Find out about the winners of the 2018 grant round and their projects by clicking through the tabs below.
Relationship of multi-morbidity with cancer incidence and outcomes in a large population cohort: use of data sciences methodology
Multi-morbidity, living with two or more long-term conditions (LTCs), is very common and is one of the major health challenges of the 21st century. Research has shown that multi-morbidity may be associated with delays in cancer diagnosis. However, until now researchers have only studied the relationship between multi-morbidity and certain types of cancers (colorectal, breast and ovarian cancer). In addition, we do not know which combinations (number and pattern) of multi-morbidity are associated with new cancer and poor cancer outcomes. Thus, there are significant gaps in the understanding of the relationship between multi-morbidity and cancer.
There is a large number of possible combinations of LTCs, and statistical models using traditional statistical methods may struggle in producing accurate results. In this study, we will apply some newer data sciences techniques to understand the relationship between different patterns of multi-morbidity and cancer.
This study will use the UK Biobank cohort, a database of approximately half a million people aged 37-73 recruited from the general population and linked with cancer registry and mortality registers, with a median follow up of 8 years. The findings will inform targeting of interventions to promote earlier diagnosis in multimorbid patients and improve cancer related health outcomes.
Risk stratification in RA patients with multi-morbidity and development of management algorithms according to individual need
Rheumatoid arthritis (RA) is a chronic musculoskeletal condition and a major burden on individuals, health and social care systems. In addition to RA, patients can accumulate several other medical conditions (‘comorbidities’). A key concern, highlighted through ‘National Voices’ is the lack of coordinated care for patients with multiple comorbidities. Although effective treatments for RA exist, only around a third of patients achieve optimal treatment targets, based on national data. A generalised approach to care alone, without taking into account individual and disease-specific characteristics, may partly account for this. Comorbidities in RA have been shown to reduce effectiveness of disease-specific treatment, with consequences on function, quality of life and survival, making patient management more complex and costly.
This study aims to develop a risk-based tool derived from individual predictors of poor function, work disability and reduced quality of life, that includes comorbidities. We will explore 25-year data from two of the largest UK RA cohorts, to identify the most important patient and disease-related factors that influence treatment outcomes in RA. This will guide development of specific algorithms and tailored management packages according to ‘risk’ for a more patient-centred approach to management that can be easily incorporated in routine clinical care.
Enthesitis is one of the hallmarks of Psoriatic Arthritis (PsA) and is defined as inflammation at the insertion of the tendons, ligaments, and capsules into bone. Enthesitis is an understudied aspect of the disease and ultrasound (US) scanning is an effective and easily accessible tool to assess it.
Secukinumab, which is a Interleukin 17 inhibitor, is now approved as a first line agent for PsA once patients have failed conventional disease modifying oral treatment. There is evidence to suggest that this newer biologic medication maybe more effective than the established anti-TNF-alpha biologic drugs in treating enthesitis.
We aim to recruit 50 patients who are to go on Secukinumab treatment and 50 patients who are to go on Anti TNF therapy and review them prior to going on treatment and then at 4 months use repeating the same clinical and ultrasound assessment.
We aim to not only establish the prevalence of enthesitis in a cohort of PsA patients but also how this aspect of disease responds to treatment. Furthermore, we hypothesise that the baseline US enthesitis score can serve as a prognostic factor and allow patients to be stratified to more appropriate treatment in the future.
My laboratory is interested in self-assembling biological systems, from viruses to transcriptional control complexes, and takes an interdisciplinary approach towards mechanistic understanding of these events. Most recently, together with a long-standing collaborator: the mathematical physicist Prof Reidun Twarock, University of York, we discovered a novel mechanism that appears to regulate virion assembly in the family of viruses having ssRNA genomes.
Short, sequence-degenerate, dispersed RNA motifs having varying affinities for cognate coat proteins (CPs) allow regulated assembly initiation along defined pathways whilst ensuring that assembly is completed efficiently and specifically in the complex cellular milieu. Single molecule spectroscopy, native mass spectrometry, structure determination (crystallography and electron microscopy), together with mathematical modelling and geometry, have allowed us to identify such RNA Packaging Signals (PSs) and define their role(s) in assembly in viruses infecting bacteria, plants and Man. The conservation of the PSs and their recognition domains on cognate CPs across viral strain variants suggests that their interactions would be an excellent drug target.
