Clinical Research Career Development Fellowships: people we've funded

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2017

Dr Robert Aldridge

University College London

Public health data science to investigate and improve migrant health

There are currently eight million migrants living in the UK and about 600,000 new arrivals each year. However, we know very little about the health problems new migrants face. When migrants settle in a new country, they experience extensive changes in terms of the people they live and work with, the type of housing they live in, the food they eat and the amount of exercise they take. These factors, compounded by inequalities in wealth, mean that despite being young and healthy when migrating, they are particularly vulnerable to illness.

This study aims to understand the health needs of migrants, how their personal and environmental risk factors for ill health change, and whether these risks can be reduced. Study 1 will use data on more than one million migrants who came to the UK before 2017 to see what diseases they had when they saw a GP or hospital doctor. Migrants arriving after 2017 will be approached to take part in a second study which uses mobile phones to follow them up and see how their risks for ill health change. Study 3 will develop and pilot a web-based personalised health quiz to see whether it can be used to improve migrant health.

Our findings can be used to help improve the health of migrants in the UK.

Dr Peter Arthur-Farraj

University of Cambridge

Schwann cell-axonal communication during axonal degeneration and regrowth

Peripheral nerves consist of two principal cellular components: nerve cells (neurons); and supporting cells (Schwann cells). If a nerve is damaged, Schwann cells transform into a specialised injury-specific cell type, called repair Schwann cells. These cells support the survival of damaged nerve cells and encourage nerve fibres (axons) to regrow, allowing the return of sensation and movement to the affected part of the body. Very little is currently known about the way repair Schwann cells bring about nerve repair, particularly which genes are important for their function. We also do not know the identity or origin of the signals that instruct Schwann cells to become repair cells.

I aim to define the function of several genes that are likely to be important for repair Schwann cell function and nerve regeneration. I will also identify signals released from injured axons that can instruct the transformation of Schwann cells into repair Schwann cells. 

Identification of new signalling molecules that regulate nerve repair will generate targets for drugs that could improve human nerve regeneration and provide novel therapies for patients with diseases that affect nerves.

Dr Benjamin Brown

University of Manchester

Actionable analytics linking patient, practitioner and population primary care

Despite increasing amounts of data from medical records that could be used to improve primary care, it is unclear how to use the data effectively.

I will develop a methodology to uncover relevant clinical actions directly from medical record data. I will build a user interface that continually improves the presentation of data for health professionals using randomised tests. I will evaluate how these methodologies translate to different healthcare systems in the UK and Canada and test a smartphone application that communicates these actions directly to patients.

This research will result in the development of a framework for generating and communicating clinical actions to practitioners and patients from medical record data, and specific software applications that can be used in clinical practice.

Dr Anita Chandra

University of Cambridge

B cell dependent susceptibility to airway infection in activated PI3K-delta syndrome

We have recently described an inherited immune disorder called activated PI3K-delta syndrome (APDS). The PI3K-delta protein generates chemical signals in immune cells but in people with APDS, PI3K-delta enzyme is too active which is unusual as most immunodeficiencies are due to a proteins having reduced function. As a consequence, APDS patients suffer from recurrent bacterial chest infections. B cells are immune cells that make antibodies that protect against infection, but in people with APDS, the B cells appear to contribute to disease and may be responsible for more severe infections, such as pneumonia.

We will use blood from patients with the syndrome and tissues from mice that have been engineered to have the same disease to determine how PI3K-delta causes APDS patients to be susceptible to pneumonia. We have also commenced a clinical trial to treat APDS patients with drugs that target PI3K-delta to determine if reducing PI3K-delta enzyme activity improves immune function and reduces infections.

These studies may also indicate if other people with immunodeficiency could benefit from drugs that target PI3K-delta.

Dr Angela Cristina Dias

King's College London

Deciphering mechanisms of altered neurodevelopment in BAF complex intellectual disability disorders

Intellectual developmental disorder (IDD) is a common condition. We still have a poor understanding of how mutations affect brain development and learning and I propose to contribute to that understanding by studying one of the most common causes of IDD: mutations in a group of genes called the BAF complex.

I will perform detailed clinical studies in patients to investigate associated health problems they may have, and I will try to identify markers in blood or saliva that can help predict outcomes. I will use stem cell models which can be transformed into brain cells, and cells derived from patients to study the function of these genes in early brain development.

