University of Exeter Medical School PhD competition

The University of Exeter Medical School PhD Competition 2014 is now closed. However, the attached projects are potentially available for self-funded students.

Projects may be held on either a full-time (3 years) or part-time (6 years) basis. Successful applicants will pursue a project within one of the principal research themes of the Medical School - a) Diabetes, Cardiovascular and Ageing; b) Neuroscience; c) Environment and Human Health or d) Health Research. Candidates are invited to discuss project areas informally with potential supervisors and to indicate in their application which of the theme areas (and within these, which projects) are of most interest. Appointees will work with the relevant supervisor(s) to develop proposals fully for approval prior to registration.

Contact UEMS Graduate Research in the first instance for more detail:

UEMS-GraduateResearch@ex.ac.uk

How to apply

Applications are invited from suitably qualified graduates, 2:1 or above, in a suitable scientific

discipline. Non UK candidates must also have IELTS [International English Language Testing

System] score of 7 and above (or equivalent qualification).

Please send a CV, Covering letter (outlining your academic interests, prior research experience and

theme and research projects of interest and reasons for wishing to undertake the project) and

copies of transcripts of degrees/awards to UEMS Graduate Research

UEMS-GraduateResearch@ex.ac.uk

Funding Notes

The full-time stipend will be £13,863 pa. Tuition fees will be paid at the UK/EU rate. Candidates from countries outside the European Union will be liable for the difference between 'home student fees' and 'international student fees' which was £14,000 in 13/14 but is likely to increase slightly each year. Non-EU students who wish to be considered for the current studentships must confirm their ability to pay the international portion of the fee. If selected, financial assurances will be required. Please also note that because of UKBA requirements non-EU students will only be eligible for full-time studentships.

The potential PhD projects are listed below in alphabetical order according to the lead named supervisor

1

ANDERSON

UEMS Internal PhD studentship – proposed title and idea

From Rob Anderson, June 2014

How does health promotion become sustainable and get embedded within schools?

Within public health there is a sizeable research literature on the effectiveness and implementation of health promotion in schools, but most of this focuses on the initial implementation of new programmes under ‘research conditions’. As part of the NIHR School for Public Health Research, UEMS researchers have recently conducted a review of the implementation (including feasibility and sustainability) of health promotion in schools (Pearson et al, 2013). This produced a detailed synthesis of evidence about what factors and contexts are important for preparing for implementing a programme in schools, and for the phase of the first implementation. There was much less evidence about the longer term sustainability (or ‘embedding’) of health promotion in UK schools, or how health promotion programmes adapt and evolve in order to be acceptable and sustainable in the longer term. This PhD will yield a much-needed evidence base on how and why some health promotion programmes and activities continue and become an accepted ‘part of school life’, while others seem to disappear after the funding and trials have finished. It will do this through a mixed-methods approach, and an overarching theoretical framework such as May’s Normalisation Process Theory, and potentially also complexity theory to design and conduct: (a) a theory-driven review of international evidence about embedding health promotion in schools (b) a cross-sectional sample survey of schools and their long-sustained health promotion activities, and (c) qualitative follow-up case studies of schools who have been involved in a number of (completed) NIHR-funded and other large-scale trials of health promotion in schools, purposively sampling stories of both success and failure at sustaining the original health programme (both ‘early abondoners’ and ‘ongoing adapters’ etc..)

Pearson, M., Chilton, R., Buckley Woods, H., Wyatt, K., Ford, T., Abraham, C., & Anderson, R. (2013) Implementing health promotion programmes in schools: A realist systematic review of research and experience in the UK. Exeter: PenTAG, NIHR School for Public Health Research

Lead Supervisor: Associate Professor Rob Anderson (PenTAG, IHR, UEMS) - R.Anderson@exeter.ac.uk

2nd supervisor: Dr Mark Pearson (PenTAG, IHR, UEMS) - Mark.Pearson@exeter.ac.uk

3rd supervisor: Dr Katrina Wyatt or Dr Tamsin Ford (IHR, UEMS) or Dr Chris Bonell (Institute of Education, UCL, London)

2

ANDERSON/PEARSON/DEAN

Achieving change in public health evaluation practice: The development and application of ‘markers of implementation’

One of the increasingly recognised dimensions of the complexity of health and public health interventions is that effectiveness is strongly mediated by how well - and how flexibly - interventions or programmes are implemented (Medical Research Council 2008; Hawe et al. 2004). In implementation research, where the goal is to understand the ‘gap’ between an organisational decision to use an intervention and what happens in practice (Damschroeder et al. 2009), this ‘chain of evidence’ about implementation processes can be limited by weakly conceptualised and operationalised measures (or ‘markers’) of implementation in evaluations. While there has been some progress in measuring individual behaviour change of patients (e.g. Michie et al. 2011) and health professionals (e.g. French et al. 2012), ‘process markers’ in evaluations of population/public health interventions (for example, in schools, or workplaces) are weakly conceptualised and operationalised (Pearson et al. 2013). This PhD would develop a set of generic implementation process measures/markers suitable for use in evaluating public health programmes, pilot their use in selected evaluations, and explore how to promote the uptake and use of these measures by the UK public health evaluation community.

The ideal candidate would have a good (1st or 2.i) or masters degree in a social science or public health and an interest in public health.

Director of Studies: Associate Professor Rob Anderson (PenTAG, IHR, UEMS) - R.Anderson@exeter.ac.uk

2nd supervisor: Dr Mark Pearson (PenTAG, IHR, UEMS) - Mark.Pearson@exeter.ac.uk

3rd supervisor: Dr Sarah Dean (IHR, UEMS)

ReferencesDamschroeder, L.J., Aron, D.C., Keith, R.E., et al. (2009) “Fostering implementation of health services research findings into practice: a consolidated framework for advancing implementation science.” Implementation Science 4: 50

French, S.D., Green, S.E., O’Connor, D.A et al., (2012) “Developing theory-informed behaviour change interventions to implement evidence into practice: A systematic approach using the Theoretical Domains Framework.” Implementation Science 7:38

Hawe, P. (2004). "Methods for exploring implementation variation and local context within a cluster randomised community intervention trial." Journal of Epidemiology & Community Health 58(9): 788-793.

Medical Research Council (2008). Developing and evaluating complex interventions. London, Medical Research Council.

Michie, S., van Stralen, M.M., & West, R. (2011) “The behaviour change wheel: A new method for characterising and designing behaviour change interventions.” Implementation Science 6:42

Pearson, M., Chilton, R., Buckley Woods, H., Wyatt, K., Ford, T., Abraham, C., & Anderson, R. (2013) Implementing health promotion programmes in schools: A realist systematic review of research and experience in the UK. Exeter: PenTAG, NIHR School for Public Health Research

3

ANDERSON/PEARSON/STEIN

Scaling-up evidence-based health and social care service re-design: Conceptual development and application

Supervisory team: Rob Anderson, Mark Pearson, and Ken Stein

Service re-design to improve the quality and safety of health and social care services whilst reducing costs is a key service delivery priority. UEMS researchers are contributing to knowledge about how to implement evidence-based improvements in areas such as the integrated care of frail older people (Pearson et al. 2013), shared care in long-term conditions (Hardwick et al. 2013), and the delivery of health promotion in schools (Pearson et al. 2014). Many frameworks, such as PARIHS, RE-AIM, Normalisation Process Theory, and the Consolidated Framework for Implementation Research, have been proposed to structure investigation and understanding of complex implementation processes. However, there is a paucity of critical reflection on the utility of these frameworks in relation to scaling-up evidence-based service changes from local to regional level. This PhD research will draw on existing collaborations between UEMS researchers, healthcare practitioners and managers. It will develop, test and refine an implementation framework that conceptualises scaling-up processes in the provision of integrated care services which cross sectoral boundaries such as acute and community care. Developing advanced research skills in theory-driven review and case study methodology, the candidate will design and conduct a coherent programme of research involving, as appropriate, network or organisational ethnography, theory-driven evaluation, and/or discourse analysis of primary and/or secondary data.

Hardwick, R., Pearson, M., Byng, R. Anderson, R. (2013) The effectiveness and cost effectiveness of shared care for long term conditions: A realist review. Systematic Reviews 2: 12

Pearson, M., Hunt, H., Cooper, C., Shepperd, S., Pawson, R., & Anderson, R. (2013) Intermediate care: a realist review and conceptual framework. Final report. NIHR Service Delivery and Organisation Programme.

Pearson, M., Chilton, R., Buckley Woods, H., Wyatt, K., Ford, T., Abraham, C., & Anderson, R. (2014) Implementing health promotion programmes in schools: A realist systematic review of research and experience in the UK. Exeter: PenTAG, NIHR School for Public Health Research

4

ANDERSON/THOMPSON COON/PEARSON

Barriers and facilitators to the implementation of person-centred care in care homesSupervisory team): Rob Anderson, Jo Thompson Coon and Mark Pearson

The uptake of evidence-based person-centred care within nursing homes is variable. Aspects of care where this has been noted include routine nutrition screening on admission, appropriate prescribing of antipsychotic medications to individuals with dementia (Thompson Coon, 2014), management of medications to reduce poly-pharmacy, infection control and mealtime interventions to improve nutritional status (Abbott, 2013; Whear 2014). Internal (e.g. resident, clinician and care home characteristics) and external (e.g. regulation, development of guidelines) factors have been shown to influence change but the relationships are not uniform. The impact of organisational culture in this context is not well understood.

