BMA Foundation for Medical Research – grant winners 2020

Dr Charlotte Warren-Gash

The effect of raised cardiovascular risk on COVID-19 incidence and outcomes.

By early August 2020, the COVID-19 pandemic had led to more than 19 million cases and over 715,000 deaths worldwide. Underlying health problems such as heart disease rapidly emerged as a major risk factor for severe illness and death from COVID-19. Cardiac injury is common among patients hospitalised with COVID-19 and increases the risk of poor outcomes. We already know that other acute respiratory infections such as influenza can trigger heart attacks and strokes among vulnerable patients. While COVID-19 affects the cardiovascular system, it is not clear exactly who is vulnerable to poor outcomes of infection. This evidence is urgently needed to guide targeted prevention and treatment strategies.

In this project, we will investigate the effect of underlying cardiovascular risk profile on severe illness and death from COVID-19. We will use large, powerful anonymised datasets of linked electronic health records from GPs and hospitals as well as national laboratory surveillance data to conduct two studies with complementary designs. Our work will inform the definition of priority groups for vaccination, when in future a vaccine becomes available, as well as other stratified public health measures and treatments for those at raised cardiovascular risk.

 

Dr Sarah Blagden

COVID-19 consortium (COVIDsortium): Healthcare worker Bioresource and preliminary analysis: Immune Protection and Pathogenesis in SARS-CoV-2.

Dr Sarah Blagden’s project “Prognostic markers for COVID-19” was successfully awarded funding from the BMA Foundation in their COVID-19 call. Her team at the University of Oxford have been exploring the factors that link conditions like diabetes and hypertension to risk of COVID-19. They hypothesise that people with these conditions have high levels of cellular stress and this predisposes them to heavier viral infection and worse outcome. Using blood samples collected from 250 London Healthcare Workers, some of whom later contracted SARS-CoV-2, Sarah will be correlating their medical history and outcomes with levels of circulating cell stress markers. This work provides an pathophysiological explanation for COVID-19 risk and a quantitative means of measuring risk. This is important in broadening our understanding of the disease susceptibility as well as defining the factors and interventions that increase or decrease viral risk.

Dr Massimiliano Di Pietro

University of Cambridge

Prospective multicentre study to identify diagnostic key performance indicators in Upper GI Endoscopy

Cancer of the oesophagus (gullet) and stomach has very poor prognosis. Upper gastro-intestinal (GI) endoscopy allows direct inspection of these organs for a timely diagnosis of conditions that predispose to these cancers (pre-malignant), like Barrett’s oesophagus, gastric atrophy and dysplasia. One diagnosed, these can be monitored to allow early cancer detection. Unfortunately, these premalignant conditions are often overlooked at endoscopy, limiting the effectiveness of preventive strategies. There are no accepted diagnostic key performance indicators based on detection of pre-malignant pathologies, to rate performance in routine upper GI endoscopy. This is due to the fact that there is limited evidence on the true prevalence these conditions in patients referred for upper GI endoscopy. We propose a population study to enrol a large number of patients referred for upper GI endoscopy via different referral routes. We plan to perform a standardised protocol to determine the true estimate of the expected rate of diagnosis of premalignant conditions.

This study will inform future development of diagnostic key performance indicators in upper GI endoscopy which are priorities for the quality assurance bodies of British Society of Gastroenterology (BSG) and Joint Advisory Group for GI endoscopy (JAG).

Dr Philip Riches _{PhD, FRCP}

Lothian University Hospitals NHS Trust

Gout Self-Monitoring to Achieve urate Target, and Evaluate Remission – GoutSMARTER.

Gout represents a rising burden on both primary and secondary healthcare services, and for sufferers is characterised by sudden attacks of intense pain which can result in reduced quality of life, work absence and disability. Effective use of urate lowering treatments leads to the dissolution of urate crystals and prevents symptoms of gout, however in routine clinical practise such disease remission is rarely achieved, and compliance with treatment is notably worse than for other chronic conditions. We have successfully piloted an innovative patient centred approach to gout management involving urate self-monitoring using a finger prick test, and prompt feedback from the clinical team through a smartphone App (Gout SMART). Our primary objective is to show that a supported self-monitoring approach to gout results in improved adherence to therapy and a correspondingly greater proportion of patients achieving sustained disease remission, when compared to usual care. A secondary objective is to evaluate disease remission criteria themselves through the long term follow up of flares in participants that have achieved control of urate levels..

