Academic foundation programme projects

A preliminary meeting with the clinical academic training manager provides advice and help with the process - so if you don't have a clear idea for your research rotation in AF2, guidance is available.

To give you an idea, here are some examples of current possible projects and previous projects undertaken in the last few years. Trainees are encouraged to approach any specialty, so these just provide examples. We have a list of about 60 academics/clinicians who have been willing to host AF2 projects - and many others who haven't been asked yet!

The F2 academic trainee will be expected to have completed a literature review, a presentation of his/her research and written up his/her research project within the 4 month academic placement. There is an annual academic presentation day which is mandatory for all F2 Academic trainees, and gives the opportunity for trainees to either give an oral presentation (subject to a selection process) or poster presentation.

Examples of possible projects for academic foundation research

These are examples of possible research projects for the AF2 year. Many other specialties are also happy to host foundation trainees. If you have a particular idea or specialty in mind, let us know and we will help you explore the possibilities.

Primary care of under-served populations

Dr Caroline Mitchell
 
Dr Mitchell co-leads this research group, which develops and tests healthcare interventions for people living in the most socioeconomically deprived communities, from ethnic minority populations or people with severe and multiple disadvantages. 

 A key focus of this work is to address inequalities in research participation, working since 2016 with the 'Deep End’ Sheffield Cluster Research Network, their practitioners, and community groups. 

Using a participatory approach, across a range of study designs, the Deep End Research Alliance (DERA) brings researchers, patients and the public  from diverse backgrounds and clinicians together to co-produce research and widen the participation of underserved groups in research

Improving experiences for incurable head and neck cancer patients

Dr Catriona Mayland

As part of the ‘Palliative Partners – Head And Neck Cancer (PP-HANC)’ collaborative, we are working to improve experiences for those who have incurable head and neck cancer. An existing study includes a longitudinal qualitative study involving patients, family members and healthcare professionals, and co-design workshops to think about priorities and solutions to improving care.

Bereavement care for all – a qualitative study to improve bereavement services for those from ethnic minority groups

Dr Catriona Mayland

The focus of this study is to help improve bereavement support services to meet the needs of people from ethnically diverse communities. The study involves a qualitative study which incorporates principles of experience-based co-design. 

Depending on the interests of the AF trainee, supporting the above studies could be considered or developing a piece of work about a specific topic within the field of Palliative Medicine. Other areas of interest include the use of routine data, the identification of those nearing the end of life and the evaluation of quality of care for the dying.

Developing AI-based imaging algorithms to improve personalised medicine in rare kidney and liver disease

Professor Albert Ong
Academic Nephrology
Translational research

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cause of kidney failure in man accounting for 10% or patients requiring kidney replacement therapy. With a genetic prevalence of 1 in 1000, it is estimated that around 8 million people globally have ADPKD.

Although liver cysts are common, a rare complication (5-10%) is the onset of polycystic liver disease (PLD) especially in women which may require surgical intervention or transplantation. The kidney and liver phenotypes are however highly variable between individuals and only partly related to the underlying genotype. 

An important area of research is to test new treatments that may slow the growth of both kidney and liver cysts in patients with the highest risk of disease progression. We have developed a rapid high-performance method for automatic kidney segmentation by machine learning on MRI kidney images to identify patients with the highest risk of kidney failure which is already being used in routine clinical practice.

This project will be to develop a similar method for liver segmentation based on the artificial intelligence (AI) approaches successfully employed for the kidney.

Research into the urgent and emergency care system

Professor Suzanne Mason (s.mason@sheffield.ac.uk)

Placement opportunities for F2 doctors would include:

• Literature or systematic reviewing of a topic of their choice
• Undertaking routine data analysis using the CUREd or CUREd+ dataset - involving analysing attendances at emergency departments and acute hospital admission. Projects of this type have involved analysing attendances of patients in particular groups, such as elderly patients, care home residents. patients with mental health conditions, patients near the end of life and also attendances following injury - such as head injury. The dataset provides an excellent opportunity to develop skills in routine data analysis supported by our data managers and statisticians.
• Undertake some qualitative or semi-qualitative work collecting information through survey or interviews of staff or patients that explore topics such as demand for emergency and urgent care, patients outcomes following and urgent care problem, seeking solutions to some of the current urgent care challenges.

Medical Education – Cardiothoracic Surgery

Mr Norman Briffa (n.briffa@sheffield.ac.uk)

At the cardiothoracic unit at the Northern General Hospital, medical students often spend 6 weeks doing a Self-selected Component (SSC). They are given an opportunity to observe and join in a whole host of clinical activities including ward rounds and observing as well as scrubbing up for cardiothoracic surgical procedures. 

We also regularly organise wetlabs for students. During their last week, students present long cases and reflect on their time in the unit. There are many opportunities therefore to formally assess the educational value of all the activities that these students undertake.

Advanced neurophysiology for nerve and muscle disorders

Dr James Alix (j.alix@sheffield.ac.uk)

We employ a range of different neurophysiological techniques to study nerve and muscle disorders, with a particular emphasis on motor neurone disease. Techniques include motor unit number index, nerve and cortical excitability testing and spectroscopy. The exact nature of the project can be adjusted to suit individual interests.