This PhD will seek to i) develop an explanatory framework of what is hindering and facilitating the implementation of person-centred care in care homes at the individual, organisation and system levels through realist review, ii) develop an implementation plan or simple intervention specific to an aspect of care taking into consideration organisational structure/culture, and iii) conduct a feasibility study to test and evaluate the impact of the implementation plan. The focus of the work and methods employed will be refined in light of emerging findings but may include using the Promoting Action on the Implementation of Research in Health Services (PARIHS) framework, an intervention mapping approach and qualitative interviews. The project will involve the collaboration of stakeholders (e.g. residents, families, care home staff and owners, GPs etc.) at all levels and in all stages to enable co-ownership of the findings.

Thompson Coon J, Abbott R, Rogers M, Whear R, Pearson S, Lang I, Cartmell N, Stein K. Interventions to reduce inappropriate prescribing of antipsychotic medications in people with dementia resident in care homes: A systematic review J Am Med Dir Assoc (under peer review).

Abbott RA, Whear R, Thompson-Coon J, Ukoumunne OC, Rogers M, Bethel A, Hemsley A, Stein K. Effectiveness of mealtime interventions on nutritional outcomes for the elderly living in residential care: A systematic review and meta-analysis. Ageing Res Rev. 2013 Sep;12(4):967-81

Whear R, Abbott R, Thompson-Coon J, Bethel A, Rogers M, Hemsley A, Stahl-Timmins W, Stein K. Effectiveness of mealtime interventions on behavior symptoms of people with dementia living in care homes: a systematic review.J Am Med Dir Assoc. 2014 Mar;15(3):185-93.

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5

CHILTON/JOURDAIN

The maintenance of healthy neuronal function by regulation of plasma membrane and cell shape

Supervisors: Dr. John Chilton (UEMS)

Dr. Isabelle Jourdain (CLES)

Defects in neuronal polarity or growth lead to neuronal death, brain atrophy and dementia but the underlying causes of degeneration remain obscure. Our strategy is to describe how a healthy neuron acquires and maintains its intricate, functional shape, apply this new knowledge to prevent the morphological changes leading to cell death and thus reverse disease processes.

Neuronal morphology and axon guidance are the result of complex interplay between the cytoskeleton and the cell membrane. Actin tracks are believed to deliver secretory vesicles to specific areas of the cell surface thereby controlling lipid and protein composition of the plasma membrane. Recent evidence indicates that the membrane in turn regulates the actin cytoskeleton but how this occurs is not understood.

You will tackle this question by exploiting the experimental power of the fission yeast S. pombe in conjunction with vertebrate neuronal cultures. The exocytic and actin machineries are highly conserved across evolution and many mechanisms that control cell shape are identical between species and cell types. Using a range of genetic, biochemical and fluorescent imaging techniques you will use yeast to identify the partners of the exocytic system in actin organisation and apply the conclusions to vertebrate neurons. These data will provide novel insights into the mechanisms of a range of human neurological disorders.

References:

Bloom & Morgan (2011) Mol. Cell. Neurosci. 48:339-348

Jourdain et al. (2012) Traffic 13:1481-1495

Tojima et al. (2014) J. Neurosci. 34:7165-7178

6

CORY

Giles Cory – University of Exeter Medical School

2014 – Internal Ph.D studentship summary

Making the Message Stick – mRNA localisation tells cells where to go.

Technological developments in science are allowing us to ask new questions about the organisation and control of cellular behaviour. Next-generation sequencing can quantify the copy number of each mRNA transcript within a cell, providing huge amounts of information on cellular regulation and function.

We have refined this technique to quantify the mRNA transcripts present at different locations within a cell, generating an unbiased catalogue of messages ‘delivered’ to a specific address. Our particular focus has been to identify a sub-population of mRNAs enriched at sites of cell/matrix adhesions. These adhesive sites are crucial controllers of cell migration and invasion –processes acquired by aggressive cancers cells enabling them to colonise secondary tissues. By understanding how, where and when this mRNA localisation occurs we are hoping to highlight possible therapeutic targets to combat the spread of tumours around the body.

The Ph.D project will use methods such as fluorescent microscopy (confocal and TIRF), genetic manipulation, cell culture and quantitative PCR to define the components of the mRNA targeting mechanism and elucidate their role in cell adhesion and migration.

Further reading

mRNA localization: gene expression in the spatial dimension.

Martin KC, Ephrussi A. Cell. 2009 Feb 20;136(4):719-30.

http://www.ncbi.nlm.nih.gov/pubmed/19239891

7

CROSBY/CHILTON/DAWE

Characterisation of genetic and molecular changes causing hereditary spastic paraplegia

Supervisors: Prof. Andrew Crosby (UEMS)Dr. John Chilton (UEMS)Dr. Helen Dawe (CLES)

The hereditary spastic paraplegias (HSPs) are a large group of motor neurone diseases causing weakness and disability of the lower limbs, although many other neurological as well as non-neurological features may be present. In Exeter we have found 10 new genes that may cause this condition, providing important new insight into the causes of the disease and identifying potential new treatment options for some forms. Two of these genes were discovered as part of an ongoing investigation of inherited disease amongst the Amish communities of Ohio, USA (see www.WOHproject.org). The first of these genes is ‘maspardin’ responsible for Mast syndrome, in which the HSP is associated with an early onset form of dementia. The second gene is ‘spartin’, in which the HSP is associated with difficulties with speaking, and poorly coordinated movement. While various cellular roles for spartin have been proposed, the function of maspardin remains entirely unknown. This project aims to investigate the role of spartin and in particular maspardin, to enable us to consider new possible treatment therapies. This project will use a range of cellular studies including modern fluorescent imaging approaches, to understand the function of these molecules. It will also use a range of cutting edge genetic techniques to investigate other related forms of HSP in order to find new genes that may cause these motor neurone disorders. A trip to the Amish community to visit patients with these conditions may also be possible as part of the ongoing community genetic program.

References:Patel et al. (2002). Nat. Genet. 31(4):347-8Simpson et al. (2003) Am. J. Hum. Genet. 73:1147-1156Noreau et al. (2014) Exp. Cell Res. 325:18-26

8

DICKENS/WATKINS/WINYARD

Exploring mechanisms by which inflammatory processes influence mood among people with chronic physical illness: a PhD proposal.Supervisors: Chris Dickens (UoEMS), Ed Watkins (UoE Psychology) and Paul Winyard (UoEMS)

Up to one quarter of individuals with chronic physical illness may also suffer from depression, compared to 2 to 3% in the general population. Such depression in people with chronic physical illness is important as it adds to the symptom load and disability of the affected individual, but also predicts worse medical outcomes, such as increased morbidity and mortality. The causes of such depression in the physically ill are multi-factorial, though recently there has been growing interest in the role of inflammation and inflammatory mediators in contributing to the development of depression in those with physical illness. Observational and experimental studies have shown that increases in inflammation are associated with increases in depression. Furthermore, clinical administration of Interferon alpha (IFN-α), which greatly increase level of inflammatory mediators, is associated with development of major depression up to one third of patients, which can lead to discontinuation of the treatment or even suicide, but which is preventable in many by pre-treatment with antidepressants. A number of mechanisms have been proposed to explain the links between inflammation and the development of depression, though it remains unclear i) who is most at risk from inflammation associated depression, ii) which components of the inflammatory response are associated with the development of depression and iii) the mechanisms by which increases in inflammation / inflammatory mediators influence psychological processing to result in depression. This PhD would be suitable for a student interested in science at the interface between physiology and psychology. Findings from this PhD could help identify which people with inflammatory disease are at greatest risk of developing depression, which in turn could lead to the development of novel interventions to reduce depression and improve medical outcomes. More importantly, findings of this PhD could elucidate basic mechanisms underlying the natural history of depression in the population at large.

1) Poole, L. Dickens, C. Steptoe, A. The puzzle of depression and acute coronary syndrome: Reviewing the role of acute inflammation. J Psychosom Res. Aug 2011; 71(2): 61–68.

2) Miller AH. Norman Cousins Lecture. Mechanisms of cytokine-induced behavioral changes: psychoneuroimmunology at the translational interface. Brain Behav Immun 2009;23:149-158.

9

EGGLETON/GUTOWSKI/SMERDON/MICHALAK

Project Title: The role of calnexin in T-cell trafficking across the blood-brain barrier in multiple sclerosis disorders in vitro and in vivo

Applicants: Paul Eggleton (UEMS), Nick Gutowski (UEMS, UK), Gary Smerdon (DDRC Healthcare, UK) & Marek Michalak (UEMS and Edmonton, Canada).

