohort study will be conducted to describe the ways social determinants of health are associated with EPaCCS creation and their content (ceiling of care and end-of-life care preferences) for individuals living with lifelimiting illnesses. The exploratory study will analyse data from EPaCCS in London, Leeds and Bradford. The team will work with patients, families, healthcare professionals, and policymakers to devise solutions leading to equitable end-of-life care decision-making for all.

Dr Marcella Bassetto PhD, MSc, FHEA

& Dr Meike Heurich PhD

University of Cardiff

Therapeutic inhibition of complement C4 binding to C1s in schizophrenia

Schizophrenia is a complex neuropsychiatric disorder with largely unresolved mechanisms of pathology. It is characterised by delusions, hallucinations, disorganised speech, thinking difficulties and lack of motivation
and begins in adolescence or early adulthood. It imposes a significant emotional and economic burden on affected people and their families. Research suggests that early diagnosis and targeted intervention improves outcomes significantly. 

While pathological mechanisms are largely unresolved, evidence suggests that immune activation, not only in the brain, but also in peripheral blood, may play an important role. Growing evidence suggests that upregulation of the blood-based innate immune system, the complement system, contributes to schizophrenia development. Recently, complement component C4 has been identified as a susceptibility locus for schizophrenia. However, current intervention strategies in schizophrenia do not address immune activation or complement dysregulation mechanisms as strategic targets.

With this work, the project team aims to develop inhibitors of key components of the complement system, as an intervention strategy to control C4 activation. They will use computational techniques to screen multiple libraries of drug-like compounds and identify protein-protein interaction inhibitors. The team will then biochemically characterise the selected molecules at the protein level and in blood serum across all
complement pathways. Such agents could provide early-stage pre-clinical drug candidates with the potential to prevent and/or treat immune activation in schizophrenia.

Dr Bo Sun MBBS, BSc, MRCP, DPhil
University of Oxford

The T-cell landscape of gliomas, towards early detection and classification

Adult diffuse gliomas are the most common cancers affecting the brain and are incurable. Patient survival
varies greatly depending on the type of glioma. Low-grade gliomas have a 5-year survival rate of up to 80%, whereas high-grade gliomas have 5-year survival rates under 5%. Current detection and monitoring
methods involve brain scans and invasive biopsies with risks. However, scans may fail to detect early tumour recurrence.

To address this pressing issue, the awarded project aims to use the genetic characteristics of T-cells to improve detection, monitoring, and treatment of brain cancers. T-cells are vital for our immune system and have demonstrated the ability to eliminate various cancer cells, including gliomas. These
immune cells recognise cancer cells through a specific receptor called the T-cell receptor (TCR), and this unique feature can be used to track the presence of cancer cells.

It is well known that longer delays to treatment affect survival negatively. Therefore, the study approach to detect the presence of cancer cells has the potential to help significantly reduce the time to treatment and improve patient outcomes. Additionally, this approach involves a blood test, providing patients with a non-invasive alternative to invasive surgical biopsies.

Mr Daniel Michalik BSc(Hons), BMBS, MRCS (ENT)

& Professor Rami Salib BM, BS, PhD, FRCS
University of Southampton

Identification of novel non-invasive nasal biomarkers to enable early diagnosis in Alzheimer’s disease

Alzheimer’s disease (AD) is the most common type of dementia, making up 60-80% of all dementia diagnoses in the United Kingdom. Almost one million people are currently affected by dementia in the UK,
with that predicted to increase to 1.6 million by 2040. Currently there is no curative treatment for AD.

The underlying mechanisms leading to AD begin in the brain twenty years before clinical symptoms, by which stage the damage is irreversible. There is considerable interest in biomarkers for AD, to enable
early diagnosis at a stage where new treatments may be more effective. Current biomarkers include the testing of cerebrospinal fluid (fluid around the brain) or positron-emission tomography (a detailed brain
scan), but these can be invasive and expensive.

Experimental studies in humans and animals show that proteins from the brain are detected in the nose. This research aims to demonstrate that markers specific to AD can be detected in the nose and therefore can be used to develop non-invasive specific and sensitive biomarkers, enabling the early diagnosis and monitoring of Alzheimer’s disease. This would be a potential game-changer and could facilitate early treatment to slow
or halt the progression of AD.

Professor Marcela Votruba, BA, MA, BM, BCH, FRCOphth, PhD, LSW

Cardoff & Vale University Health Board 

Mitochondrial transplantation for retinal ganglion cell rescue and health in mitochondrial optic neuropathies

Mitochondrial optic neuropathies (MON) affect at least 1 in 10,000 people worldwide. They are characterised by the dysfunction of mitochondria due to defects in either nuclear or mitochondrial DNA. In MON, mitochondrial dysfunction drives visual dysfunction due to the loss of retinal ganglion cells (RGCs), resulting in progressive and irreversible loss of vision, often starting in childhood and early adulthood. RGC regeneration is challenging to repair or reverse. The research team want to take a completely new approach to this problem and replace or enhance the poorly functioning mitochondria in retinal ganglion cells by supplementing them with fresh, normal mitochondria from donor cells. The awarded project will provide a much-needed additional approach to therapy in this group of diseases. The project aims to determine if healthy transplanted donor mitochondria transfer, integrate, maintain morphology, show activity, and improve the bioenergetic profile of disease model recipient RGCs and, if so, for how long.