Digital capture of side effects and quality of life outcomes in pulmonary arterial hypertension

Dr Frances Varian (f.varian@sheffield.ac.uk)

Cardiology registrar, Clinical Research Training Fellow

Background

Approved therapies for PAH target three distinct biological pathways.  During follow-up, patients at intermediate-low risk on dual combination treatment are recommended to intensify therapy. There is clinical equipoise between addition of selexipag, or switching another medication to add riociguat. These therapeutic choices have differential side effect profiles, and outside of trial publications, adverse event reporting does not reflect clinical experience. Reporting through the UK MHRA yellow card system is low – only 114 and 86 events for selexipag and riociguat (2016-2023) respectively. This compares to the USA (2016-2023) where FDA-reported adverse events are >13000. Reporting of side effects alongside physiological changes may help inform future prescribing practices. Disease burden can also be captured through quality of life (QoL) and mental health measures. Digital reporting increases accessibility within a trial design to match qualitative to physiological outcomes.  

Aim

Digital capture of patient reported outcomes to include medication adherence, side effects, quality of life and mental health experience within a randomised clinical trial.

Methods

Real-world experience of prescribing practices, adherence, and side effects of selexipag and riociguat will be evaluated through the ASPIRE registry. Patients recruited within the PHoenix clinical trial will be invited to consent to use a mobile application designed with validated questionnaires to capture weekly QoL (Emphasis-10), and twice monthly generalised anxiety (GAD2) and depression (PHQ2) screening tools. Weekly side effects and adherence questionnaires are also completed to mirror dose/drug changes in a randomised 2x2 crossover of selexipag and riociguat (PHoenix). Team: PHoenix study group.

Clinical prediction in emergency medicine

Professor Steve Goodacre (s.goodacre@sheffield.ac.uk)

Emergency Medicine, Clinical Research

The Centre for Urgent and Emergency Care Research is based in the School of Health and Related Research (ScHARR). Emergency medicine researchers have collaborated with statisticians in ScHARR on major NIHR-funded studies evaluating clinical prediction in emergency medicine.

Our recent projects include the PHEWS (Prehospital Early Warning Scores for sepsis), PRIEST (Pandemic Respiratory Infection Emergency System Triage), and DiPEP (Diagnosis of PE in Pregnancy) studies.

An academic F2 placement provides an opportunity to undertake a secondary analysis of the PHEWS, PRIEST or DiPEP data, with support from clinical and methods experts, potentially resulting in a presentation at a national conference and peer-reviewed publication.

Systematic reviews in emergency medicine

Professor Steve Goodacre (s.goodacre@sheffield.ac.uk)

Emergency Medicine, Clinical Research

The Centre for Urgent and Emergency Care Research is based in the School of Health and Related Research (ScHARR). Emergency medicine researchers regularly collaborate with systematic reviewers in ScHARR to undertake systematic reviews related to emergency medicine, and are involved in the Sheffield Evidence Synthesis group for NIHR (EnSygN).

Our recent reviews include diagnostic tests for suspected acute aortic syndrome, early warning scores for sepsis, prediction tools for venous thromboembolism, and prehospital non-invasive ventilation for acute respiratory failure.

An academic F2 placement offers the opportunity to undertake a systematic review and possibly a meta-analysis relevant to emergency medicine, with support from clinical and methods experts, potentially resulting in presentation at a national conference and peer-reviewed publication.

https://www.sheffield.ac.uk/scharr/research/centres/cure

GI research projects

Professor David S Sanders david.sanders@sth.nhs.uk

Gastroenterology, Clinical Research

The Sheffield GI department is the premier UK GI unit. There are 6 Professors, 2 Senior Lecturers,1 Wellcome Fellow and 7 Clinical Fellows. The unit has won 9 National and International research awards in the last decade. This is a happy vibrant department and we are always looking to help and support those who seek a career in gastroenterology. Any are of interest can be accommodated - come and chat with us. You will have a fun four months and that may even be the beginning of your career in our department!

Application of advanced structural, functional and metabolic imaging in thoracic radiotherapy

Dr Matthew Hatton matthew.hatton@sth.nhs.uk

Oncology

Application of advanced structural, functional and metabolic imaging in thoracic radiotherapy Clinical Research

The Academic Foundation (AF) trainees would participate in a program of research that has the aims: (a) Early detection of radiation response (tumour/normal tissue) in the pre-clinical and clinical setting. (b) Personalised image-guided RT planning for better controlled RT delivery and reduction of damage to normal tissue.

Improved visualisation of tumours has underpinned the ablative RT techniques that have become a standard of care in the treatment of early lung cancer. However, it is becoming increasingly clear that intensifying RT can have measurable adverse effects on short as well as longer term outcomes (RTOG 0617). We will harness the POLARIS group’s unique infrastructure and expertise with novel functional imaging methods for lung RT planning and assessment. Sheffield have pioneered the use of novel fractionation with functional lung MRI for lung RT planning optimisation to avoid normal structures (lung and heart). with the potential to significantly reduce the risk of radiotherapy side effects. Our new hybrid PET-MR system will enhance our platform to build on work with advanced MRI, combining structural, functional and metabolic imaging to detect tumour response and early effects on organs at risk and will be applied in the thoracic oncology setting.

Planned studies include -
1 Imaging tumour oxygenation.
2 Contrast agent free surrogates of regional lung function for image-guided RT. 3 PET-MRI based functional image-guided thoracic RT.
4 Assessment of radiation-induced lung pneumonitis.
5 Functional lung MRI for personalised RT planning and in oesophageal cancer
6 Accelerated RT in NSCLC.