Proinflammatory T-cells in MS patients cross the blood-brain barrier (BBB) becoming sensitized by as yet unknown mechanisms to proteins specific to myelinating oligodendrocytes within the central nervous system (CNS) 1. Our immunopathology groups in Exeter and Canada study the function of endoplasmic reticulum chaperones including calnexin (CNX) 2. Our combined data implicates a role for CNX in MS, as we have shown CNX-deficient mice are resistant to experimental autoimmune encephalomyelitis (EAE) and observed that CNX protein is over-expressed in MS patient brains. The tissue location and inflammatory phenotype of T-cells isolated from CNX-deficient mice differ from wild-type EAE mice. We will investigate changes in the expression of key molecules involved in T-cell tissue distribution in the context of CNX deficiency in mice and overexpression in MS patients. As CNX deficiency may alter adhesion or trafficking of T-cells to the CNS, we shall identify differences in the adhesion/target molecules on the surface of T-cells from wild-type and CNX-deficient mice and from human T-cells in which CNX has been deleted in vitro. Finally we will study in vitro and in vivo trafficking of T-cells across brain endothelial cells, and investigate oxidative stress treatments that alter CNX expression and how that effects T-cell trafficking. The candidate will get the opportunity to study in Canada.

Refs:

1. Holley J, Bremer E, Kendall AC, De Bruyn M, Helfrich W, Tarr JM, Newcombe J, Gutowski NJ & Eggleton P. CD20+ inflammatory T-cells are present in blood and brain of multiple sclerosis patients and can be selectively targeted for apoptotic elimination. Multiple sclerosis and related disorders 2014 (In Press)

2. Kraus A, Groenendyk J, Bedard K, Baldwin TA, Krause KH, Dubois-Dauphin M Dyck J, Rosenbaum EE, Korngut L, Colley NJ, Gosgnach S, Zochodne D, Todd K, Agellon LB & Michalak M. Calnexin deficiency leads to dysmyelination. J Biol Chem 2010;285:18928-38.

10

GARSIDE/GWERNAN-JONES/BRITTEN

Meta-study: transforming qualitative research synthesis for evidence-based practice

Ruth Garside, Senior Lecturer in Evidence Synthesis, ECEHH; Ruth Gwernan-Jones, Associate Research Fellow, PenTAG; Nicky Britten, Professor of Applied Healthcare Research UEMS.

There's nothing so practical as good theory (Lewin, 1951)

OutlineThis PhD will apply an innovative method of evidence synthesis for qualitative

research, meta-study, to two case studies and explore with researchers and policy makers how this method impacts on the reviews’ reliability, utility and value.(1)

Evidence-based practice is the cornerstone of medical decision-making. Systematic reviews are at the top of the evidence hierarchy. Systematic reviews of qualitative research evidence are gaining increasing credence to complement reviews of effectiveness based on quantitative trial data. Qualitative evidence syntheses can provide information about how to implement interventions successfully, the socio-cultural contexts which may impact on effectiveness for different people or in a given locality, as well as how different people experience conditions, their treatment and services. Methods for the review and synthesis of qualitative research evidence are still in development, but standard practice involves methods such as thematic analysis or meta-ethnography. In such approaches the themes and concepts across research projects on a shared topic are brought together to produce a synthesised account that encompasses all the existing studies.(2) These methods have been influenced by approaches to systematic review for quantitative evidence, and do not fully take account of the variability in theoretical and methodological approach taken across qualitative research traditions. Typically then, existing synthesised accounts pay more attention to the findings of the studies than the epistemological and ontological frameworks that produce these findings. Meta-study explicitly addresses this lack.

The candidate will explore how findings from two existing syntheses, undertaken by the supervisors and produced using synthesis methods currently established as standard, would be transformed by the additional application of meta-method and meta-theory (steps in meta-study). This represents the further development of a sophisticated method of synthesis of qualitative research that has, thus far, been little used by researchers.

The candidate will appraise the resultant meta-studies through seeking feedback from researchers (systematic reviewers and qualitative researchers from different disciplines) and policy-makers (both within healthcare and other arenas where systematic review methods are less commonly applied), about the value and utility of the meta-studies in transforming understanding of a phenomenon and producing policy relevant findings.

1. Paterson B, Thorne S, Canam C, Jillings C. Meta-study of qualitative health research: a practical guide to meta-analysis and meta-synthesis. Brink P, editor. Thousand Oaks, California: Sage Publications; 2001.2. Noblit GW, Hare RD. Meta-Ethnography: Synthesizing qualitative studies. London (England): Sage Publications Ltd; 1988.

11

GOODING/SHORE

Classifying diabetic retinopathy using an integrated approach

Supervisors: Dr Kim Gooding and Professor Angela Shore

Diabetes related eye problems, known as diabetic retinopathy (DR), is the leading cause of blindness in the working age population in the western world. Dysfunction of the small blood vessels at the back of the eye (retina):  excessive leakiness (haemorrhages / macular oedema) and ischaemic (impaired blood flow / oxygen delivery) changes, are primary contributing factors to the development and progression of DR.

DR is currently diagnosed and monitored by grading colour retinal photographs for vascular morphological abnormalities eg microaneurysms, haemorrhages and cotton wool spots. However, the current screening grading scale isn’t always effective in identifying patients with early signs for clinical significant macular oedema (back of the eye becomes swollen due to fluid accumulation) or fast progressing, proliferative DR, both of which are sight threatening if untreated. What is needed is a more robust method to diagnose individuals at most risk of future complications and to do this early in the progress of retinopathy so treatments can be instigated.  The student will investigate whether classifying DR in relation to its underlying pathology (eg ischaemic vs leakiness) may be a more effective method of identifying patients ‘at risk’ of sight threatening complications. To achieve this they will use an integrated approach by, for example, implementing new software to provide novel information about how individual vessel abnormalities (microaneurysms) develop and regress over time (this is important as currently we simply count the number at a given time which is the result of how many microaneurysms are created and how many have been “healed”, individuals with many microaneuryms because they are not being “healed” may require completely different treatment to those with many microaneuryms who are also “healing” many), measuring the thickness of the macula and assess which components contribute to changes in thickness and exploring risk of diabetic retinopathy/ change of retina measurements with a combination of genotype and biomarker information including recruiting patients by genotype where appropriate.  Many resources are already available to enable the student to make excellent progress in their studies. These include the ongoing large, EU funded multi-centre SUMMIT study in which retina, genotype and biomarker data are available from 3 years ago and are now being repeated; over 20 years of clinical retinal photographs, and the Exeter 10, 000 bioresource of volunteers ready for recruit by genotype studies. The project will offer the student opportunities to train in experimental medicine research with particular emphasis in eye physiology and pathophysiology, epidemiology, bioinformatics and to an excellent understanding of the diagnostic framework needed to create new genomic/biomarker/imaging diagnostic tools.

12

GOODWIN/ABBOTT/TARRANT

Proposed PhD Title: Mealtime interventions and the health, quality of life and well-being of older people in residential care

Supervisors: Dr Rebecca Abbott, Dr Vicki Goodwin, Dr Mark Tarrant

Malnutrition is one of the greatest threats to the health, wellbeing and autonomy of older adults, particularly those living in care homes. Older individuals identified at risk of malnutrition have poorer quality of life, are more likely to be admitted to hospital, and are at increased risk of mortality. Furthermore, mealtimes have a critical socio-cultural role in care; ‘enjoying food and being able to eat food’ are central to the UK Government’s nutrition action plan. Whilst the need to improve nutrition of older people living in care has long been recognised, how this can best be achieved and whether (and which) interventions are successful in reducing morbidity and improving well-being is less understood. The proposed PhD will build on the findings from two of our recent reviews1,2 which suggest that simple changes to the mealtime environment, such as provision of real food snacks, the style of food service, seating arrangements (group or alone),the playing of music and the ambience of the dining room can significantly impact resident health and well-being. These findings, however, need to be supported by controlled, pragmatic studies that take into consideration care home policies and staffing.

References:

1 Abbott RA, Whear R et al Effectiveness of mealtime interventions on nutritional outcomes for the elderly living in residential care: A systematic review and meta-analysis. Ageing Research Reviews, 2013; 12: 967-981

2 Whear R, Abbott RA et al. Effectiveness of mealtime interventions on behaviour symptoms of people with dementia living in care homes: A systematic review. Journal of the American Medical Directors Association, 2014; 15: 185-193

For further information please contact Dr Mark Tarrant (m.tarrant@exeter.ac.uk); Dr Vicki Goodwin (V.Goodwin@exeter.ac.uk) or Dr Rebecca Abbott (R.A.Abbott@exeter.ac.uk)

13

GREENDirector of Studies/Supervisor – Prof Colin Green, Health Economics

Supervisory Team TBC

PhD Topic

The development of methods to model Alzheimer’s dementia (AD) over time for use in health technology assessment (HTA). 

The current methods available for modelling AD progression offer useful insights but all have limitations.  The main concerns, raised in previous reviews, are on model structure.  One of the key limitations with current methods is on the limited characterization of disease progression through use of a narrow description of the natural history of AD (e.g. using broad categories for cognitive function), and on the use of a limited number of health states to capture events related to disease progression over time (e.g. moving into full-time care setting).  Advances are needed in the methods available to model disease progression in AD in order to capture the effects of AD on people’s lives and to quantify the influence of health technologies on the experience of AD.  Proposals/plans here (for this PhD) include development of a descriptive system for AD using the key symptomatic domains of the condition, including cognition, function (ADLs) and behaviour/mood, and methods to predict disease progression through this descriptive system over time.  A model-based framework for assessment of AD progression over time, and related costs and outcomes, will be developed.  Such a model-based approach, using a descriptive system for AD, is expected to be sensitive to change in both symptomatic and disease modifying effects, and is expected to be able to support HTA, and the conduct of economic evaluation of health care interventions (such as those evaluations undertaken by NICE).