This study will not only contribute to our clinical understanding of disease but also generate models for future research into therapies.

Dr Robert Hunter

University of Edinburgh

Message in a bottle: signalling from glomerulus to renal tubule via RNA in extracellular vesicles

Kidney disease affects 10% of people worldwide. There are no treatments for the tubular cell damage that invariably occurs in people with kidney disease. Many diseases begin in the podocyte cells of the kidney but progress through injury to the tubular cells but it is not understood why this happens. I hypothesise that diseased podocytes send injurious signals to tubular cells by packaging RNA into microscopic vesicles that travel from cell to cell in the urinary stream: a biological ‘message in a bottle’.

I will attach a tag to RNA made in podocytes so I can track the RNA signals as they move between cells. I will then extract the mobile RNA to read the encoded signal. I shall study living kidneys as well as cells grown in a dish to mimic a common kidney disease caused by diabetes. 

I aim to identify RNA signals that could be subverted to therapeutic effect using new RNA-based medicines.

Dr Joseph Jacob

University College London

Computer-based analysis of early fibrosing lung disease

Over 5,000 people are diagnosed with advanced, aggressive fibrosing lung disease (FLD) annually in the UK. Severe breathlessness precedes death which occurs within three to five years after diagnosis. It is essential to diagnose FLD early, before the lungs are irreversibly damaged. However, the human eye has limited ability in recognising subtle early changes of FLD on computed tomography (CT) scan images of the lungs.

We will use advanced computer tools to evaluate CT imaging and identify early stages of FLD. Repeated CT imaging in 20,000 patients participating in a London-based lung cancer screening study will be evaluated to identify early signs of FLD. Lung cancer screening populations are ideal to study early FLD, as smoking is a common risk factor for FLD and lung cancer.

The computer tool that we develop will eventually allow early identification of FLD in thousands of people worldwide.

Dr Christopher Lucas

University of Edinburgh

Macrophage-epithelial communication promotes lung repair after injury

Lungs are continually exposed to infections and toxins from the air we breathe. These infections frequently damage the epithelium which is the internal lining of the lungs. With severe damage, the epithelium can die and compromise lung function, and widespread epithelial damage is frequently seen in fatal lung infections. It is therefore vital that the lung can repair itself promptly, but this process is very poorly understood.

After lung injury, it is known that cells called macrophages are important for repair. After eating dead cells and exposure to substances present during injury, the macrophages release small fluid-filled communication ‘packages’ called microvesicles. Simultaneously, macrophages release a protein called IGF-1 which instructs epithelial cells to take up microvesicles. Higher levels of IGF-1 and microvesicles are associated with improved survival in patients with lung injury but the mechanism behind this is not yet understood.

We intend to investigate this process with the aim of informing treatments for lung injury.

Dr Peter MacPherson

Liverpool School of Tropical Medicine

A pragmatic randomised study to optimise screening, prevention and care for tuberculosis in Malawi (PROSPeCT Study)

Tuberculosis (TB) is the leading cause of death from infection worldwide. In Africa, HIV has led to very high TB rates, and progress towards reducing deaths from TB has been too slow. People attending clinics often do not get the tests they need and they have a high risk of dying before they begin their treatment.

This research will investigate a new strategy to find out how people with TB symptoms can be most effectively diagnosed and given TB and HIV treatment if needed. We will take chest X-rays from adults with TB symptoms in Malawi and use a new computer tool to identify X-rays that show any abnormality. We will then confirm TB disease in the clinic using a new rapid sputum test. We will test how good this strategy is at improving the timeliness of TB and HIV diagnosis and uptake of treatment by comparing it with the current method used to diagnose TB and HIV in the clinic.

This pragmatic trial will provide urgently needed information for patients and policy makers about how TB can be best diagnosed in areas where poverty and HIV are common.

Dr Omar Mahroo

University College London

Investigating mechanisms involved in retinal signalling in health and disease through detailed in vivo human electrophysiological investigation

The retina is the structure at the back of the eye that changes light into electrical signals. These signals travel to the brain allowing us to see. Short-sightedness is driven by abnormal signals in the retina, it is becoming more common and it can have complications that cause blindness. Although technology allows us to see single cells in the eye, it has not been easy to measure retinal electrical function. This project will address this.