Mental health research

Professor Scott Weich s.weich@sheffield.ac.uk

Psychiatry Mental Health Research, Clinical Research

Trainees will be based in the Mental Health Research Unit (MHRU) at ScHARR, where they will be supported to select and/or develop an applied clinical project that fits with their interests and experience. This may be working alongside researchers on an existing project (eg evaluating the role of social prescribing interventions for people with complex mental health, physical and social problems, or undertaking quantitative analysis of complex datasets to answer questions about causes and outcomes of mental illness), or undertaking a systematic literature review on a subject of their choosing.
Trainees will have a senior academic mentor and will receive regular, individual supervision. They will also have the opportunity to be part of a world-class academic department (the largest in the University), and benefit from the extensive methodological expertise available at ScHARR, including in statistics, health economics, qualitative research and evidence synthesis."

Identifying new genetic variants that modify chronic kidney disease

Professor Albert Ong a.ong@sheffield.ac.uk

Nephrology, Clinical Research

Chronic kidney disease (CKD) affects 10% of the general population and is a major cause of morbidity and mortality especially in an ageing population with multiple co-morbidities. It has been estimated that 10-15% of all CKD is due to a monogenic cause. This is a significant group as such patients can be identified through genetic screening and could be amenable to specific treatments. This project will seek to characterise the phenotype of several Sheffield families with CKD associated with recently identified gene mutations. The results will form the basis for a longer-term study to identify new genetic variants that modify the disease phenotype that could be further investigated as potential therapeutic targets in genetic and non-genetic forms of CKD.

Computational modelling of coronary artery blood flow

Professor Julian Gunn J.Gunn@Sheffield.ac.uk

Cardiology

Cardiologists use the coronary angiogram to plan revascularisation for patients with ischaemic heart disease. But the images are 2D and give little information about flow limitation. We have developed a system to model the blood flow through diseased arteries based upon the angiogram images. You will help take our work to the next stage by using this system to assess flow in patients with complex patterns of coronary disease.

Using patient reported outcome measures to evaluate quality of care for those with palliative care needs

Dr Catriona Mayland C.R.Mayland@sheffield.ac.uk

Palliative Medicine

Within palliative care, we are starting to use specific patient reported outcome measures to evaluate holistic needs assessment and 'phase' of illness. The project would involve collecting and reporting of this data to assess the impact of the input received from palliative care.

Arrhythmic burden and outcomes in pulmonary arterial hypertension

Dr Alex Rothman a.rothman@sheffield.ac.uk

Cardiology, Clinical Research

Arrhythmic burden and outcomes in pulmonary arterial hypertension

Background: Pulmonary arterial hypertension (PAH) is a life-limiting disease driven by small vessel vascular remodeling leading to a rise in pulmonary vascular resistance and leads to right heart failure and death. Patients present with a range of symptoms including shortness of breath, exercise intolerance, palpitations or syncope. Arrhythmic burden is high in patients with heart failure, however incidence and prevalence of arrhythmias and their effect on cardiac haemodynamics and outcomes in patients with PAH is not well described

Aims: To use assess the burden of cardiac arrhythmias in patients with PAH and relationships to clinical outcomes.
Methods: The UK National Cohort has recruited over 1200 patients with PAH. We have established with ethics to place insertable cardiac rhythm monitors (ICM) into a 100 patient sub-group providing daily data on cardiac rhythm for a period of 3-5 years. Data will be collected, related to disease characteristics and outcomes.

Team: An appropriate candidate would have the opportunity to join and established project team with full ethics and funding and develop skills identifying and recruiting patients, inserting devices and collecting and analysing data for publication.

Disease stratification for neurodegenerative disorders

Professor Oliver Bandmann o.bandmann@sheffield.ac.uk

Neuroscience

It is increasingly recognised that Parkinson’s disease (PD) is aetiologically heterogeneous. Mechanistic disease stratification will dramatically increase the likelihood of PD patients responding to putative disease-modifying compounds aiming to address specific mechanisms such as inflammation, protein aggregation or mitochondrial dysfunction.

Academic trainees will be given the opportunity to engage in a range of projects and approaches all focussing on mechanistic disease stratification for PD.

The gut-brain axis in Parkinson’s disease

Professor Oliver Bandmann o.bandmann@sheffield.ac.uk

Neuroscience

There is growing interest in the gut-brain axis in Parkinson’s disease (PD) but the precise mechanisms are still poorly understood. We are particularly interested in studying the effect of microbiome alterations and their effect on energy homeostasis in PD and related disorders. 

Pain in Parkinson’s disease

Professor Oliver Bandmann o.bandmann@sheffield.ac.uk

Neuroscience

Pain is a common, poorly understood and frequently very troublesome non-motor symptom in Parkinson’s disease (PD). We have developed a novel functional imaging paradigm which investigates the differences in pain network stimulation between PD patients and controls. Robust identification of distinct PD pain networks with distinct alterations of activity in well-defined neuronal subpopulations will improve our understanding and greatly facilitate subsequent intervention studies to confirm target engagement of compounds aiming to specifically alleviate pain in PD. 

Factor analysis of online PROMS (patient reported outcome measures) questionnaire used for remote assessment of patients with heart valve disease.