14

GREEN/SPENCER/MEDINA-LARA

Comparing generic and condition-specific preference-based (QALY) measures of health-related quality-of-life

This PhD will investigate health outcomes assessment in the context of health technology decision-making. Two prominent approaches for estimating health state values used in quality-adjusted life years (QALYs) will be compared. QALYs are a health outcome measure, commonly used in health policy settings, which incorporate both length and quality of life, with quality of life (health state values) estimated using preference-based measures. Such preference-based measures can be either generic or condition-specific. The most widely used generic preference-based measure, the EQ-5D, uses a simple descriptive system covering five dimensions of health, and it has been criticised for its limited applicability to certain conditions. This has led to consideration of the effect on health state values of adding ‘bolt-on’ dimensions to the EQ-5D descriptive system (such as vision or fatigue) (Longworth et al., 2013). However, there has been little, if any, consideration of the impact of the loss of dimension information when estimating health state values, as can occur with movements between generic and condition-specific measures. This PhD will explore the impact of information gain/loss on estimating health state values (Spencer et al., 2014) and the reasons for differences between generic and condition-specific measures. The PhD findings will have implications for the assessment of competing treatments in health technology assessments, as differences in health state values derived from generic/condition-specific measures can affect the decision to accept treatment (Rowen et al., 2012). Moreover, it will help to explain the additional contribution that condition-specific measures have in priority areas such as Multiple Sclerosis. The PhD will build on existing high quality health outcomes research already being undertaken within UEMS in the disease area of MS (Hawton et al., 2013), and will utilise data available to the Health Economics Group from the South West Impact of MS (SWIMS) longitudinal, a large (n=approx. 1,500) cohort study of people with MS.

HAWTON, A., SHEARER, J., GOODWIN, E. & GREEN, C. 2013. Squinting through layers of fog: Assessing the cost effectiveness of treatments for multiple sclerosis. Applied Health Economics and Health Policy, 11, 331–341.LONGWORTH, L., YANG, Y., ROWEN, D., TSUCHIYA, A., YOUNG, T. & BRAZIER, J. 2013. Development and valuation of a vision bolt-on to EQ-5D. Health Economists' Study Group conference, University of Exeter. Exeter ROWEN, D., YOUNG, T., BRAZIER, J. & GAUGRIS, S. 2012. Comparison of generic, condition-specific, and mapped health state utility values for multiple myeloma cancer. Value in Health, 15, 1059-1068.SPENCER, A., ROBINSON, A., PINTO-PRADES, J-L., Exploring differences between generic health states values derived using time trade off methods and choice based methods. iHEA conference Dublin 2014.

Lead Supervisor: Colin Green. Supervisors: Anne Spencer and Antonieta Medina-Lara.

15

HARRIES/GALLOWAY

Does Bisphenol A (BPA) cause human disease through epigenetic mechanisms?

Lorna Harries and Tamara Galloway.

Epigenetic modifications to our genome (DNA methylation, miRNA gene regulation and histone alterations) are now known to form a key interface between our genes, the environment and human health. This has particular importance for exposure to environmental chemicals, to which we all have near ubiquitous exposure, where exciting new data on human health effects are now emerging. Bisphenol A (BPA), for example, a synthetic oestrogenic compound widely used in food packaging has been shown to be causally-linked with disruption of cardiovascular and metabolic function. Despite these advances, the underlying mechanisms that lead to these associations are largely unclear. We have recently demonstrated that the effects of BPA on metabolism may act via changes to the expression of estrogen-responsive genes such as the estrogen-related receptor alpha (ESRRA) and estrogen receptor (ESR2) genes; major regulator of metabolic and immune function [1, 2]. In this studentship, we aim to examine the precise epigenetic mechanisms by which BPA may cause these effects. We will assess the effects of BPA on epigenetic regulation of gene expression at the level of a) DNA methylation and b) small RNA (miRNA) expression with a particular focus on genes involved in cardiac function, obesity or type 2 diabetes. Finally, we will assess the potential for population-level dietary intervention to reduce BPA exposure to levels which would be unlikely to cause health effects. This project will provide a robust and varied programme for a student resulting in highly employable skills, and delivering enhanced understanding of wider significance.

1. Melzer, D., et al., Bisphenol A exposure is associated with in vivo estrogenic gene expression in adults. Environmental health perspectives, 2011. 119(12): p. 1788-93.

2. Cipelli, R., et al., Bisphenol A modulates the expression of Estrogen-Related Receptor-alpha in T-Cells. Reproduction, 2013.

For further information please contact Dr Harries (L.W.Harries@exeter.ac.uk)

HARRIES/WEEDON/LOCKE

16

Functional characterisation of susceptibility genes for type 2 diabetes

Lorna Harries, Michael Weedon and Jon Locke

Type 2 diabetes (T2D) is a major public health problem in the UK. Genome-wide association studies (GWAS) have identified over 70 regions of the genome associated with susceptibility to this disease [1-3], but a large and critical gap exists in translating these findings into an improved understanding of the disorder. Many groups are working on how these variants may affect gene function, but very few are doing so at the level of the mRNA transcript. Over 90% of the associated variation is located in ‘non-coding regions’ of the genome, RNA-based mechanisms are therefore likely to play a major role in how polymorphic variants influence gene function. This work will test the hypothesis that RNA-based mechanisms are critical to how DNA variants translate to disease and provide mechanistic links between inherited genetic variation and disease susceptibility. We will assess the potential of genetic variants associated with T2D to disrupt genomic regions essential for 1) transcription 2) mRNA processing or 3) small and long non-coding RNA regulation of candidate genes in a large series of human pancreatic islet samples. This study will provide valuable insight into the molecular mechanisms by which genetic variation can lead to susceptibility to human common, chronic disease.

1. Perry, J.R. and T.M. Frayling, New gene variants alter type 2 diabetes risk predominantly through reduced beta-cell function. Curr Opin Clin Nutr Metab Care, 2008. 11(4): p. 371-7.

2. Zeggini, E., et al., Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science, 2007. 316(5829): p. 1336-41.

3. Voight, B.F., et al., Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat Genet. 42(7): p. 579-89.

For further information please contact Dr Harries (L.W.Harries@exeter.ac.uk)

17

HENLEY/LIN/LLEWELLYN

Title: A unifying approach to quantifying bias in sensitivity analysis for treatment effects

Research area: Health statistics

Director of studies: Professor William Henley

Other supervisors: Dr Nan Lin, Dr David Llewellyn

Project outline: This is an exciting opportunity to contribute to developing statistical methodology for quantifying bias when estimating the effectiveness of medical interventions. Risk of bias due to uncertainty about untestable assumption is common in both observational studies and randomised controlled trials. Complete control for the risk of bias is unlikely in practice, but its impact can be estimated by means of sensitivity analyses (Lin, Logan and Henley, 2013). The aim of this project is to develop a unifying approach for sensitivity analysis, facilitate efficient implementation and make the proposed approach accessible. The unifying approach will make it possible to systematically integrate the assessment of bias into conventional analyses for a range of statistical models (including logistic regression, survival analysis, Poisson regression, meta analysis) for both randomized and non-randomized studies. Application of these methods will help facilitate better research planning, reporting and decision making. The studentship is linked to a project funded by the MRC Methodology Research Panel and forms part of a growing programme of work on sensitivity analysis methods.

References

Lin NX, Logan S, Henley WE (2013). Bias and sensitivity analysis when estimating treatment effects from the Cox model with omitted covariates. Biometrics 69: 850-60.

18

HENLEY/RODGERS/MELZER

Title: Quasi-experimental methods for pharmacovigilance

Research area: Health statistics

Director of studies: Professor William Henley

Other supervisors: Dr Lauren Rodgers, Professor David Melzer

Project outline: Pharamacovigilance studies involving post-marketing surveillance of new drugs play a vital role in ensuring that patients receive safe treatments. One increasingly important approach is to study adverse drug reactions using longitudinal data from electronic health record systems. However, a major challenge in making use of these data is the problem of confounding by selective prescribing based on indication, severity, or prognosis (The European Network of Centres for Pharmacoepidemiology and Pharamcovigilance (ENCePP), 2013). In many cases the sources of confounding are unmeasured, preventing adoption of standard adjustment methods to remove bias. The prior event rate ratio (PERR) method (Tannen, Weiner, & Xie, 2009), and other recent developments in quasi-experimental analytic methods, offer a promising strategy for addressing unmeasured confounding in observational studies. This project will seek to extend and apply the PERR method to establish a framework for reducing confounding bias in drug safety studies. Given the range of adverse events that may be attributable to drug treatment, the PERR model will be extended to include competing risk events. Another important consideration, reflecting the need for long-term monitoring of drug safety events, will be exploring the performance of the PERR method in the presence of time dependent confounding. The project will make use of data from large-scale clinical databases, together with biologically realistic simulations, to evaluate methodological developments. This studentship will be based in the health statistics (Prof Henley, Dr Rodgers) and epidemiology (Prof Melzer) research groups, and will benefit from growing links with industrial partners.