Dr Connor G. G. Bamford

Tipping the balance: Investigating Novel Genetic Regulators of Type 3 Interferon Signalling to Promote Antiviral Immunity in the Lung

Our lungs play home to myriad respiratory viruses, such as influenza virus, respiratory syncytial virus and - now infamously - coronaviruses. While most infections remain mild, a small but significant number progress to severe and potentially-fatal lung failure for which there are often little treatment options. Successful viruses are able to overcome our own natural immune defences. My research focuses on understanding the interactions between these disease-causing viruses and a part of our immune system called ‘interferons’, which is dedicated to stopping viruses (interferons interfere with infection!). This project will aid work on dissecting the molecular workings underlying the regulation of the antiviral interferon response during infection.

Building upon exciting preliminary work we believe we have found new genes that block or activate the antiviral immune response. We will now test whether - and how - these genes interact with viruses in lung cells. This work will help develop new ways to control serious respiratory viral diseases.

Since my PhD on mumps virus, through my postdoctoral work on hepatitis c, and now a fellowship on respiratory viruses at the Wellcome-Wolfson Institute for Experimental Medicine at Queen’s University Belfast, I remain dedicated to the advancement of fundamental science on clinically-relevant infections.

Dr Thomas Waterfield

Biomarkers To Predict Evolving paediatric infections (BIOTOPE2).

I am grateful to the British Medical Association Foundation for awarding me the Helen H Lawson grant to pursue research into paediatric sepsis. I intend to use the award to design and conduct a programme of research, over the next three to four years, to investigate the role of clinical features and biomarkers in the diagnosis of paediatric sepsis. This will include traditional biomarkers such as C-reactive protein and procalcitonin as well as novel biomarkers derived from proteomics. The project will be a collaboration between the Wellcome-Wolfson Institute for Experimental Medicine at Queen’s University Belfast and the Paediatric Emergency Research in the UK and Ireland (PERUKI) network.

 

Dr Tiffany Patterson

Investigation into the mechanisms of leaflet thrombosis following transcatheter aortic valve implantation.

The aortic valve is the main outlet of the heart that delivers oxygenated blood to the rest of the body. Aortic stenosis is a significant narrowing of this valve and affects one in ten people over 75. This can cause breathlessness, chest pain and sudden death. Untreated, the death rate is higher than most cancers. A large number of patients are too high risk for conventional surgery and therefore do not get treated. Trans-catheter aortic valve implantation (TAVI) is a keyhole alternative to surgery that has saved thousands of lives in the UK alone since its introduction in 2007. However, 15% of patients have an incidental finding of blood clots and reduced function that increases the risk of stroke and death after TAVI. Treatment is with blood thinners, but we cannot give this to everyone because the risk of major bleeding outweighs the benefits. It is very important for us to predict and prevent blood clots on TAVI valves.

This study will determine if a blood test or changes that can be identified on a CAT scan can identify those at higher risk of blood clots on the TAVI valve so we can tailor blood thinning treatment appropriately.

       

Dr Ahmed Al-Hindawi & Dr Marcela Vizcaychipi

Continuous Non-Invasive Eye Tracking for the Early Detection of Delirium on the Intensive Care Unit (CONfuSED)

Delirium, an acute confusional state, is unfortunately a common occurrence in Intensive Care where it occurs in up to 80% of patients. It is associated with increased mortality, reduced cognitive function, increased hospital length of stay, and increased hospital cost.

Current methods of delirium detection are laborious, intermittent and rely on snapshot assessments conducted by busy nursing staff.

This project aims to automate the diagnosis of delirium though eye-tracking. We have developed a calibration free, non-invasive, real-time camera-based system that tracks the patient’s attention as a surrogate marker of delirium. The system uses well tested state-of-the-art machine learning and artificial intelligence algorithms to track the patient’s gaze and compare the gaze to simulations.

We have gained provisional ethical approval to perform a feasibility study on patients in Intensive Care who are at high risk of developing delirium and hypothesise that eye tracking correlates with current assessment methods. This finding could potentially create a continuous measure of delirium in Intensive Care and pave a unique pathway into functional non-invasive brain monitoring on Intensive Care.

Dr Robin Brown

Analysing cerebrospinal fluid to understand cerebral small vessel disease.