Mr Norman Briffa N.Briffa@sheffield.ac.uk

Cardiothoracic Surgery

Clinical research patients with heart valve disease from all over Yorkshire are managed at the Chesterman Unit at NGH. Patients with native or prosthetic Heart Valve disease need regular clinical assessment. Currently this takes place during a clinic visit held in Sheffield. As the numbers of patients undergoing heart valve intervention increases exponentially there is a need to rationalize these visits and develop smart solutions to address this increasing problem. A detailed questionnaire, based on published validation work performed in this department, has been incorporated into a package designed for online and mobile device use. In this project, the researcher will work with Mr Stephen Radley, a consultant gynaecologist who uses a system which is similar in concept in his practice as well as Professor Georgina Jones, a social scientist at Leeds Beckett University. They will perform factor analysis and validation of the whole package trialled in around 2-300 patients who are either waiting for heart valve intervention or who have already undergone heart valve surgery. The results of this work will be presented at learned conferences and published in specialist (social science and cardiology) journals. It will also provide the pilot data for application for a grant for a randomised control study of the new system.

The role of RNA editing in the pathogenesis of pulmonary arterial hypertension.

Dr Roger Thompson R.Thompson@sheffield.ac.uk

Medical Specialities, Laboratory

Pulmonary arterial hypertension (PAH) is a devastating disease characterised by pulmonary vascular remodelling that leads to increased pressure in the pulmonary circulation followed by right heart failure and premature death. The bone morphogenetic protein (BMP) signalling pathway is strongly implicated in disease susceptibility, with mutations in the BMPR2 gene found in around 15% of patients with idiopathic disease and over 70% of patients with heritable disease. Reduction in BMPR2 signalling in the absence of mutations has been reported, but how signalling is suppressed remains unclear. RNA editing is a form of post-transcriptional modification that can alter protein translation or function. BMPR2 has over 2000 possible editing sites and at least one of these sites matches a disease-associated mutation. However, the level of editing at sites that could alter BMPR2 function in PAH has not been assessed.

This project will introduce the trainee to big data analysis and how it can be applied to disease. The project will use RNA sequencing data from the UK Cohort Study of patients with idiopathic PAH to determine the level of editing of BMPR2 and compare this to data from healthy controls. The informatic pipelines that will be developed will facilitate work to test how editing alters the function of BMPR2 and other PAH-associated disease genes and will be a significant contribution to ongoing work on this topic. Furthermore, analysis of differential editing between patients and controls may reveal other novel targets of relevance to the disease, leading to future high impact publications.

Use of metagenomic approaches to diagnose causes of neonatal sepsis in The Gambia

Dr Thushan de Silva t.desilva@sheffield.ac.uk

Infectious Diseases, Laboratory

The lack of laboratory capacity in many low income countries limits the surveillance for infectious diseases required to make appropriate public health decisions. As next generation sequencing methods become more accessible, enhancing access to these culture free methods of pathogen identification could rapidly upscale this capacity. Via a Bill and Melinda Gates Foundation funds, a pilot project to establish methods for metagenomic sequencing of blood and cerebrospinal fluid samples from neonatal sepsis cases in The Gambia will take place in 2020 (at the MRC Unit The Gambia at LSHTM). This project will focus on the bioinformatic analysis of the sequencing data obtained to identify causative organisms. Depending on the progress with the study and the interests of the student, there may be opportunities to visit the MRC Gambia and be involved in the laboratory aspect of the study.

Computational modelling of coronary blood flow

Professor Julian Gunn J.Gunn@Sheffield.ac.uk

Cardiology

Clinical Research Coronary artery disease is the commonest major medical condition we deal with. The most serious cases come to the cath lab for a coronary angiogram for treatment planning. Our group at the University of Sheffield, which includes interventional cardiologists and engineers, has developed a system which can use computational fluid dynamics to model blood flow from the angiogram images. This means we can start to tailor treatment. We are currently developing global models of myocardial perfusion and also conducting home monitoring to investigate how it affects the patient. We have a track record of training ACFs and PhD students, and have published extensively in this area. Come and join us!

Interpretable artificial intelligence to improve cardiothoracic imaging diagnoses

Dr Andrew Swift a.j.swift@sheffield.ac.uk

Radiology, Clinical Research 

Cardiovascular and respiratory diseases account for close to half of all deaths in the UK, 26% and 20%, respectively. Magnetic resonance imaging (MRI) and computed tomography (CT) studies are key to cardiac and pulmonary diagnoses, however only a small amount of data available is measured. Human error is common in imaging diagnosis, and reporting varies by specialist expertise. Machine learning, the cornerstone of artificial intelligence, holds the power to transform healthcare via learning from data examples. Great advantages are development of quantitative biomarkers, automation of repetitive measurement tasks, autonomous triaging of emergent findings, and the potential to make early diagnoses for patients, and reduce the burden on a critically stretched Radiology workforce.

Tensor-based machine learning, best known from applications in facial recognition, provides powerful tools to analyse MRI/CT studies. We have developed a tensor-based machine learning approach capable of assessing a physiological cycle, a world first. This approach using MRI has 97% accuracy for the diagnosis of pulmonary hypertension and disease features are discovered. Advantages of this revolutionary approach are rapid diagnosis in seconds, no manual segmentations, near elimination of inter-observer variability. And, unlike the popular deep learning, typically a ‘black box’ method, true learnt disease features are visualised in disease feature maps, with huge potential for biomarker discovery.