References

Tannen, R. L., Weiner, M. G., & Xie, D. W. (2009). Use of primary care electronic medical record database in drug efficacy research on cardiovascular outcomes: comparison of database and randomised controlled trial findings. British Medical Journal, 338. doi:ARTN b81 DOI 10.1136/bmj.b81

The European Network of Centres for Pharmacoepidemiology and Pharamcovigilance (ENCePP). (2013). Guide on Methodological Standards in Pharmacoepidemiology (Revision 2).

19

KOS/GOODING

Diabetes and Microvascular function

Supervisors: Dr Katarina Kos (lead supervisor), Dr Kim Gooding (co-supervisor)

Obesity is associated with cardiovascular disease and the development of Type 2 diabetes. With increasing weight gain fat/adipose tissue is prone to become compromised with limitation of its capacity to store fat. A diversion of fat storage from adipose tissue to non-adipose tissue such as liver, muscle, heart and perivascular fat (which is also known as ectopic fat) occurs with increasing dysfunction of adipose tissue. There is increasing evidence that ectopic fat is pro-inflammatory and may be causing structural and functional harm to surrounding tissues, for example blood vessels [1]. In previous studies we demonstrated altered vascular function in obese individuals compared to lean individuals. Type 2 diabetes, preceded by insulin resistance, is also associated with vascular dysfunction, which contributes to the development of diabetes related complications in the eyes, kidney and heart. As obesity is closely associated with type 2 diabetes it is difficult to distinguish the vascular impairment resulting from diabetes from obesity. Exciting new evidence suggests that microvascular function improves with drastic weight loss such as in obese subjects after bariatric surgery however not in subjects with diabetes [2].

The overall objective of this project is thus to test the hypothesis that

Microvascular impairment is a result of diabetes rather than obesity.

This studentship will have the opportunity to take a patient to bench side approach with the student performing vascular assessments with state of the art microvascular laser Dopplers in human clinical studies as well as learning molecular biological techniques.

References:

1. Berg AH, Scherer PE. Adipose tissue, inflammation, and cardiovascular disease. Circ Res. 2005 May 13;96(9):939-49.

2. Martín-Rodríguez JF,et al. Effect of bariatric surgery on microvascular dysfunction associated to metabolic syndrome: a 12-month prospective study. Int J Obes (Lond). 2014.28. doi: 10.1038/ijo.2014.15.

20

KOS/WINLOVE/SCOTTON

Multi-photon image analysis and adipose tissue mechanics in diabetes

Supervisors: Dr Katarina Kos (lead supervisor), Professor Peter Winlove and Dr Chris Scotton (co-supervisors)

Obesity is associated with considerable metabolic complications, including diabetes. This is derived in part from an increasing dysregulation of fat/adipose tissue and limitation of its capacity to store fat. A diversion of fat storage from adipose tissue to non-adipose tissue such as liver, muscle, heart and perivascular fat (also known as ectopic fat) occurs with increasing dysfunction of adipose tissue. Type 2 diabetes is one of the complications of obesity, whereby insulin resistance results from overfeeding-induced changes affecting adipose tissue. This includes inflammation, and dysregulation of the extracellular matrix (ECM) composition - with an increase in the content of structural proteins such as fibrillar collagens [1,2]. The ECM in obese individuals therefore differs from that in lean subjects, with the presence of fat fibrosis (akin to excessive scarring of the adipose tissue). As a group we have a track record in investigating adipose tissue mechanics and function; we are able to assess fibrillar collagen content and ECM composition, plus the regulation of gene expression (mRNA and protein level) which relates to biomechanical properties [3]. The purpose of this study is to increase the understanding of changes in mechanical properties of fat tissue in diabetes and how a change in ECM structure of subjects with diabetes affects the storage function of adipose tissue, using cutting-edge multiphoton imaging microscopy and in vitro cell biology. Identification of the pathogenic processes which affect the ECM fibrillar structure of adipose tissue will aid development of therapies for diabetes treatment and its prevention.

The objectives of this study are therefore: To compare the composition of ECM and the mechanical coupling between cells and

matrix of subjects with/ without diabetes with novel biophysical techniques (multiphoton microscopy and CARS)

To determine the role of adipose ECM in fatty acid uptake and its storage

References:1. Spencer M et al. J Clin Endocrinol Metab. 2011;96(12):E1990-8.2. Tam CS et al. Diabetes. 2010;59(9):2164-70.3. Alkhouli N et al. AJP 2013. 305(12):E1427-35.

21

MELZER

ANALYSIS PATIENT RECORD DATA TO EVALUATE CLINICAL EFFECTIVENESS OF TREATMENTS

Director of Studies:  Prof David Melzer

Large-scale clinical record databases offer novel opportunities to examine the effects of treatment in groups who are seldom included in clinical trials.  This project will use primary care clinical records linked to hospital episode and mortality data on over a million older patients.  We will apply emerging statistical approaches including instrumental variables analysis and the prior event rate ratio approach (Tannen et al, BMJ 2009) to estimate likely effects of interventions in clinically important groups. Areas of particular interest include cardiovascular prevention and psychotropic drugs in older patients. This studentship will build on statistical, epidemiological or computational skills and will be based in the epidemiology (Prof Melzer) and medical statistics (Prof Henley) research groups.  For further information contact Prof Melzer at D.Melzer@exeter.ac.uk

Ref: Tannen RL, Weiner MG, Xie D. Use of primary care electronic medical record database in drug efficacy research on cardiovascular outcomes: comparison of database and randomised controlled trial findings. BMJ. 2009;338:b81.

22

MELZER

GENOME WIDE EXPRESSION STUDIES IN HUMAN POPULATIONS

Director of Studies: Prof David Melzer

The Melzer and Harries groups at UEMS have recently identified novel gene expression markers of key phenotypes of human ageing, by analysing transcriptome wide array data in human cohort studies. By studying gene expression in human blood we can identify promising biomarkers and gain mechanistic insight into diseases and traits relevant to ageing. Working with the Framingham Heart Study and the CHARGE collaboration, we currently lead the international meta-analyses of transcriptome wide data on muscle strength and other phenotypes of ageing. In this studentship we will explore gene expression signatures related to dynamic changes in phenotypes over time. We will also analyse data on the white cell subtype origins of key expression markers in blood. This studentship will build on bioinformatic, statistics or epidemiology skills and will be based in the epidemiology group (Prof Melzer) and molecular genetics (Dr Lorna Harries). .  For further information contact Prof Melzer at D.Melzer@exeter.ac.uk

REF: Harries LW, Hernandez D, Henley W, Wood AR, Holly AC, Bradley-Smith RM, Yaghootkar H, Dutta A, Murray A, Frayling TM, Guralnik JM, Bandinelli S, Singleton A, Ferrucci L, Melzer D. Human aging is characterized by focused changes in gene expression and deregulation of alternative splicing. Aging Cell. 2011 Oct;10(5):868-78. PMID: 21668623

23

MORGAN/RUSSELL

Role of STAT transcription factors in diabetes pathogenesis

Professor Noel G Morgan & Dr Mark A Russell

In both type 1 and type 2 diabetes, the pancreatic islet is exposed to a complex milieu of cytokines. Pro-inflammatory cytokines within this milieu (e.g. IL-6) can reduce pancreatic β-cell viability, whereas anti-inflammatory cytokines (e.g. IL-4, IL-13) are cytoprotective1, 2. Understanding the molecular mechanisms by which these proteins impact on β-cell viability (and function) may uncover novel pathways to therapeutically target in diabetes.

Our laboratory focusses on STAT family transcription factors which likely underpin many of the effects described above. We are particularly interested in STAT3 (activated by IL-6) and STAT6 (activated by IL-4 and IL-13) and are dissecting their roles in regulating β-cell viability and also examining whether they are altered in diabetes. Furthermore, we are functionally investigating novel rare mutations within the STAT3 gene which are implicated in early diabetes onset. To achieve these goals, our approach is to use a combination of cutting-edge molecular biological techniques in cell-based model systems alongside the use of more conventional histological methods in a unique bank of human tissue samples.

1. Russell MA, Cooper AC, Dhayal S, Morgan NG. Differential effects of interleukin-13 and interleukin-6 on Jak/STAT signaling and cell viability in pancreatic beta-cells. Islets 2013; 5.2. Kaminski A, Welters HJ, Kaminski ER, Morgan NG. Human and rodent pancreatic beta-cells express IL-4 receptors and IL-4 protects against beta-cell apoptosis by activation of the PI3K and JAK/STAT pathways. Biosci Rep 2010; 30:169-75.