Progressive narrowing and malfunction of small blood vessels deep within the brain (cerebral small vessel disease) is responsible for 20% of strokes and is the most common cause of vascular dementia. This process is known to occur more frequently in patients who are older and those who have cardiovascular risk factors such as high blood pressure or cholesterol; however, treating these risk factors does not completely reduce the risk of cerebrovascular disease.

Based on an accumulating body of evidence that an inflammatory response around these blood vessels occurs in patients with small vessel disease, our research aims to establish the cellular and molecular basis for this response. Using positron emission tomography combined with MRI scanning, we aim to determine how areas of inflammation progress and whether they become damaged. We are also testing samples of blood and spinal fluid to investigate which cell types and inflammatory molecules are involved in this pathway, in the hope that these might provide a target for futue therapeutic options.

Dr Katherine Fairhurst

The BE FIT Study: Biomarkers related to weight and lifestyle in young adults.

The prevalence of obesity is rising, with a dramatically earlier onset. The ‘seeds of adult disease’ will manifest initially as pre-clinical abnormalities in such critical organs as the liver, heart, and systemic vasculature. However, estimates of obesity-related disease in younger adults is unreliable owing to the lack of effective screening measures. Clinical practice relies primarily on body mass index (BMI), family history, and blood tests, often neglecting to consider or address modifiable lifestyle factors. Magnetic Resonance Imaging can be used as a fast and accurate screening tool that can identify individuals at risk, even at an early stage when the disease is still reversible.

Our work adopts state of the art MRI techniques as part of a comprehensive study to highlight the deleterious effects of modern lifestyles in young persons aged 16-25 years. Specifically, we explore the inter-relationship between lifestyle (modifiable factors including physical activity, diet and sleep pattern) and general health (including liver and cardiovascular health, and body composition).

Preliminary results from our pilot data demonstrate that we can identify subclinical pathological changes even in young people. These findings related to modifiable risk factors can be used to guide clinical practice to prevent progression of disease into adulthood.

Dr Haamed Al Hassan

Imaging the recovery of retinal ganglion cells in experimental glaucoma.

I will collaborate in the development of a novel technique to image the recovery of retinal ganglion cells in the eye following the induction of experimental glaucoma. Retinal ganglion cell damage is characterised by dendritic shrinkage which can be reversed with a combination of treatments that restore the energy levels of the cell.

Current practice is to consider that the vision loss in glaucoma is irreversible. However, the accumulated evidence that retinal ganglion cells enter a prolonged phase of comprise (or sickness) raises the possibility that some visual impairment can be reversed. To test this hypothesis, I will use a novel transscleral imaging technique to image the recovery of single retinal ganglion cell dendrites over time following the administration, by intravitreal injection, of agents that can enhance neuronal recovery. This novel optical approach overcomes the optical limitations of the mouse eye when imaging fine retinal ganglion structure such as dendrites.

The study will provide a critical proof of concept that it is possible to recover retinal ganglion cell structure. This will provide a foundation for the development of clinical treatments for the restoration of vision in patients with glaucoma.

 

Mr Cathal Hannan

The use of serum VEGF as a peripheral biomarker of growth in patients with Vestibular Schwannoma.

Vestibular Schwannomas (VS) are tumours arising from the hearing and balance nerve at the base of the skull. Although these tumours do not spread to other areas of the body, as they grow they can cause hearing loss, balance problems and even death due to pressure on adjacent structures. Around a half to two thirds of these tumours do not grow following their diagnosis. Therefore, the majority of patients with VS initially undergo a period of observation with MRI scans, to assess whether or not their tumour is growing. When these tumours do grow, they require treatment with radiotherapy or neurosurgery. The risks of both of these treatments are less when the tumours being treated are smaller.

Our research focuses on whether a simple blood test will be able to predict, at the time of diagnosis, whether a particular VS will go on to demonstrate growth. If this were the case, this blood test could be used to recommend treatment at an earlier stage when the risks of treatment are lower.

    

Dr Emanuele Osimo & Professor Oliver Howes

Inflammatory correlates of cardiac remodelling in schizophrenia.

 We have known for many years that people who suffer from schizophrenia die younger than expected, as much as 20 years earlier than the general population. Most people thought that this added risk of death was mostly due to the higher prevalence in schizophrenia of smoking, obesity and to other lifestyle differences, however no one really knew the reason.