Hypothesis:
Tensor-based machine learning on MRI/CT images is accurate for the diagnosis of common cardiac and pulmonary diagnoses.
Aims and objectives
Aims: Utilise MRI/CT tensor-based machine learning tools to make accurate and rapid diagnoses and characterise the disease specific features of cardiac and pulmonary diseases.
Objectives:
1. Determine diagnostic accuracy of tensor-based machine learning
2. Determine the added value of tensor-based machine learning in conjunction with Radiologist reads
3. Determine the effect of tensor-based machine learning on diagnostic confidence.
Diagnostic studies:
Train and validate tensor-based machine learning algorithms to identify cardiac diseases, utilising cardiac imaging studies from Sheffield repositories, 8,000 MRI and 4,000 CT with diagnoses made at multidisciplinary team meetings. Multiple cardiac diseases will be learnt, ischaemic and non-ischaemic. Secondly, train and validate algorithms to detect acute pulmonary diseases, such as pneumonia and acute pulmonary embolism using CT studies in the Sheffield Hospitals repository of patients, n=30,000. Training in will be in 2/3 and validation in 1/3 of cases selected at random.
Biomarker discovery:
Disease feature maps generated for each disease learnt by the tensor machine learning approach will be reviewed by the study team. Disease feature patterns will be described and disease specific biomarkers developed. The anthropological, pathophysiological and serological and clinical correlations of these biomarkers will be assessed.
Potential benefits include more accurate, early and more consistent diagnosis and identification of new disease specific biomarkers."

Spectroscopy for neuromuscular disorders

Dr James Alix j.alix@sheffield.ac.uk

Neuroscience,   Clinical Research

Neuromusclar disorders can be difficult to diagnose and monitor. This project will explore various electrophysiological and spectroscopic techniques for identifying such diseases. The exact techniques, types of analysis and diseases studies can be adjusted to suit the interests of the individual.

Physical Activity in Treatment & Prevention of Chronic Disease

Dr Liddy Goyder (e.goyder@sheffield.ac.uk)

Our NIHR Public Health Review Team and our NIHR Health Services & Delivery Research Evidence Synthesis Centre can offer a range of evidence synthesis/systematic review projects which have a direct impact on policy and practice, as well as generating a peer reviewed journal article.

The research topic would be flexible and the scope of the attachment would be as described below.

Public Health Clinical Research

The fellow would lead a systematic review in a specific topic area in this field to synthesis evidence to inform public health policy and/or clinical practice. This would involve:

1. Refining the review question
2. Developing a search strategy
3. Identifying, critically appraising and synthesising relevant research evidence
4. Writing up as conference abstract and journal paper for publication

Clinical projects on functional gastrointestinal disorders

Dr Imran Aziz  (imran.aziz1@nhs.net)

Affiliations: Academic Department of Gastroenterology (STH) and b) Department of IICD (University)

Clinical projects on Functional Gastrointestinal Disorders

Clinical Research

A number of projects in clinical gastroenterology are available. These are all themed towards functional gastrointestinal disorders (FGIDs), which are disorders of gut-brain interaction in the absence of organic disease. They are the most common GI conditions seen in primary and secondary care. The current studies include i) randomized trial of therapies for FGIDs, and ii) looking at the association between FGIDs and COVID/food intake disorders. Ethics has been gained and all these studies are either running or soon to start. The plan would be for the fellow to be involved in one of the studies, and use the data for write up and submit an original article for publication

The supervisor (Dr Imran Aziz) is internationally renowned for his work in FGIDs and was a recipient of the United European Gastroenterology Rising Star Award. He has successfully supervised under/post graduate students to thesis completion, presentation at conferences and scientific publication.

AF2 Project in primary care

Christopher Burton chris.burton@sheffield.ac.uk

Primary Care

Two possible areas which can be developed with the AF doctor:
1. Clinical communication around persistent "medically unexplained" physical symptoms. This links with a current multicentre trial and other work I am leading.
2. Health Data Science in relation to either primary care or emergency medicine. I have experience of supervising AF doctors and students to publication in innovative analyses of "big data"

Using Artificial Intelligence to Personalise Treatment in Painful Diabetic Neuropathy

Dr Dinesh Selvarajah d.selvarajah@sheffield.ac.uk

Diabetes and Endocrinology, Neurology and Radiology, Clinical Research

One in 16 people in the UK has diabetes and half of these develop nerve damage. This can cause severe pain in the feet and legs. Unfortunately, current medications provide only partial benefit in some, with many enduring inadequate pain relief. Part of the problem is that a ‘one-size fits all’ ‘trial and error’ approach is used hoping to achieve meaningful pain relief. Current treatments at best achieve partial pain relief in only one in three patients. Hence, a new, more personalised approach is needed where the right treatment is given to the right patient first time. Over the last 10 years, we have performed a series of brain imaging studies known as functional magnetic resonance imaging (fMRI) in patients with painful DPN and identified a number of fMRI measures that could be used to guide treatment decisions.
The main objective of this application is to determine if and how fMRI measures can be used to predict the treatment response of an individual patient. You will learn to apply artificial intelligence methodologies to analyse neuroimaging datasets to internally validate algorithms that will be used to stratify patients for neuropathic pain treatments. Ethical approvals and funding is in place to complete this project.