24

MUJICA-MOTA/MELZER/HENLEY

Title: Evaluating the costs and health benefits of medical treatments used by older adults in routine practice

Director of Studies: Ruben E Mujica-MotaSupervisor: David MelzerSupervisor: William Henley (TBC)

The recent availability of large clinical record datasets has created the opportunity to use observational data from routine health care use and practice to evaluate the costs and health outcomes (markers) of commonly used medical treatments. Studies using such data may add to the evidence base generated from traditional experimental studies (i.e. randomised controlled trials (RCTs)), which are internally valid sources of treatment effects but often of limited generalizability to the relevant patient population, thus resulting in improved medical decisions in the NHS. Established methods of observational data analysis used in labour and education policies or programmes (Angrist and Pischke 2008) are increasingly being applied to the evaluation of health programmes and interventions. These include quasi-experimental methods of evaluation that employ ‘natural experiments’ arising from variations in the way patients are managed to produce treatment effect estimates that may be free from confounding and apply to a broader population than that included in RCTs. This PhD programme seeks to evaluate the strengths and weaknesses of natural experiment methods to assess the economic costs and health outcomes of treatments in older adults (aged 65+) and it is intended to inform methodological practice on using administrative observational data for health care economic evaluation. The prospective student will gain experience in methodological review using systematic methods, quantitative skills for managing and analysing large databases, applying health econometric principles to policy evaluation, and using the results of observational data analysis to populate health economic models informing NHS policy decisions. This studentship will build on econometric, statistical, epidemiological or computational skills and will be based in the Peninsula Technology Assessment group (Dr Mujica-Mota) with input from epidemiology (Prof Melzer) and medical statistics (Prof Henley) research groups.  For further information contact Dr Ruben Mujica-Mota (r.e.mujica-mota@exeter.ac.uk).

Angrist, JD & Pischke JS. 2008. Mostly Harmless Econometrics: An Empiricist's Companion. 2008. Princeton University Press. 392 pp.

25

MURRAY/WEEDON

The genetics of reproductive ageing:

Supervisors: Anna Murray (UEMS)Mike Weedon (UEMS)

More women are having children in their 30s than in their 20s for the first time in history, in the UK. Yet the risk of infertility increases exponentially after 35 years of age, with 50% of women not able to conceive naturally by the age of 40. Thus there is increasing need to resort to assisted conception techniques such as IVF to achieve a pregnancy. Natural fertility declines because the pool of eggs that women are born with are depleted gradually over a woman’s lifespan until they reach menopause. The end of reproductive life occurs about 10 years before menopause. Our group is interested in the genetic control of the reproductive ageing process. We have led several international collaborative projects in this area, which have resulted in publications in the top biological journals, eg. Nature and Nature Genetics. Our PhD students typically publish 4-5 papers during their studentship, which form the basis of their thesis.

This project will be involved in discovering new genes involved in reproductive ageing and determining what biological role those genes play. The project will use the extensive data resources available to the group, including access to genetic and phenotype information from half a million individuals in the UKBiobank study (http://www.ukbiobank.ac.uk/). We will also use data from the Exeter based study EXTEND, which has recruited 10,000 individuals and enables us to re-contact those carrying a particular genetic variant and investigate how it affects the individual. The project is a computer-based project and would suit someone with an aptitude for bioinformatics/computing/mathematics. Full training will be provided however from our multidisciplinary team of computer scientists, bioinformaticians, medics, molecular biologists and geneticists. The student will develop skills that will make them extremely employable in this era of ‘Big data’ and genomics.

For more information contact: Anna Murray a.murray@exeter.ac.uk

References:Perry et al. Parent-of-origin specific allelic associations among 106 genomic loci for age at menarche. Nature, in press.Stolk et al., Meta-analysis of genome-wide association studies of age at menopause: novel loci highlight DNA repair and immune pathways. Nature Genetics, 2012 Jan 22;44(3):260-8.

26

PETERS/COOPER/ANDERSON

Project Title: Identifying evidence to evaluate the cost-effectiveness of health care technologies: how systematic and transparent can, and should, we be?

Supervisors: Jaime Peters, Chris Cooper, Rob Anderson

Decision analytic models (DAMs) are routinely used in Health Technology Assessments to aid the decision making process when recommending new treatments or tests to be funded by healthcare systems, such as the NHS. DAMs are used to predict the costs and health impacts of different treatments, or test strategies over time, to evaluate their cost-effectiveness within a health care system. Results from DAMs are estimated to be responsible for the approval of 82% of new technologies in the UK between 1999-2013 (Helen Dakin., 2014), so their importance as a decision making tool is well established. A great deal of evidence is required to populate DAMs. This might include (but is not limited to): data on the clinical effectiveness of treatments or tests, associated costs, and the quality of life of individuals. These data might come from a variety of sources, such as: published randomised controlled trails, systematic reviews, grey or unpublished literature, or unpublished case study reports. In spite of the range of evidence which might be needed to populate a DAM, and the wealth of evidence sources to be considered, there is no methodological guidance on how to systematically and transparently search, identify and appraise, all of the evidence required for a DAM (Kaltenthaler et al., 2013). Whilst guidelines for reporting DAMs exist (Husereau et al., 2013), and international working parties are actively discussing the need for transparency in the evidence gathering process, transparent models are not common place. The lack of transparency in DAMs creates uncertainty about the relevance and credibility of the DAMs results, limiting the usefulness of these models for decision-making.

This PhD seeks to address this weakness. It will aim to identify methods to pragmatically, systematically and transparently identify evidence for DAMs and seek to develop a method of documenting the process of building the DAM, with a view to making the process and the model transparent.

For further information please contact Dr Jaime Peters (j.peters@exeter.ac.uk)

References

HELEN DAKIN., N. D., YAN FENG., NIGEL RICE., PHILL O’NEILL., DAVID PARKIN., 2014. The Influence of Cost-effectiveness and Other Factors on NICE Decisions: Research Paper 13/06r Office for Health Economics.

HUSEREAU, D., DRUMMOND, M., PETROU, S., CARSWELL, C., MOHER, D., GREENBERG, D., AUGUSTOVSKI, F., BRIGGS, A. H., MAUSKOPF, J. & LODER, E. 2013. Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement. BMJ, 346.

KALTENTHALER, E., TAPPENDEN, P. & PAISLEY, S. 2013. Reviewing the evidence to inform the population of cost-effectiveness models within health technology assessments. Value Health, 16, 830-6.

27

PITT/CHALK/BRITTEN

Project Title :Using agent-based simulation to predict individual behavioural changes in models of health and social care systems

Supervisors: Martin Pitt, Daniel Chalk, Nicky Britten

A focus on patient- or person-centred care is increasingly important in health and social care, and a growing factor for strategic decision making (e.g. healthcare commissioning). Traditional simulation modelling approaches such as discrete event simulation have been used to determine the potential impact of changes to clinical pathways, but necessarily assume an idealisation of the real world in which patients follow a prescribed protocol. Agent-Based Simulation offers a means of modelling a system in which patients are represented explicitly as individuals, with specific behaviours, characteristics and motivations. By modelling a population of patients as agents, it is possible to observe the emergent population-level dynamics of a system of individual behaviours, and determine the impact of both behavioural changes on the system, and system changes on behaviour. Agent-based simulation therefore offers an important way to model aspects of person-centred care, such as patient choice, one to one interactions, and person-centred outcome measures, in such a way that the potential reconfigurations of service systems can be assessed in a patient-centred context. The use of agent based simulation in healthcare is in its infancy with few studies demonstrating the potential benefits. This project would seek to explore the use of Agent-Based Simulation and assess its value in healthcare modelling. Specific case-study areas would be chosen to demonstrate the use of “what if” analysis for the assessment of alternative health and social care service configurations which more suitably meet the individual needs of patients, and improve individual patient outcomes.

Reference:Multi-agent systems for healthcare simulation and modeling; applications for system improvement (2010). Paranjape R and Sadanand. A. (eds). IGI Global

28

RICHARDSInvestigating a Novel, Sustainable and Ecological Psychological Therapy for Depression and Anxiety.

Supervisor: Professor David A Richards. http://medicine.exeter.ac.uk/about/profiles/index.php?web_id=david_richards

This project will investigate the feasibility, acceptability and preliminary efficacy of Morita Therapy (MT), a novel and sustainable treatment for depression and anxiety widely practised in Japan but unknown in the UK. Morita Therapy has its roots in Zen Buddhist philosophy. It helps patients to re-orientate themselves in the natural world and teaches that symptoms of depression and anxiety are part of the natural ecology of the human experience. Morita Therapy takes a ‘restorative’ or ‘revitalizing’ approach to potentiate the individual’s natural capacity for health. Morita therapists help patients’ move away from symptom preoccupation and combat, which interferes with this natural recovery process. Therapists encourage the emergence of the sustainable Morita Therapy concept of ‘desire for life’, grounded in an understanding of the place of human beings in the natural world. This mixed methods project will consist of feasibility and pilot work, both quantitative and qualitative, to develop and test MT in a UK clinical population. It will be part of a programme of work linking the Medical School with the School of Psychology and the NHS and will pave the way for a planned fully powered randomised clinical trial of MT.

Richards, D.A., Mullan, E.G., Ishiyama, F.I. and Nakamura, K. (2011). Developing an Outcome Framework for Measuring the Impact of Morita Therapy: A Report from a Consensus Development Process. Journal of Morita Therapy, 22:(2);165-173.