Dr Helen Harris, MB BCh, BAO, MRCPI, MD
Western General Hospital

Fatigue in Lupus Intervention Programmes (FLIP): A randomised controlled trial investigating the eff ectiveness of fatigue management in Systemic Lupus Erythematosus (SLE)

Systemic Lupus Erythematosus (SLE) is an autoimmune disease in which the immune system attacks its own tissues, causing widespread infl ammation and tissue damage. Despite good control of infl ammation using new drug therapies, many SLE patients continue to experience debilitating fatigue that does not improve with increased dosages of medication. Using a process based on psychology techniques the project team have developed an interactive online fatigue management programme (FMP) that has shown signifi cant improvements in fatigue. The current study generously funded by the Doris Hillier award will establish if patients can benefit from a shortened version of the interactive online FMP. This could facilitate more widespread provision of FMPs to help many more of the UK’s 50,000 SLE patients that suffer with debilitating fatigue.

Dr Rishi Gupta

University College London

Precision RNA-guided evaluation for viral respiratory infections

Respiratory viruses cause thousands of deaths each year and put major strain on the NHS. It is critical to diagnose viral respiratory infections early so that correct treatment can be started, and to reduce the risk of transmitting infection to others. We do not currently have an accurate blood test to predict who is likely to have a viral infection, but promising candidate tests are being developed. These include tests that measure blood “gene expression” levels.

In this project, we will first compare the accuracy of a range of emerging tests for viral infections by analysing data from adults with suspected lung infections attending emergency departments. After identifying the most accurate tests, we will then combine these results with other routinely measured information – such as bedside measurements and standard laboratory tests – to see if they perform better when used in combination.

Through this work, we hope to identify the most accurate approach to detect people with respiratory viruses. The tools that we develop could then be tested in a future trial, to see if they might enable earlier viral diagnosis, reduce unnecessary antibiotic use, and lower risk of viral transmission.

Dr Jonathan Chuo Min Lee, MBChB, BSc, MRCP, PGCert and Professor Sanjay Sinha, MBBChir, MRCP, PhD

University of Cambridge

“A Slice of My Heart”: Using myocardial slices to revolutionise cardiomyocyte cell therapy development in ischemic heart failure patients

Ischemic heart disease is one of the most common causes for chronic heart failure and impacts over 20 million people worldwide. Current medical therapies fall short of addressing the irreversible loss of cardiomyocytes after a heart attack. Though heart transplants remain the only available cure, accessibility remains a major issue with only around 200 transplants occurring in the UK each year.

Cell therapy using stem cellderived cardiomyocytes has recently emerged as a promising strategy to regenerate the damaged myocardium in these patients due to its relative accessibility and scalability. Pre-clinical studies in large animals have shown encouraging improvements in cardiac function post-treatment, but the benefi ts remain limited largely due to poor graft survival and integration.

This project will utilise heart tissue slice technology to deliver stem cell-derived cardiomyocytes into patient tissue slices therefore mimicking cell therapy – ‘cardiac regeneration in a dish’. The project team will use this technology to study the behaviour of these cardiomyocytes when delivered into healthy versus diseased heart slices to determine what factors can help improve graft survival and function. This will subsequently de-risk and enhance stem-cell derived cardiomyocyte therapeutic efficiency, guiding future clinical trials.

Dr Susan Ayres, BSc, MSc, PhD, CPsychol
City University of London 

Maternity Care Systems and Childbirth-Related Trauma

Worldwide, 140 million babies are born every year. For some women, childbirth can be traumatic and 1 in 25 suffer post-traumatic stress disorder (PTSD) as a result. Childbirthrelated PTSD has a substantial negative impact on women and their families, yet there is very little worldwide research, so it remains largely unrecognised.

This research examines the role of maternity services in childbirth-related trauma and PTSD in low, middle-and high-income countries. It is embedded in the International Survey of Childbirth-Related Trauma (INTERSECT), a research programme involving over 18,000 women in 45 countries which provides an international databank and resource for researchers and policy makers.

The project team will review different ways to classify maternity care systems (e.g., hospital or community
services) and develop a robust method of classifying maternity system characteristics across different countries. This information will be linked with INTERSECT databank, allowing the researchers to examine the impact of how maternity care systems are structured and provided on women’s birth experiences and childbirthrelated PTSD in low, middle and high-income countries.

This research has implications for policy and practice, with potential to support changes to maternity care provision, funding, and policy both nationally and internationally, informing initiatives such as the World Health Organisation’s campaign to prevent disrespect and abuse during childbirth.