In concert with colleagues at the National Institutes of Health, we have identified small molecule ligands specific for the PS-like motifs within Hepatitis B Virus pre-genomic RNA, and shown that these can be potent assembly inhibitors in cell culture, opening up novel anti-viral targets. We hope to apply similar techniques to Human Rhinovirus, where we also have evidence of PSs, during the HC Roscoe award.
Helen H Lawson grant to assist research into novel health technologies & T P Gunton grant to assist research into public health relating to cancer
There is no national population-based screening programme for prostate cancer. Yet the mortality rate from prostate cancer remains high, with 1 in 24 men dying from the disease, which is higher than other cancers with screening programmes. The current prostate-specific antigen (PSA) test is too unreliable for population screening and the national screening committee has called for further research into alternative tests.
This study, the PROSTAGRAM trial, is designed to look for new imaging tests which could be offered to screen for aggressive prostate cancer. The aim is to find an imaging technique, like mammograms for breast cancer, which could be used as a reliable screening test.
Men will be recruited from the community, attend a screening clinic and complete all tests in a single day. This will include a standard-of-care PSA test, a fast MRI scan lasting less than 15 minutes and a novel ultrasound technique measuring the stiffness of the prostate. The BMA Foundation grants have allowed the inclusion of prostate ultrasound in the design. PROSTAGRAM will be the first trial which will offer MRI and Ultrasound to men in the community and test their ability to detect aggressive prostate cancer in men independent of PSA.
Rheumatic heart disease (RHD) is the leading cause of cardiac death and disability in children and young adults in developing countries. On a global scale, the disease causes a similar number of deaths to major cancers such as breast and prostate but remains relatively neglected by funders and policy-makers alike.
Having been awarded the BMA Foundation Josephine Lansdell grant in 2012, we have taken some important first steps towards understanding the genetic basis of RHD, providing some explanation as to why only some individuals exposed to the causative bacteria develop disease. Nonetheless, we have not yet determined how HLA genes, which usually play a major role in autoimmune disease genetics, contribute to susceptibility.
The project funded by the Josephine Lansdell grant 2018 has been designed to address this issue and will involve more detailed analysis of our existing samples and recruitment of additional participants in India and Pakistan over an initial twelve months. Using these newly obtained samples, we will then do further targeted genetic analysis to confirm or refute what we have found in our existing sample collection. In the longer-term, this work could potentially have profound implications for the design of a much-needed vaccine against this devastating disease.
The impact of the asthma gene, ADAM33, on innate immunity and susceptibility to allergic airways inflammation
Asthma is common and affects about 5.4 million in the UK. Asthma runs in families suggesting a genetic predisposition that interacts with the environment and initiates the condition. A Disintegrin and Metalloproteinase 33 (ADAM33) is an asthma gene that is associated with asthma, twitchiness of the airways and decline in lung function in children and adults. ADAM33 makes an enzyme that is normally attached to cells in the airway muscle. In people with asthma, the ADAM33 enzyme loses its anchor to the cell surface and it is prone to going rogue around the lung causing poorer lung function.
Our previous study found that when rogue human ADAM33 was put into mouse lungs, it causes airway remodelling which results in more muscle and blood vessels around the airways but it did not cause inflammation. When a house dust mite allergen was introduced, which is a common human allergen, both airway remodelling and allergic airway inflammation were enhanced.
This study will now test if this rogue human ADAM33 in mouse lungs not only induces airway remodelling but also changes the underlying immune cell microenvironment in the airways which then promotes allergic airway disease and asthma. Blocking this rogue ADAM33 protein could become new treatment for asthma.
Emergency medicine is in the midst of a staffing crisis. From the first to the fourth year of specialty training half of trainees leave. This points towards a problem with retention. The exodus of senior trainees from the specialty puts added pressure on the remaining healthcare team and system which in turn makes further exodus more likely.
Research to study this problem, and work to remediate it, has focused on reasons for leaving. What has not been studied is why people stay. Retention of medical staff in emergency medicine was recently highlighted as a research priority, one this study aims to address.
The primary method for this study is ethnography. This will involve two twelve-week periods of intensive field work in two different departments where I will record field notes made during observations of the people and environment being studied. This will be supported by formal interviews with key informants from both research sites and from relevant national organisations, and a scoping review.
By increasing our understanding of retention in emergency medicine, changes and initiatives can be developed to help sustainable careers in emergency medicine and other related working environments.
An analysis of the serological, demographic, psychiatric and immunological characteristics of patients who developed lupus psychosis at University College London Hospital NHS Foundation Trust
Systemic Lupus Erythematosus (SLE) is a multi-system autoimmune disorder. Psychosis associated with SLE is a rare complication, which is little understood and affects approximately 2% of patients with SLE. It has a distinct clinical presentation, with an early and florid course that usually proceeds to remission, and is responsive to immunosuppressive and antipsychotic therapy.