We will make safe, non-invasive recordings of retinal electrical responses from large numbers of patients with retinal diseases and thousands of twin volunteers. This will help us understand how the retina works and why alterations in retinal function cause blindness or short-sightedness, opening the door to new approaches for developing treatments. As the retina has similarities with the brain, this can also help us understand some brain diseases.

We are testing new treatments that use gene and stem cell therapies to try to restore function to parts of the retina. This project will provide new ways of precisely measuring retinal function, so we know whether these treatments work.

Dr Emma Matthews

University College London

Skeletal muscle channelopathies: severe infantile phenotypes and sudden infant death syndrome

Electrical signals that control muscle contraction occur when ions move in and out of muscle cells. Ion channels lie across the muscle cell wall and act as a gateway for ions to move through. If a channel malfunctions, muscles such as those that are part of the respiratory system, cannot function properly. Pilot data implicates gene mutations in ion channels in severe conditions where infants’ breathing is impaired. We think this may include some cases of sudden infant death syndrome (SIDS)

I will look for ion channel gene mutations in infants whose breathing muscles are impaired and in SIDS. Using immunohistochemistry and RNA analysis I will determine if developmental changes in ion channels and muscle fibre types make the respiratory muscle of infants more susceptible to the effects of these gene mutations. We will develop a national registry of SIDS cases so we can better understand laboratory-based findings. 

This research will uncover a novel mechanism of respiratory failure in SIDS.

Dr Jacqueline Maybin

University of Edinburgh

Examining physiological hypoxia at menstruation to define the mechanisms that underpin endometrial resilience and heavy menstrual bleeding

Heavy menstrual bleeding (HMB) is a common debilitating condition. As its cause remains undefined, current medical treatments are non-specific hormonal therapies and the side effects mean that many women end up having surgery that can affect fertility. I have revealed that low oxygen levels (hypoxia) occur in the lining of the womb (endometrium) during menstruation and this drives repair after the lining has been shed. Women with HMB have a defective hypoxic response during menstruation. I significantly improved endometrial repair in a mouse model using an injection that mimics hypoxia,.

I will give mice and women oral medication that mimics physiological endometrial hypoxia to determine if it could be used as a novel, non-hormonal treatment for HMB that can also preserve fertility. Alongside these studies, I aim to determine specific actions of endometrial hypoxia at menstruation and its effects at other times in the menstrual cycle.

This research will lead to precise treatments for women with HMB with limited side effects and improved efficacy.

Dr Ruth Morgan

University of Edinburgh

Carbonyl reductase 1 and 20β-dihydrocortisol: a novel glucocorticoid metabolism pathway in the pathogenesis of mineralcorticoid activation in obesity

Glucocorticoids, such as cortisol, are hormones which regulate stress, inflammation, infection and blood pressure. Levels of glucocorticoids are tightly regulated by the brain and adrenal gland but also by individual organs. High glucocorticoid levels are associated with conditions such as obesity and high blood pressure, which are risk factors for heart attacks and strokes. Glucocorticoids are broken down in tissues by several metabolic pathways and this normally results in an inactive product.

We have discovered a pathway, called CBR1, which breaks down glucocorticoids into an active product which has strong effects on the receptors regulating blood pressure and salt balance. The enzyme responsible for this pathway is found in almost every tissue of the body. The pathway is up-regulated in obesity and there is evidence that it may be important in other diseases such as liver disease and cancer. Food and supplements may interfere with its action.

We aim to ascertain the role of this pathway in health and determine its importance in diseases such as obesity and high blood pressure.

Dr Alexander Rothman

University of Sheffield

Determining novel SMURF1 signalling pathways and precision medicine strategies in patients with pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a devastating disease caused by abnormal growth of cells in the wall of the arteries that supply blood to the lungs. Altered cell function leads to narrowing of the arteries, increased blood pressure in the lung and right heart failure. Patients experience shortness of breath and premature death. Despite differences in the underlying disease process, current treatment guidelines are identical for all patients and treatment options are limited to drugs that relax muscles in the blood vessel wall. Not all patients respond and many experience side effects. An alternative would be to target the cell growth that drives disease.