The Early and Late Costs of Bleeding After Cardiac Surgery

Mr Norman Briffa N.Briffa@sheffield.ac.uk

Cardiothoracic Surgery

Bleeding after cardiac surgery is common. Although the immediate effects of bleeding are known, very little has been written on the late consequences and the costs of bleeding after heart surgery. Data from a large cardiac surgery database will be used to study the effect using statistical techniques of propensity matching and regression analysis.

Determinants of Failure After Repair of a Degenerative Mitral Valve

Mr Norman Briffa N.Briffa@sheffield.ac.uk

Cardiothoracic Surgery

Mitral Valve Prolapse (MVP) occurs in 3% of the adult population and is the commonest cause of mitral valve regurgitation in the UK and US. Durable repair of a prolapsing mitral valve is possible and is associated with better outcomes than with Mitral Valve Replacement. There are modifiable and non-modifiable causes of Repair Failure. All patients who underwent mitral valve repair surgery in Sheffield over the past 15 years (cardiac surgery database) and who had at minimum of 1 echocardiogram (heart ultrasound) at least 1 year after surgery: Patients with moderate or worse mitral regurgitation will be classed as having a failed repair. Pre-operative, intra-operative and post-operative variables of the patients will be entered into a multivariate regression analysis to determine independent factors associated with repair failure.

Optimisation of antithrombotic medication for ischaemic heart disease

Professor Rob Storey (r.f.storey@sheffield.ac.uk)

Cardiology

The majority of heart attacks and strokes are caused by thrombosis, hence the pivotal role of antithrombotic drugs in treating and preventing these events. Different individuals have different risks of thrombosis and bleeding, which creates challenges in deciding on the best antithrombotic strategy and how this might vary over time. We have a programme of research studying antithrombotic drug effects and biomarkers of thrombosis and bleeding risk. You will engage in a project in this area to advance our understanding and guide treatment strategies.

Examples of projects undertaken by previous trainees

Risk assessment methods for venous thromboembolism (VTE) prophylaxis for hospital inpatients

Professor Steve Goodacre s.goodacre@sheffield.ac.uk

Emergency Medicine, Clinical Research

Risk assessment methods for venous thromboembolism (VTE) prophylaxis for hospital inpatients Clinical Research

This is a 2-year project, from 1/7/2019 to 30/6/2021, funded by the National Institute for Health Research, that will use a variety of research methods (systematic reviews, decision-analytic modelling and analysis of routine NHS data) to determine the effectiveness and cost-effectiveness of providing VTE prophylaxis to hospital inpatients on the basis of different risk-assessment methods. A 4-month secondment will offer the opportunity to join the project and learn about research methods used in health technology assessment with a research team based in the Clinical Trials Research Unit and the Centre for Urgent and Emergency Care Research in ScHARR.

Prehospital triage tools for suspected sepsis

Professor Steve Goodacre s.goodacre@sheffield.ac.uk

Emergency Medicine, Clinical Research

This is a 2-year project, from 1/7/2019 to 30/6/2021, funded by the National Institute for Health Research, that will use a variety of research methods (systematic reviews, decision-analytic modelling and analysis of routine NHS data) to determine the accuracy, operational impact and cost-effectiveness of different prehospital triage tools used to select patients with suspected sepsis for urgent treatment. A 4-month secondment will offer the opportunity to join the project and learn about research methods used in health technology assessment with a research team based in the Clinical Trials Research Unit and the Centre for Urgent and Emergency Care Research in ScHARR.

Developing a questionnaire to aid differential diagnosis of transient loss of consciousness (TLOC) - SiTRAN (Sheffield Institute for Translational Medicine)

Over 90% of TLOC is due to either syncope, epilepsy or psychogenic non-epileptic seizures. Accurately distinguishing between these is vital for appropriate further management and identification of patients at risk of severe morbidity or mortality.

Epigenetic regulation of the HPA axis: focus on pro-opiomelanocortin - Dept of Oncology & Metabolism

Glucocorticoids are prescribed to over 5 million patients in the NHS in the UK per year for inflammatory conditions. A major side effect is suppression of the Hypothalamo-Pituitary-Adrenal axis, and this may continue after steroid withdrawal, and is major reason why withdrawal is prolonged, even when the inflammatory disease has gone into remission. The exact mechanism for this is unknown. We have previously demonstrated de-novo DNA methylation of a key positively-regulating POMC (which encodes ACTH) transcription factor in response to long term glucocorticoid exposure. Using cell culture and molecular biology techniques, this project will ask a simple but key question as to whether histone deacetylases that are in clinical use (sodium valproate) can offset the impact of glucocorticoid repression of POMC.

Investigating cumulative genetic defects in Parkinson’s disease mutant zebrafish - Bateson Centre and SiTRAN

The zebrafish is a well-established model of human disease and has been successfully utilised in the modelling of PD. Zebrafish models exist of parkin, LRRK2, pink1, gba1 and DJ-1. The aim of this project is to explore any cumulative effect of multiple genetic risk factors (namely gch1, parkin and atp13a2 mutant zebrafish) on mitochondrial function and dopaminergic cell number in zebrafish embryos.