In this study, we aim to utilise a large cohort of patients with SLE followed up over 40 years to further understand this fascinating complication. We will analyse the characteristics of patients who developed psychosis associated with SLE, and perform an array of antibody and antigen tests on their serum. The study will form pilot data for larger explorative studies on this interesting cohort, and ultimately contribute to our understanding of the immunologic basis of psychosis.
Investigating diabetes engagement, prescribing and outcomes in adults with diagnosis of schizophrenia and diabetes
Mortality rates for individuals with schizophrenia are twice that of the general population, and it is well known that individuals with schizophrenia have high levels of diabetes, along with other chronic diseases. Initial work in this area suggests that individuals with schizophrenia are experiencing suboptimal health screenings for diabetes.
This study aims to describe a cohort of people with a diagnosis of schizophrenia and diabetes, and compare them to similar people with diabetes and no evidence of schizophrenia. We will compare attendance at clinics and how many in each group have undertaken the usual diabetes checks. Admissions to hospital and mortality rates will be examined, along with cause of death data. The overall aim is to use novel machine learning approaches to see if there is a relationship between individual medicines or combinations of medications over time in the health of those in the cohort. If we can characterise this group of patients better, and understand how medications interact, we can review services to establish ways that this high-risk group of patients can access better diabetes care and get the best treatment for them.
Charcot Marie Tooth disease (CMT) is the commonest inherited neuromuscular disorder with an estimated prevalence of 1 in 2500 and CMT1A is the commonest genetic subtype accounting for 50% of all cases of CMT. Rapid advances in the field of genetic therapies have begun to focus on CMT1A, culminating in the recent successful preclinical study of a type of synthetic DNA (anti-sense oligonucleotide) therapy in two rodent models of the disease.
Clinical trials for antisense oligonucleotide therapy in CMT1A are on the horizon, however for these trials to provide meaningful results and for regulatory authorities to approve clinical trial protocols, robust trial designs must be established including the selection of sensitive outcome measures.
We have previously shown that measuring lower limb muscle fat content using MRI is sufficiently sensitive to detect disease progression in patients with CMT1A over 12 months. This study will investigate additional clinical, skin and blood biomarkers of disease progression in CMT1A and whether these correlate with changes in muscle MRI. The outcome of this research will be the validation of sensitive biomarkers of disease progression in CMT1A for use in clinical trials.
Scholarship Grant to assist research into the effectiveness of reasonable adjustments for patients with learning disabilities
Using a picture booklet as a reasonable adjustment to improve epilepsy management for people with learning disabilities
One in five people with learning disabilities has epilepsy, and their seizures are often frequent, severe and difficult to control with medication, having a negative effect on quality of life. People with learning disabilities and epilepsy often do not receive the same standard of care, services and investigations as the general population. Our previous research has shown that picture booklet intervention, used as a reasonable adjustment to epilepsy services, could benefit people with learning disabilities.
This study aims to explore the key features of the picture booklet intervention and how best to deliver the intervention in a routine care setting. People with learning disabilities and epilepsy will use the booklet in a routine appointment with a nurse, and we will also ask them to use the booklet at home. We will explore the key features of the intervention that may lead to improved epilepsy management and quality of life, and any barriers and facilitators to effective delivery. We will use these findings to produce written and audio-visual guidance for optimal use of the booklet, which will be shared with patients, carers and healthcare professionals.
Community diabetes services for adults with a mild or moderate learning disability: evaluating the impact of making reasonable adjustments
Health inequalities experienced by people with a learning disability are well known. Adults with a learning disability are twice as likely as the general population to be obese and, as a group, have low levels of physical activity. It is unsurprising therefore that people with a learning disability are more likely to develop Type 2 diabetes, which they do at an earlier age. Most people with a learning disability are in the mild to moderate range and access mainstream health services. Improving access to these services is therefore essential in addressing health inequalities.
The Equality Act 2010 mandated that reasonable adjustments must be made to healthcare services for people with a learning disability. However, it is unknown to what degree diabetes services have made the necessary adjustments, or if they have at all, and whether the adjustments are improving the health of this disadvantaged group.
The study will evaluate the implementation of recommended reasonable adjustments within community diabetes services from the perspective of service providers and service users. It will consider barriers to the implementation of reasonable adjustments and how to assess the impact of their implementation on relevant health outcomes.