I have recently demonstrated that SMURF1 levels are increased in patients with PAH and that SMURF1 is critical to cell growth and disease. I will examine how SMURF1 functions in disease using biological techniques and new SMURF1 targeted drugs. I will try to find ways to identify patients who are most likely to benefit from this approach by examining clinical samples and data from the UK National Cohort, the world’s largest cohort of patients with PAH.

My findings will help to improve treatments for patients with PAH.

Dr Claire Scantlebury

University of Liverpool

Tackling histoplasmosis; a neglected disease impacting on equine health and human livelihoods

Histoplasmosis causes epizootic lymphangitis (EZL), a severe fungal infection that occurs frequently among working horses in Sub-Saharan Africa. This disease has a significant effect on the health and welfare of horses and a subsequent effect on the livelihoods of the people who depend on them for agriculture and transport. Little work has been done to understand how this disease is transmitted, meaning that the best methods for controlling the disease are unknown.

This research programme will investigate how this disease is transmitted in Ethiopia and The Gambia by analysing information about animal management as well as environmental and clinical samples. Molecular, biological and statistical analyses will be used to compare animals with and without EZL. We will establish the main routes for infection and investigate whether there are particular strains of histoplasma that contribute to disease and whether there are similarities between histoplasma species that infect horses and people. This project brings together an international team including experts in infectious disease, fungal pathobiology, global and population health and veterinary non-governmental organisations.

Findings will be shared with local communities, regional clinics and laboratories with the aim of designing achievable and practical prevention strategies.

Dr Sarah Stock

University of Edinburgh

Medicines in pregnancy: predicting harms and benefits of antenatal corticosteroids

Half of pregnant women are prescribed medicines, but the safety and long-term effects of many of these treatments remain unknown.

I will use new ways to get information about prescriptions that are given during pregnancy using computers to 'read' records and pull out data from Scottish electronic health records. I will then link this information to child health records. I will also ask international researchers to send me their data from birth registries and research studies. I’ll use the resulting ‘big data’ from 1.5 million women to study how medicines might lead to stillbirth or faulty brain development in their children. I’ll also look for ways to predict which women and babies are more likely to have complications and how we can minimise this.

The results of my study will be used to improve the way medications are prescribed in pregnancy to help reduce the risk of stillbirth or impaired brain development.

Dr David Thomas

University of Cambridge

The role of Eros in innate and adaptive immunity

Genes act as a code telling our cells which proteins to make. I have discovered a gene, which I have named Eros (essential for reactive oxygen species), which is essential for our immune system’s ability to kill harmful bacteria such as Salmonella. This is because the protein encoded by the Eros gene is needed for the stability of a complex of proteins called the NADPH oxidase, which generates chemicals, such as hydrogen peroxide, that kill bacteria and fungi. Without Eros, this process cannot occur. I have found that Eros also controls other important processes within the immune system that are unrelated to its effects on the NADPH oxidase, such as the behaviour of T cells.

I will investigate exactly why Eros has these diverse effects by using biochemical techniques to dissect what happens in its absence in different cell types.

My findings will give new information about how the immune system defends itself against harmful pathogens and may inform the design of new therapies.

Dr Alastair Webb

University of Oxford

Reducing risk of recurrent stroke and cognitive decline after transient ischaemic attack (TIA) and stroke through characterisation and treatment of novel physiological markers

Strokes, dementia and blood flow-related damage to the brain related to blood flow continue to occur despite excellent control of blood pressure and other recognised risk factors. Stroke is the second leading cause of death worldwide.

This study will recruit 1,000 patients already participating in a long-term follow-up study after having a stroke, who are receiving the best available investigations and treatments. We will use non-invasive techniques to measure the characteristics of these patients’ blood vessels and blood supply to the brain to assess how much these contribute to their ongoing risk of chronic injury to the brain or a further stroke. We will identify the most important abnormalities and systematically test potential treatments in a series of focused studies. This will include medications to expand blood vessels and control blood pressure, to determine which improve these measures and therefore have the potential to reduce the risk of stroke. Ultimately, we will test the effects of these agents in large clinical trials to determine their effect on recurrent strokes, death and other events.

This study has the potential to identify novel treatments that will significantly reduce the incidence of stroke and associated chronic brain injury and dementia.