To further validate several compounds shown to modify the zebrafish (Danio rerio) pkd2 phenotype and to the expression of pkd2 in vivo - Bateson Centre and the Dept of Infection, Immunity and Cardiovascular Disease (IICD)

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease leading to end-stage renal disease in man. Mutations in two genes, PKD1 and PKD2, account for at least 90% of cases. Zebrafish are a new and powerful vertebrate model to study human disease. Induced and targeted mutations or knockdown of pkd1 or pkd2 are associated with cystic dilation of the pronephric kidney make these useful models to study disease and develop new treatments.

Secondary Loss of Response to Vedoluzimab in Inflammatory Bowel Disease (IBD): Systematic Review and Experience from a Tertiary Referral Centre – Gastroenterology Department, Royal Hallamshire Hospital

Vedolizumab is a recently introduced biologic agent used to treat IBD. It is a monoclonal antibody and targets α4β7 integrin and blocks its interaction with MAdCAM-1 hence preventing leukocyte extravasation from the circulation to the areas of active disease in the bowel. The gastroenterology department at Sheffield Teaching Hospitals NHS Trust has the single largest dataset of patients using vedoluzimab in the United Kingdom. The aim of this research is to determine the characteristics which are associated with risk of secondary loss of response to vedoluzimab from this dataset.

Heterogeneity of reason for consultation in frequent attenders to accident and emergency – Academic Unit of Primary Care

Frequent attenders are a burden on many aspects of the healthcare system. In accident and emergency they represent around 1.5% of all admissions. Work by Professor Burton has shown that in primary care frequent attenders have bursts of activity where they present multiples times in a relatively short period of time and has also found that heterogeneity in the reasons for consultation is associated with attendance for mental health problems but not with increasing age. This project will apply the methods from that research to an established local dataset of A&E attendance.

Can Potassium Channels Control Uterine Gene Expression? - Academic Unit of Reproductive & Developmental Medicine

The C-terminal of the L-type Calcium Channel has been shown to enter the nucleus where it acts as a transcription factor controlling a diverse array of genes. It is possible that this transcriptional activity of the channel adds a further layer of control over the timing of parturition. Dr Chapman’s group have detected nuclear localisation of the MaxiK potassium channel and preliminary ChIPseq data suggests that the MaxiK Channel can also function as a transcriptional regulator. The main aims of the project are 1) To obtain greater clarity of MaxiK nuclear localisation; 2) To understand how nuclear localisation of the MaxiK protein is regulated; 3) To verify our preliminary ChIPseq data in vivo.

Comparison of long term safety of percutaneous access for EVAR - Dept of Vascular Radiology, Sheffield Vascular Institute

Abdominal aortic aneurysms can be treated through either open surgery or endovascular repair. Endovascular aneurysm repair (EVAR) involves the placement of expandable stent grafts that adhere to the linings of the aorta. EVAR has traditionally been performed by a surgical femoral artery access (open access EVAR). Recently, with the advent of percutaneous closure devices for large-bore arterial access, percutaneous femoral access techniques have been devised and being increasingly utilised (P-EVAR). P-EVAR has been shown to have a high success rate (98%), shorter operating time and shorter length of stay. Although surgical access is considered a minor procedure, access-related complications have been shown to occur in 14-22% of patients. Whilst recent studies have reaffirmed the advantages of P-EVAR over open access EVAR, there exists very little data on the long-term follow up of groin access and resulting potential complications. This study has two parts and aims: 1. To retrospectively assess the Sheffield cohort of Percutaneous EVAR cases for groin complications in the long term; 2. To retrospectively assess the Sheffield cohort of P-EVAR and open access EVAR cases for complications in the long term and to compare and comment on the safety of both techniques in a large tertiary referral centre.

Does routine corticosteroid use reduce the response of bone to mechanical stimulation? - Academic Unit of Child Health and Sheffield Children's Hospital CRF

Bone responds to mechanical loading by increasing bone formation. We have developed a method of standardising mechanical loading using a whole body vibration platform. Studies in prepubertal boys indicate that 5 consecutive days of WBV for 10 minutes each day increases a biomarker of bone formation by 25% after one week. We plan to use this methodology to assess the extent to which bone formation is abrogated in chronic disease states; the specific focus in this project will be to determine the effects of inhaled steroids on bone formation rates.

Detection of radiation-induced lung injury in non-small cell lung cancer patients using ventilation and perfusion magnetic resonance imaging and CT ventilation. POLARIS (Pulmonary, Lung and Respiratory Imaging Sheffield), Dept of IICD

Previous work in Sheffield demonstrated that inhaled gas MRI can provide significant clinical information for lung cancer radiotherapy planning and post-treatment evaluation. A multidisciplinary team is currently conducting a new inhaled gas and proton lung MRI study known as Lung HeXeRT. One aim of this work is to investigate radiation pneumonitis and fibrosis, which are commonly occurring dose-limiting side-effects of radiotherapy. The aim of the project is to investigate if ventilation and perfusion MRI and CT ventilation can detect radiation pneumonitis or other post-treatment dose-related changes. Post-radiation changes will be assessed from pre and post-treatment MR ventilation and perfusion images and CT ventilation, which will be compared and analysed along with the clinical dose distribution.