For this reason, we recruited patients with schizophrenia and an equal number of healthy controls, and scanned their hearts using a state-of-the-art approach, called cardiac magnetic resonance.

We found that even after matching patients and healthy controls for age, sex, ethnicity and body mass index (BMI, deriving from height and weight); and after excluding any participants with any medical conditions, and other risk factors for heart disease, people with schizophrenia show hearts that are smaller and chunkier than controls (Osimo et al, 2020).

In a previous study we had also found that the muscle tissue in the hearts of people with schizophrenia shows changes seen in inflammatory conditions, such as evidence of scarring (Pillinger & Osimo et al, 2019).

Our research to date has shown that schizophrenia is associated with heart changes, and that these changes could lead to an increase in the risk of heart disease and death in this group. Previous research from several groups including ours had also shown that schizophrenia is a pro-inflammatory condition.

Thanks to the BMA Margaret Temple award we will be able to test for differences in several pro-inflammatory markers between our cases and controls. We will also determine if elevations in inflammatory markers underly cardiac structural and fibro-inflammatory changes. These analyses we propose promise to provide insights into some of the potential schizophrenia-specific causes (e.g. inflammation) of the potentially dangerous cardiac changes we have found in schizophrenia.

 

 

Dr Miruna Barbu

Pathway-focussed polygenic and gene expression risk scores for schizophrenia and impact on brain structure across the lifespan.

Dr Barbu’s main area of research interest is understanding the causes and consequences of psychiatric disorders by linking genetic and environmental risk factors for these with neuroimaging techniques. She has recently finished her PhD, which focussed on identifying the underlying causes of major depression by integrating genetic and neuroimaging data in large, population-based studies.

Dr Barbu is now investigating DNA methylation in relation to depression and depression-related traits. Her plans for the future include the investigation of pathway-specific polygenic and gene expression-based scores for schizophrenia in relation to brain imaging and disease-related phenotypes.

Professor Andrew J Grant

Enhanced Stress Resilience Training in graduate entry medical students: A randomised controlled trial

Concerns have been expressed repeatedly in the last few years about the mental health of medical students and doctors.

We will be exploring a technique that may help medical students deal with stresses and pressures and reduce levels of mental illness. The technique that will be evaluated is one that fits in with the time pressures of medical students’ busy lives.

Enhanced Stress Resilience Training (ESRT) provides training in mindfulness, which has been shown to help in many stress-related. This form of training has been chosen over Mindfulness Based Stress Reduction (MSBR) because it can be completed in less time. Time has been a limiting factor for medical students undergoing mindfulness training previously.

The stress and anxiety levels of the participants and a control group will be measured before the training, immediately after and six months after the training. Mental health, stress and burnout will be measured by participants completing a pack of specialised questionnaires and by measurement of heart rate variation (HRV) which gives a physical measure of stress levels.

We will compare stress, burnout and markers of mental health as well as HRV in those who have undergone ESRT and the control group.

 

Dr Bethan Davies

Spatio-temporal patterns in kidney cancer incidence in adults in England, 1981-2019.

Each year, 12,900 people in the UK receive a new diagnosis of kidney cancer making it the 7th most commonly diagnosed cancer in the country. Incidence rates have doubled since the 1990s and are predicted to continue increasing dramatically in the coming decades. Smoking, overweight/obesity and hypertension are the only established modifiable risk factors for kidney cancer. Each are associated with modest risk differences, suggesting that this temporal trend cannot be fully explained by secular changes in smoking or obesity prevalence, and recent reductions in smoking rates have failed to curb rising kidney cancer incidence.

This trend cannot also be explained by increased detection of asymptomatic tumours: the rise in incidence pre-dates widespread use of sensitive abdominal imaging, and the incidence of late stage tumours has also increased. Almost half (40%) of cancers in the UK are diagnosed at a late stage with a much poorer prognosis. With relatively poor survival and dramatic and unexplained increase in incidence, kidney cancer represents a serious public health concern for the UK.

There is an urgent need to advance our knowledge of the epidemiology and aetiology of kidney cancer, to inform effective prevention interventions. We will apply advanced spatio-temporal epidemiological methods to analyse variability in the incidence of kidney cancer in England over almost 40 years to advance the evidence base for prevention interventions and to generate hypotheses for further research..

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