29

RICHARDSON/MORGAN

Investigation of the relationship between enteroviral infection and the development of islet cell autoimmunity in type 1 diabetes

Dr Sarah J Richardson & Prof Noel G Morgan

There is a considerable weight of circumstantial (epidemiological) evidence implicating infection with strains of enterovirus and the development of type 1 diabetes (T1D) in human populations. It has also been shown by ourselves, and others, that viral antigens can be detected in the pancreatic islets of T1D patients, suggesting that enteroviral infection may spread to the islets under some circumstances. However, the progression of such islet infections appears unusual in that large scale lysis of islet cells does not occur, as might be expected. Rather, we have evidence that a sustained, more persistent, infection develops in which viral replication is relatively low and direct cell damage is minimal. This represents a rather novel aspect of enteroviral biology which is still to be understood but we hypothesise that the presence of latent enterovirus in islet cells may lead to impaired handling of cellular proteins and that this leads to the aberrant presentation of antigens to the immune system leading to islet autoimmunity. In the present project, this hypothesis will be tested directly by the development of in vitro model systems in which cultured islet cells are infected with attenuated strains of enterovirus that are capable of developing persistent infections. The cells will then be monitored to discover whether they mount specific anti-viral responses, display evidence of increased stress or altered metabolism, aberrantly process islet antigens and display these on their surface in association with HLA Class 1 molecules and/or have altered secretory properties. The overall aim is to establish the influence of a persistent infection on beta –cell function and viability as a means to understand how autoimmunity might develop in type 1 diabetes.

References:

Richardson, S.J., Willcox, A., Bone, A.J., Foulis, A.K. and Morgan, N.G. 2009. The prevalence of enteroviral capsid protein, vp1, immunostaining in pancreatic islets in human type 1 diabetes. Diabetologia. 52, 1143-1151.

Richardson, S.J., Willcox, A., Bone, A.J., Morgan, N.G. and Foulis, A.K. 2011. Immunopathology of the human pancreas in type 1 diabetes. Seminars Immunol. 33, 9-21.

Richardson, S.J., Morgan, N.G. and Foulis, A.K. 2014. Pancreatic pathology in type 1 diabetes. Endocrine Pathol. 25, 80-92.

30

SCOTTON/GIBBONS/JAYASINGHE

Title: Development of a three-dimensional in vitro lung organoid model for pre-clinical drug evaluation

Lead supervisor: Dr Chris Scotton, Senior Lecturer, UEMS

Co-supervisors: Dr Michael Gibbons, RD&E Consultant and Honorary University Fellow

Dr Suwan Jayasinghe, University College London

Pulmonary fibrosis (PF) is the end stage of several interstitial lung diseases (ILDs), characterized by excessive matrix deposition and destruction of the lung architecture. In the UK, >5000 people die each year from the commonest form, Idiopathic PF (IPF) - and the incidence is rising. IPF has a five-year survival rate of only 20%; novel therapeutic strategies are therefore urgently required. A variety of animal models of PF are in common usage, but their applicability to the human disease is the subject of constant debate (1); no single model recapitulates all of the pathological features seen in PF, and throughput for pre-clinical screening is limited. In the human disease, epithelial-mesenchymal crosstalk is thought to be central to disease progression (2). The development of an in vitro lung organoid model, incorporating epithelium and fibroblasts in a relevant three-dimensional network, would be of enormous benefit for translational medicine, providing insight into the underlying biology of the disease and a high-throughput screening tool for anti-fibrotic agents. This could enable pre-screening of lead compounds as a viable alternative to testing in vivo, thereby having a significant impact on the ‘replacement, reduction and refinement’ of animal use in research. Our preliminary work has established that lung fibroblasts can self-organise into a three-dimensional spheroid. Using bio-engineering technology (3, 4), this studentship would establish the incorporation of airway epithelium into these structures, and investigate downstream epithelial-mesenchymal crosstalk to test the hypothesis that “Epithelial-fibroblast spheroids will provide a unique three-dimensional in vitro model of pulmonary fibrosis for screening of anti-fibrotic interventions”.1. Scotton, C. J., Chambers, R. C. (2010). Bleomycin revisited: towards a more

representative model of IPF? American Journal of Physiology - Lung Cellular & Molecular Physiology 299(4), L439-41.

2. Datta A., Scotton C.J. and Chambers R.C. (2010). Novel therapeutic approaches for Idiopathic Pulmonary Fibrosis. Br J Pharmacol. 163(1), 141-172.

3. Jayasinghe, S.N., Warnes, G., Scotton, C.J. (2011). Bio-electrosprayed living composite matrix implanted into mouse models. Macromol Biosci. 11(10), 1364-1369.

4. Peng, Y., et al. (2012). Human fibroblast matrices bio-assembled under macromolecular crowding support stable propagation of human embryonic stem cells. J Tissue Eng Regen Med, 6: e74–e86. doi: 10.1002/term.1560

For further information please contact Dr Scotton (c.j.scotton@exeter.ac.uk)

31

THOMPSON COON/GWERNAN JONES/ABBOTT

How can we improve the accessibility, utility and usefulness of systematic reviews?

Supervisory team: Jo Thompson Coon, Ruth Gwernan-Jones and Rebecca Abbott with support and mentoring advice from Ken Stein

Systematic reviews are recognised as being at the heart of evidence-based practice and the first port of call for those seeking solutions to their clinical uncertainties. However, the production of systematic reviews is not sufficient to ensure that their messages will be incorporated into routine practice; qualitative research suggests that there are many barriers to the uptake of evidence from systematic reviews (e.g. lack of awareness, lack of access, lack of usefulness). One approach that has been proposed to ensure that systematic reviews are accessible, credible and relevant is to involve stakeholders in their production. However, there are few published evaluations of stakeholder involvement in systematic reviews and little is known about the impact of this approach on the subsequent uptake of evidence.

Using a suite of systematic reviews (see below) recently completed by the NIHR CLAHRC South West Evidence Synthesis Team on topics relevant to the care home setting, this PhD will seek to i) explore and develop methods to assess the barriers and facilitators to the uptake of evidence into routine practice in this setting, ii) to use this information to develop guidelines for the effective involvement of stakeholders to ensure that systematic reviews are useful and the findings widely incorporated into routine practice, iii) to co-create a template for a communication strategy that could be used to share the findings of systematic reviews with a range of different audiences and incorporated into the standard protocols of future reviews and iv) to develop methods to assess the impact and value of stakeholder involvement in systematic reviews on subsequent uptake of research findings. The focus of the work and methods employed will be refined in light of emerging findings but may include using qualitative interviews, focus groups and surveys. The project will involve the collaboration of stakeholders at all levels and in all stages (e.g. residents, families, care home staff and owners, GPs etc.) to enable co-ownership of the findings.

Whear R, Abbott R, Thompson-Coon J, Bethel A, Rogers M, Hemsley A, Stahl-Timmins W, Stein K. Effectiveness of mealtime interventions on behaviour symptoms of people with dementia living in care homes: a systematic review. J Am Med Dir Assoc. 2014 Mar;15(3):185-93.

Abbott RA, Whear R, Thompson-Coon J, Ukoumunne OC, Rogers M, Bethel A, Hemsley A, Stein K. Effectiveness of mealtime interventions on nutritional outcomes for the elderly living in residential care: A systematic review and meta-analysis. Ageing Res Rev. 2013 Sep;12(4):967-81.

Whear R, Thompson Coon, Bethel A, Abbott R, Stein K, Garside R. What is the impact of using outdoor spaces such as gardens on the physical and mental well-being of those with dementia? A systematic review of quantitative and qualitative evidence. J Am Med Dir Assoc (in press).

Thompson Coon J, Abbott R, Rogers M, Whear R, Pearson S, Lang I, Cartmell N, Stein K. Interventions to reduce inappropriate prescribing of antipsychotic medications in people with dementia resident in care homes: A systematic review J Am Med Dir Assoc (under peer review).

32

VOS/GAZE

Experimental Lateral Gene Transfer in pathogenic bacteria

Supervisors: Michiel Vos and Will Gaze

Unit: Coastal Pathogens Group, European Centre for Environmental and Human Health

Location: Penryn Campus

The genetic diversity harboured by bacteria is enormous. Your own genome is made up of around 30.000 genes. However, your microbiome (the bacteria that live in and on you) encodes for millions of unique genes. One reason for this diversity is that bacteria do not only slowly accumulate point mutations, but that they are able to promiscuously exchange genes at a high frequency. This process of Lateral Gene Transfer (LGT) is fundamental to the evolution to bacteria, from the formation of distinct Phyla over hundreds of millions of years to the rapid evolution of antibiotic resistance over the course of the treatment of an infection. Much of our knowledge on LGT comes from retrospective sequencing studies. In this PhD project, we will design controlled experiments to directly quantify distinct modes of LGT. Using flow cytometry and genome sequencing, we will collect fundamental data on the rate at which genes are transferred under various relevant conditions, and how this can impact antibiotic resistance and virulence.

Please feel free to contact Dr Vos for more information (m.vos@exeter.ac.uk).

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WELTERS/WHATMORE/MORGAN

Title: Investigation of Wnt4 activated signalling pathways that lead to inhibition of proliferation and insulin secretion in pancreatic beta-cells

Supervisory team: Hannah Welters, Jackie Whatmore and Noel Morgan

Type 2 diabetes is a rapidly growing health problem estimated to become the 7 th leading cause of death worldwide by 2030. The pancreatic beta-cells produce insulin to regulate levels of blood glucose. Diabetes occurs when insufficient insulin is produced to maintain normal blood glucose levels; this is often due to a reduction in beta-cell numbers.