2016

Dr Andrew Conway Morris

University of Cambridge

Regulatory T cell-neutrophil interaction in the development and maintenance of secondary pneumonia

Secondary bacterial pneumonia after influenza is a significant, worldwide health problem. Secondary infections were responsible for many deaths in the pandemics of 1918 and 2009. These infections also occur with seasonal influenza and with other respiratory viruses. It is striking that the bacteria that cause these infections commonly live harmlessly in patients’ throats beforehand, and it is unclear how this changes to cause disease.

In previous work I have identified several ways by which systemic inflammation can impair white blood cell function. The aim of this project is to evaluate whether these also facilitate secondary pneumonia and allow colonising bacteria to  cause disease. The goals are to determine whether blocking a key signalling molecule (PI3K delta) can prevent development of secondary pneumonia, and to explore the mechanisms by which influenza can impair white blood cells, looking at numbers and function of specific cell types. I will also set up a more life-like model of secondary infection arising from colonising bacteria and explore the changes in the microbes found in the lung (‘lung microbiome’) during infection, and how these may relate to secondary pneumonia.

The ultimate aim is to develop novel, non-antibiotic strategies for preventing and treating secondary pneumonia.

Dr Mariya Moosajee

Institute of Ophthalmology, University College London

Unravelling the molecular complexity behind ocular maldevelopment

Eye birth defects, known as ocular maldevelopment, including abnormally small eyes, clefts of the eye and complete absence of any eyes, occur within the first 4-9 weeks of pregnancy. They cause over a third of the cases of blindness in children worldwide, resulting in profound life-long problems for both the patient and their family. Only a few genes have been found to cause ocular maldevelopment, the majority remain undiscovered and currently there is no treatment available.

The goals of this study are to determine the genetic causes of ocular maldevelopment while carefully detailing the disease characteristics over time to see if any specialist care is needed to minimise associated health problems. Another aim is to identify chemical changes, called methylation, in our DNA that influence genes being switched on or off at crucial points during normal eye development, to form a reference guide for comparison with patients. Using this information, a 3D model of the developing eye will be made from stem cells derived from patient’s skin to investigate changes in genes that cause ocular maldevelopment. This will allow us to develop new therapies.

Once we understand the genetic causes, a real focus on treatments can be made. This study will allow accurate diagnosis and genetic counselling and improved care pathways for patients and families.

Dr Eleanor Raffan

University of Cambridge

Obesity: exploiting genomes for novel insights

When so many people share sedentary lifestyles and ready access to junk food, why do only some become fat? Evidence shows that 40-70% of the difference is down to genes, but only a fraction of those responsible are known. I study pet dogs to find links between genes and obesity. Dogs are commonly obese, share genes and lifestyles with humans and selective breeding means they have unusual genetics which can be helpful when trying to identify obesity genes. Labradors are prone to obesity and they are notoriously obsessed with food. I recently showed that a quarter of Labradors have a genetic mutation, known as POMC, which breaks a brain mechanism that usually switches off hunger.

I intend to study Labradors to learn about how the affected gene controls the body’s energy balance. The affected part of POMC is important in people but different in rodents so it has been difficult to study before. I will also test several other breeds of dog to find new obesity genes. Early results show that my approach works and the genetic areas identified are important in humans too.

Comparing dogs and humans will identify genes influencing obesity in both which can be targeted for future study with the aim of understanding the biology obesity and how to treat it.

Dr Carlo Rinaldi

University of Oxford

The role of BMP signalling in diseases of the motor unit

Spinal and bulbar muscular atrophy (SBMA) is a genetically transmitted neuromuscular disease characterised by muscle weakness and atrophy secondary to dysfunction and death of motor neurons. Recent evidence about SBMA and other neuromuscular diseases has shown that skeletal muscle also plays a critical role in the disease and strongly influences motor neuron survival. These observations hold great potential for therapeutic pathways, particularly because muscle is much more accessible than motor neurons for pharmacological intervention.

The focus of my research is to understand the mechanisms causing the muscle atrophy in SBMA and how muscle signals back to motor neurons to affect their function. In this study I will investigate the role of the bone morphogenic protein (BMP) pathway in SBMA. The reasons why I chose to study this pathway are because the BMP pathway has been recently found to be the most important regulator of muscle mass and BMPs are known to act as muscle-secreted retrograde signals to motor neurons. Preliminary data have shown that this pathway is severely dysregulated in SBMA.