Dr Ahilanandan Dushianthan, MBBS, PhD
University Hospital Southampton NHS Foundation Trust

Assessment of mitochondrial capacity in post-acute long-COVID

The interaction between prolonged viral illness and mitochondrial dysfunction has come under closer scrutiny since the start of the COVID-19 pandemic. Our understanding of the long-term outcomes of patients after acute COVID-19 infection remains limited. Some patients will develop persistent symptoms or prolonged illness, known as post-acute COVID syndrome (PACS). These symptoms overlap with other post viral conditions. However, the exact biological mechanisms for these persistent symptoms are poorly understood. Studies suggest that SARS-CoV-2 localisation of RNA transcripts in mitochondria hijacks the host cell’s mitochondrial function for its replication and survival, leading to an impaired host’s immune response.

We hypothesise that the PACS symptoms may be related to reduced mitochondrial capacity following an acute severe COVID-19 infection. We propose investigating mitochondrial capacity using a novel non-invasive isotope-labelled breath test. The 13C-ketoisocaproate (13C-KICA) can quantitatively measure whole-body mitochondrial capacity. We will also quantify mitochondrial oxidative phosphorylation from blood cells and perform a cardiopulmonary exercise test to measure maximal oxygen consumption as a non-invasive proxy marker of mitochondrial capacity.

This multi-model analytical study will help to quantify the global mitochondrial capacity and its contribution to PACS symptoms in relation to persistent inflammation

Dr Caroline Jolley, MBBS, PhD

King's College London

Physiological basis of breathlessness and fatigue in long-COVID

The global healthcare crisis of the COVID-19 pandemic has resulted in over 760 million cases worldwide. Although most people with COVID-19 feel better within a few weeks, symptoms last longer for many people. The term “long-COVID” includes both ongoing symptomatic COVID‑19 (from 4 to 12 weeks) and post-COVID-19 syndrome (12 weeks or more). Fatigue and breathlessness are common and highly distressing symptoms of long-COVID, affecting personal and social function, and quality of life. The current lack of evidence-based interventions for long-COVID is explained in part by the complex and multidimensional nature of breathlessness and fatigue, and limited understanding of mechanistic underpinnings.

The project team have designed a suite of detailed physiological tests of lung, muscle, and exercise capacity to investigate mechanisms of breathlessness and fatigue in long-COVID. In this study, they will explore the relationship between physiological, behavioural, and psychological responses and symptom burden, specifically fatigue and breathlessness, in individuals with long-COVID, aiming to define mechanistic pathways. Findings of this study will inform design of large-scale interventional studies for longCOVID, targeting the predominant mechanism(s) driving individual symptomatology and functional impairment, and enabling personalised rehabilitation programmes for affected individuals.

Dr Anna Freeman, MBBS, MRCP, SCE, PhD

University of Southampton

Living better with asthma study (LIBERTY)

Asthma affects over 5 million people in the United Kingdom, and 10-20% of asthma patients have difficult-to-treat (difficult) asthma which remains uncontrolled despite maximal treatment. Difficult asthma is increasingly recognised as a complex multimorbid health state. Our work with patients living with asthma has identified that finding effective nonpharmacological approaches to address multimorbidity is a high research priority.

Through NIHR Biomedical Research Centre support, the research team are codeveloping with patients a multimodal lifestyle intervention (LIBERTY) for difficult asthma to address multimorbidity. Their previous work has shown that treatable traits such as obesity, anxiety and depression, breathing pattern disorder and inactivity predict future exacerbation risk. The project aims to address these with a combined 24-week intervention of prescribed exercise training, breathing retraining, dietary and behaviour change support. The research team will record symptom scores, lung function testing and body composition, and take blood and urine samples to understand if and how this intervention improves symptoms.

Addressing multimorbidity in asthma is a key patient priority and could improve asthma related patient outcomes. There is potential to upscale this intervention as part of clinical guidelines with demonstration of efficacy in a fully powered study.

Dr Padmanabhan Ramnarayan, MBBS, MD, FICM, FRCPCH 

Imperial College London

Reinforcement learning to optimise fluid management in sick children

Nearly 20,000 children require admission to a paediatric intensive care unit (PICU) each year in the UK. A universal feature of managing a sick child is the administration of fluid. However, fl uid management in the PICU remains controversial, with little evidence to support clinical practice. Fluid overload is associated with poor outcomes such as prolonged ventilation and organ support, while fluid depletion may lead to cardiovascular instability and kidney injury, resulting in considerable variation in fluid management practice. One way to leverage the inherent variability in practice is to use reinforcement learning (RL), a machine learning paradigm, to ‘learn’ from the myriad (optimal and suboptimal) decisions made by clinicians to discern the most appropriate fluid management strategy in individual patients. One particular RL success is the AI Clinician for sepsis, developed at Imperial College, as a collaboration between adult critical care clinicians and artifi cial intelligence (AI) experts. In this project, the team will extend the AI Clinician (sepsis) model to the paediatric environment to advise on fl uid management. Researchers will train the AI Clinician for fluid management by using retrospective data from a multicentre cohort of sick children, validate the performance of this model, and test the performance of the model in an independent dataset. The datasets for this purpose have already been prepared from 4 diff erent PICUs in London and will cover nearly 20,000 admissions of children.

For more information, please get in touch:

Corporate development, British Medical Association, Tavistock Square, London, WC1H 9JP

Tel: 0207 383 6341 

Email the team: researchgrants@bma.org.uk