The aim of this PhD is to investigate how insulin secreting beta-cells (located in pancreatic islets) respond to a relatively under-studied signalling molecule, Wnt4. We have preliminary data revealing that Wnt4 can inhibit beta-cell growth and insulin secretion. Hence, we propose that Wnt4 may be one of the factors which promotes beta-cell dysfunction in type 2 diabetes. In this PhD we propose to study the actions of Wnt4 in beta-cells including; investigating whether Wnt4 acts in an autocrine fashion, which of the branches of the non-canonical pathways Wnt4 activates, and how Wnt4 inhibits the canonical Wnt signalling pathway. In addition to test the potential importance of Wnt4 in diabetes, we will measure the expression of Wnt4 mRNA in human islet samples from controls and patients with diabetes. This work will generate unique information about the role of Wnt4 in beta-cells. The data will give an important insight into the molecular mechanisms by which Wnt4 is able to inhibit beta-cell growth and insulin secretion. This should uncover new mechanisms important in regulating beta-cell mass and function, which is an important step towards the development of new drugs for diabetes treatment.

References:Welters, H.J., and Kulkarni, R.N. 2008. Wnt signaling: relevance to beta-cell biology and diabetes. Trends Endocrinol Metab 19:349-355.Butler, A.E., Janson, J., Bonner-Weir, S., Ritzel, R., Rizza, R.A., and Butler, P.C. 2003. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 52:102-110.Heller, C., M.C. Kuhn, B. Mulders-Opgenoorth, M. Schott, H.S. Willenberg, W.A. Scherbaum, and S. Schinner, Exendin-4 upregulates the expression of Wnt-4, a novel regulator of pancreatic beta-cell proliferation. Am J Physiol Endocrinol Metab, 2011. 301(5): p. E864-72.

For further information please contact Dr Welters (h.j.welters@exeter.ac.uk)

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WHATMORE/GUTOWSKI

The role of platelets in lung tumour cell metastasis to the brain

Supervisors: Dr Jacqueline Whatmore and Dr Nicholas Gutowski

Lung tumour metastasis to the brain is a major clinical problem1. Primary lung tumours frequently metastasise to the brain via the blood stream. This process involves growth of a local tumour into a mass that invades blood vessels in the lung, dispersal though the circulation, arrest of circulating tumour cells in the blood vessels in the brain and finally entry into brain tissue and secondary tumour growth. We are particularly interested in the process by which lung tumour cells survive in the blood stream and how they arrest in small blood vessels in the brain.  Indeed, circulating tumour cells are subjected to both destructive haemodynamic forces generated by the blood flow and the defences of the innate immune system. There is evidence to suggest that circulating tumour cells form aggregates with blood platelets and white blood cells that not only shield them from these insults, but also help attachment of the tumour cells to the blood vessels walls of their target organs by acting as linkers between the tumour cells and the cells lining the blood vessels i.e. endothelial cells2. This project will build on our existing programme of work and examine how factors secreted from lung tumour cells influence platelet activation and tumour cell/platelet interactions with each other and brain endothelial cells.

For further information about this project please contact Dr Jacqueline Whatmore (J.L.Whatmore@exeter.ac.uk)

1. Gutowski N. (2007) Neurological problems in cancer. Clin Med. 7:159-642. Stegner D, Dütting S, Nieswandt B. (2014) Mechanistic explanation for platelet contribution to cancer metastasis. Thromb Res. 133:S149-57.

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WHITEMAN/WHATMORE/WOOD

Hydrogen sulfide and diabetic microvascular complications

Supervisors: 1Matt Whiteman, 1Jacqueline L. Whatmore, 2Mark E. Wood

1University of Exeter Medical School, 2Biosciences, College of Life and Environmental Sciences

Hydrogen sulfide (H2S) is rapidly emerging as an important mediator in diverse physiological and pathophysiological settings [1] including the regulation of vascular tone, suggesting H2S may be a novel endothelium dependent hyperpolarising factor (EDHF) [2]. We (and others) have previously shown that there are decreased levels of H2S in the vasculature in obesity and diabetes, and that lower plasma H2S levels were associated with impaired glycaemic control, insulin sensitivity, adiposity, blood pressure and impaired microvascular function in vivo [3]. These studies strongly suggest that strategies that increase H2S bioavailability may be useful pharmacological tools to prevent or treat the vascular complications associated with obesity and diabetes (e.g. hypertension, retinopathy, nephropathy etc.). This project will investigate the effects of novel slow release and mitochondria-targeted H2S donor molecules on vascular signalling using (i) human microvascular endothelial cells and (ii) pressure myography of human microvessels. The project will also investigate how H2S dilates human microvessels in health and in the pro-diabetic environment. You will work closely with the Exeter National Institute for Health Research Clinical Research Facility to consent volunteers for this study (cells and microvessels). As part of the European Network on Gasotransmitters (http://www.gasotransmitters.eu), you will be expected to engage in network meetings and study visits to relevant partner laboratories in Europe. There will also be opportunities to learn basic synthetic organic chemistry and contribute to the Intellectual Property protection process associated with novel H2S modulators where appropriate. You will join a rapidly expanding research group examining H2S and diabetes in Exeter which has recently attracted major funding and published in this area [4].

1. Whiteman et al., Emerging role of hydrogen sulfide in health and disease: critical appraisal of biomarkers and pharmacological tools. Clin Sci (Lond). 2011;121(11):459-88.(open access)2. Mustafa et al., Hydrogen sulfide as endothelium-derived hyperpolarizing factor sulfhydrates potassium channels. Circ Res. 2011;109(11)1259-68.3. Whiteman et al., Adiposity is a major determinant of plasma levels of the novel vasodilator hydrogen sulphide. Diabetologia. 2010;53(8):1722-6. 4. Sophie Le Trionnaire, Alexis Perry, Bartosz Szczesny, Csaba Szabo, Paul G. Winyard, Jacqueline L. Whatmore, Mark E. Wood and Matthew Whiteman. The synthesis and functional evaluation of a mitochondria-targeted hydrogen sulfide donor, (10-oxo-10-(4-(3-thioxo-3H-1,2-dithiol-5-yl)phenoxy)decyl)triphenyl phosphonium bromide (AP39). Med Chem. Commun., 2014;5:728-736

For further information about this project please contact Prof. Matt Whiteman (m.whiteman@exeter.ac.uk; www.researcherid.com/rid/C-6079-2009

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WINYARD/SMERDON/CURNOW

Can the efficacy of photodynamic skin cancer therapy be improved by increasing the oxygen concentration in treated cells?

University of Exeter Medical School, proposal for a match-funded PhD project

Paul Winyard, Gary Smerdon* and Alison Curnow, University of Exeter Medical School, Exeter and Tremough, UK and *Diving Diseases Research Centre, Plymouth, UK

Protoporphyrin IX (PPIX)-based photodynamic therapy (PDT) is a sophisticated and highly selective way to ablate tissue, and is clinically used for treating non-melanoma skin cancers. PPIX-based PDT involves three components: pro-drug(s) aminolaevulinic acid/or methylaminolaevulinate (ALA/MAL, which are converted intracellularly to the natural photosensitiser PPIX), light and – importantly – oxygen. The combination of these components leads to the production of reactive oxygen species (ROS) which kill the targeted cancer cells. To further improve the efficacy, we propose to combine the use of PDT with hyperbaric oxygen therapy (HBO) which increases skin tissue O2 concentrations. The proposed PhD project will test in vitro whether this could be a feasible approach, using cultured cells (normal human skin keratinocytes and squamous cell carcinoma cells) which have been exposed to different concentrations of O2 for varying periods of time prior to photodynamic irradiation. Cell death (apoptosis and necrosis) will be measured by flow cytometry and confocal microsocopy. PPIX accumulation will be measured by spectrofluorometry. ROS will be detected using fluorescence-based probes and by electron paramagnetic resonance spectrometry (EPR) in conjunction with spin trapping. Gene expression will be determined at the mRNA level (qRT PCR) and the protein level (Western blotting). The effects of inhibitors of various antioxidant enzymes (e.g. thioredoxin-1, SOD-2, etc) will be tested. The study will build on on-going and published work from the group, part of a collaboration with the Diving Diseases Research Centre (DDRC). The DDRC has agreed to provide 50:50 matched funding of the studentship.

References:Curnow A, Dogra Y, Winyard PG, Campbell S. Using iron chelating agents to enhance dermatological PDT. Proceedings of SPIE 7380, 738026. Published online: June 29, 2009. DOI: 10.1117/12.822239.

Kendall AC, Whatmore JL, Harries LW, Winyard PG, Smerdon GR, Eggleton P. Changes in inflammatory gene expression induced by hyperbaric oxygen treatment in human endothelial cells under chronic wound conditions. Experimental Cell Research, 2012; 318: 207-16.

Tyrrell J, Thorn C, Shore AC, Campbell S, Curnow A. Oxygen saturation and perfusion changes during dermatological methyl-aminolevulinate photodynamic therapy. Br J Dermatol, 2011; 165: 1323-31.

For further information please contact Professor Winyard (P.G.Winyard@exeter.ac.uk)

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