This work has the potential to pave the way to develop a new therapeutic strategy for SBMA and other neuromuscular diseases.

Dr Anna Seale

London School of Hygiene and Tropical Medicine

Which maternal infections are associated with stillbirths and early neonatal deaths in East Africa?

Reducing stillbirths and deaths of babies shortly after birth is an international public health priority. Many of these deaths are caused by infections passed on from the mother. Identifying the infections is important for devising vaccination or treatment, but there is not much data on this.

I propose to describe which maternal infections contribute to the deaths of babies in Kilifi, Kenya, and Harar, Ethiopia, where child mortality is very high and three times that of Kilifi. I will begin by investigating mothers who had their baby at Kilifi County Hospital, Kenya from 2011-16. I will include 350 mothers with stillbirths or babies who died shortly after birth and 350 women who had a healthy baby. I will test stored maternal blood samples for infection and compare the two groups. Then, in a prospective study in Hiwot Fana Hospital, Harar, I will recruit similar numbers of mothers at delivery and test for infection using traditional and new laboratory methods.

This study is based at a new site for the Child Health and Mortality Prevention Surveillance (CHAMPS) network. As this network widens it will be possible to use the results to design studies investigating births outside hospital as well as preventive public health measures.

Dr Andrew Swift

University of Sheffield

Stratification and phenotyping of pulmonary vascular disease with imaging

Pulmonary hypertension (PH) is when a person has high blood pressure in their pulmonary arteries. They patients are short of breath, fatigued and have poor life expectancy. Even in the pure form, called idiopathic pulmonary arterial hypertension (IPAH), there can be big differences in the disease from patient to patient. There is a big challenge to better understand the different types of disease, particularly IPAH and lung diseases, in terms of genetics, response to treatment and life expectancy.

I aim to develop a better way to diagnose patients using computer-based methods to combine information from magnetic resonance images (MRI), together with computed tomography (CT scans). I will also identify patients with common clinical and scan features (called phenotypes) and predict life expectancy. Working with the national IPAH cohort, I will perform a detailed analysis of CT and MRI scans comparing genetic mutations. In addition, working with researchers in the USA on a group of patients with chronic obstructive pulmonary disease (COPD), I will use patient images alongside genetic data to investigate which patients are prone to developing PH, how PH is related to lung disease in COPD and the effect on life expectancy.

Dr Lance Turtle

University of Liverpool

Understanding cross-reactive immunity to Japanese encephalitis virus

Japanese encephalitis (JE) virus is transmitted by mosquitoes and causes brain swelling mostly in children in Asia. It is a member of a family of viruses that includes yellow fever, dengue and Zika. The body responds to viruses by making antibodies. For this family of viruses, antibodies against one virus can cross-react with another virus, because they are all similar. Surprisingly, this cross-reaction can make a second infection worse. This is a particular problem with dengue. However, the cross-reaction can also be helpful. Studying cross-reactions where these viruses naturally occur is difficult, because you cannot tell which virus was first.

This study has a new way of getting round this problem. I will give a live JE vaccine to people in the UK. The body makes antibodies to a live vaccine in the same way it does for a real infection. I will then test the antibodies of the participants who I will split into two groups: people who have never been exposed to these viruses and those who have been vaccinated against yellow fever.

The aim is to identify helpful cross-reactions and minimise the harmful cross-reaction.

Dr Rimona Weil

Institute of Cognitive Neuroscience, University College London

Using visual dysfunction to understand dementia in Parkinson’s disease

Although Parkinson’s is a disease affecting movement, it can also cause problems with thinking and memory. Parkinson’s affects people in different ways, making it difficult to predict what will happen to each patient. If there was a reliable way of telling who will develop dementia, we could work out who would benefit most from early treatments to prevent it. I have developed a sensitive visual test for people with Parkinson’s that can detect whether the ‘thinking’ parts of the brain are involved even before the memory is affected. This test may predict who will get dementia. I have also developed a website where people can sign up to take part in the study.

The aim of this project is to use visual tests combined with brain scanning techniques to understand how dementia develops in Parkinson’s. I want to find out whether this visual test can pick out who will develop dementia before they show any memory problems, what are the changes in structure and wiring in the brains of patients that do not perform as well in the vision test and whether vision tests explain why some patients have distressing hallucinations.