Biological effects of tribocorrosion products on the bone micro-environment and prosthesis osseo-integration - Metabolic Bone Unit

The use of metal-on-metal hip replacement (MOMHR) has highlighted the adverse effects of prosthetic metal debris on human tissues, with bone-related complications accounting for 70% of revision indications in this group. It is also now becoming increasingly clear that wear-accelerated corrosion at the taper junctions of all modular implants generates metallic wear debris, particularly in the setting of large diameter bearings, and has implications for the large number of brands that use these junctions. Previous studies by us and others have highlighted the detrimental effects of metal debris on survival and function of bone cells. The cellular mechanisms that mediate the adverse effects of metal debris on bone cells are poorly understood, and our overall aim is to address this gap in knowledge. Our specific objectives are to identify the cellular pathways affected by metal exposure in primary human bone cells, including those modulating osteogenic responses of primary human osteoblasts on different implant surfaces. Furthermore, we will determine whether metal exposure induces systemic epigenetic DNA modification in monocyte/macrophage cells from patients with MOMHR that affects differentiation and function of these cells. The data generated by the proposed research will contribute to technological development in this field by developing our understanding of the mechanisms by which clinically relevant prosthetic metal substrates impact prosthesis osseointegration, local and systemic bone health.

Evaluation of predictive models for single versus multigland parathyroid disease in primary hyperparathyroidism - Royal Hallamshire Hospital

Primary hyperparathyroidism (PHPT) is a common endocrine disorder. Most cases of PHPT are due to single PTH secreting adenoma (85%), followed by multigland parathyroid hyperplasia in up to 15% and parathyroid carcinoma is rare (less than 1% of cases). The definitive treatment for PHPT is surgical removal of abnormal gland(s). The traditional operation involves bilateral neck exploration (BNE) to visualise all four parathyroid glands, as around 15% will have multigland disease. This approach is increasingly been replaced by targeted, limited or minimal invasive parathyroidectomy. Reported benefits of minimally invasive parathyroidectomy include reduced complication rates, shorter hospital stays and the potential for local or regional anaesthesia particularly in elderly patients with comorbidities. Minimally invasive parathyroidectomy is dependent on accurate preoperative localisation and in some centres, intraoperative adjuncts such as intraoperative PTH assay is used to ensure adequate treatment. Few studies have proposed predictive tools to differentiate between patients who have single and multigland disease with a view to directing the need for preoperative imaging, intra-operative adjuncts and the extent of surgery. These tools use a combination of serum calcium, parathyroid hormone, imaging (Ultrasound, sestamibi scan), excised parathyroid gland weight. This retrospective cohort study aims to determine if these tools (such as Wisconsin index, CaPTHUS model) can influence decision making at key stages in the management of patients in our population.

Virtual coronary physiology - To compare the physiological impact of two segmentation methods - Dept of Immunity, Infection and Cardiovascular Disease

The final common pathway for patients requiring revascularization with coronary artery disease is the coronary angiogram. The cardiologist makes decisions based upon narrowings seen in the arteries on the 2-dimensional angiogram. This is subjective and inaccurate. We have developed a system of virtual (in silico) 3-dimensional anatomical reconstruction with estimation of the impairment to blood flow using computational flow dynamics based upon those reconstructions. This can provide more accurate information for the cardiologist to use to make decisions about stenting or bypass surgery. Coronary angiograms will be segmented and reconstructed using two similar but distinct methods. The first is a proprietary Philips system which operates on rotational angiography. This has been the basis of our work so far. But we need to allow our system to be applicable to any coronary angiogram. Therefore, the second is a system developed locally within our Group which operates on any standard angiogram. Intracoronary physology will be simulated on paired datasets and the impact of the difference in methods will be analysed. Phantom arteries will also be analysed for a gold-standard comparison.

Liquid biopsy-based testing for melanoma relapse - Dept of Oncology & Metabolism

Melanoma is the most aggressive form of skin cancer, and is increasing in incidence throughout the developed world, with around 15,400 new cases and 2,500 deaths from melanoma in the UK in 2014. The aim of the project is to investigate new ctDNA approaches to detect early metastases in melanoma. Longitudinal samples collected at 3-6 monthly intervals, and matched clinical/pathological data are available for 100 melanoma patients.
The F2 will access patient records to update the follow-up information for all patients, recording disease progression events, sites and dates of progression and dates of death/dates last seen. The existing copy number profile data will be used to investigate the relationship between copy number profile and progression-free survival and overall survival, using graphical approaches and Cox regression adjusting for repeated measures. In addition there will be an opportunity to extend this work by applying novel bioinformatics approaches to the copy number profile data, which will be publishable. The F2 will also determine the tumour mutation burden and neo-antigen burden from a subset of ctDNA samples using an in-house custom-designed sequencing panel.

Neurological complications in patients with Sjogren's syndrome - Rheumatology and neurology department at the Royal Hallamshire Hospital

Neurological complications are common in Sjogren's syndrome. These can in some cases precede the diagnosis of Sjogrens. However, there has been little research done into the prevalence and nature of neurological complications. The study aims to describe neurological manifestations and their prevalence in a cohort of patients with Sjogrens syndrome. The will help to highlight neurological features to be aware of in Sjogrens syndrome and, in some cases, may lead to earlier diagnosis of the disease when neuropathology is the presenting feature.

The cohort used will be patients with primary Sjogren's syndrome attending rheumatology outpatient clinic at Sheffield Teaching Hospital. Data collected from this sample will include demographics (age, gender etc); disease related information (such as time since diagnosis); and neurological symptoms identified during clinic visits. The primary outcome is to analyse the nature and prevalence of neurological complications in patients with primary Sjogrens syndrome.