Clinical Medicine projects

Consult this page for a list of research projects based in the Division of Clinical Medicine.

A skin test conducted by a medical researcher

Viral inflammatory memory in respiratory epithelial stem cells

To quantify the rate and magnitude of interferon-stimulated genes in basal cells that have recently been exposed to Human Rhinovirus (HRV) and Influenza A infection (IAV) and determine the duration of transcriptional memory.

Learn more about this project

Supervisors

Professor Colin Bingle (c.d.bingle@sheffield.ac.uk)
Professor Thushan de Silva (t.desilva@sheffield.ac.uk)
Dr Ben Lindsey

Objectives

Culture basal cells from previous in vitro infected respiratory epithelium.
Quantify expression of specific interferon-stimulated gene mRNAs, pre and post-stimulation with recombinant interferon-ɑ (IFN-ɑ) at several time points (3 days, 7 days, 14 weeks) post-infection.
Compare the magnitude and rate of mRNA expression between HRV and IAV-exposed cells.

Methodology

The student will be trained to independently carry out cell culture which will include counting, seeding and splitting cells. Previously infected and uninfected cultured cells will then be stimulated with varying concentrations of IFN-ɑ (Month 0-3). They will undertake RNA extraction and polymerase chain reaction (PCR) experiments to quantify the mRNA expression under the various conditions outlined above (months 3 to 6). After generating the data they will be supported in analysing and interpreting the data (Months 6-8).

Expected outcome

We hypothesise that the expression of certain interferon-stimulated genes (ISGs) will continue for at least 14 days post-infection with HRV and IAV. It is anticipated that the rate and magnitude of ISGs will be greater in cells that have recently been exposed to viral infection. The effect size may differ between the two viruses and the overall effect will persist for at least 2 weeks.

Type of project

This project primarily involves working in a lab environment

Additional training

Cell culture (counting, seeding, splitting cells)
Light microscopy
RNA extraction
PCR
Data analysis
Opportunity to learn about high-fidelity respiratory epithelial cell culture and transcriptomic methods

Measuring change In MSA (MINIM study)

Does MR volumetry and MR spectroscopy show progressive declines in patients with probable and possible MSA-C, the rate of which will reflect the clinical state of the patients and their survival?

Learn more about this project

Supervisors

Professor Nigel Hoggard (n.hoggard@sheffield.ac.uk)
Professor Marios Hadjivassiliou (m.hadjivassiliou@nhs.net)
Dr I Croall

Objectives

Does MR volumetry and MR spectroscopy show progressive declines in patients with probable and possible MSA-C, the rate of which will reflect the clinical state of the patients and their survival?
Will MR imaging of patients with probable and possible MSA-C reflect the underlying neuropathology causing changes in myelination of the brainstem-cerebellar pathways be demonstrable with MR diffusion tensor imaging (DTI) and magnetisation transfer imaging (MTI) and be reflective of the clinical state of the patient?
Will FDG PET imaging of patients with probable and possible MSA-C detect metabolic changes in brain function that correlate with measurable anatomical changes on MR imaging and the clinical state of the patient?
Will FDG PET imaging of patients with severe and aggressive ataxia help differentiate early MSA-C from autoimmune ataxia?

Methodology

Work Package (WP) 1: Observational, retrospective study of the natural history MSA-C in the Sheffield cohort of around 140 people. This is an opportunity to learn image processing skills such as voxel based morphometry (VBM). Ethics is in place, this will be the main focus of the project.
Work Package (WP) 2: We have commenced recruitment to a single centre pilot study evaluating the use of a range of imaging biomarkers for use in future therapeutic trials. This will be an opportunity to learn PET data analysis skills. Students will not be expected to play a central role in recruitment.

Expected outcome

WP 1: The rate of change in atrophy and MR spectroscopy will be determined in relation to clinical severity and the date of death/disease duration in deceased patients.
WP 2: Comparison of PET imaging with magnetisationisation transfer and DTI to determine the best outcome measures for trial use.

Type of project

Clinical project - based in the clinical environment with patients/including service evaluation

Additional training

This is an opportunity to undertake image processing in the context of neurodegenerative diseases such as voxel-based morphometry (VBM). There will also be an opportunity to gain experience in analysis of PET imaging data, diffusion tensor imaging and magnetisation transfer imaging. These generic skills are widely used across the spectrum of neurodegenerative disease. The software platforms used will mainly be SPM and FSL.

Immune long-term toxicities or late effects in patients on cancer immunotherapy

This project is ideal for a student who is interested in Oncology, endocrinology or indeed other areas of medicine such as respiratory, gastro, renal, Hepatology in view of long term toxicities involved also those who want to understand the increasing role of big data and developing national protected research environments

This is also likely to be a very active area going forward that Sheffield is leading that could late form basis for a PHD project

Learn more about this project

Supervisors

Professor Janet Brown (j.e.brown@sheffield.ac.uk)
Dr Joanne Bird (joanne.bird4@nhs.net)

Objectives

To help review and understand what late effects data should be collected as part of this project and contribute to a published review publication.
To allow students to gain knowledge of immunotherapy toxicity, literature reviewing and designing core datasets.
To gain experience working in a multidisciplinary research team.
For candidate to have opportunities to also present at UK and possibly international meetings on this area.
To develop an understanding of how such national databases contribute to the identification and treatment of late effects

Research Methodology

This project is largely built around data review of existing literature. This is likely to include a modified Delphi exercise with clinicians.

Expected outcome

Review with significant guidance of literature of chosen late effects to include within the data set and to lead in writing a publishable review in this area with guidance.

Type of Project

This is a clinic-based project which will involve attending cancer immunotherapy clinics.

Additional Training

Clinical training in immunotherapy and toxicity scoring, learning about late effects of cancer in the clinic
How to write a relevant review
How to work with digital teams and learn about protected research environments and research ethics
Principles of qualitative research and Delphi exercise
Creating a national research database
Research university ethics and good clinical practice
How to present information at an invited talk
How to make and present a poster

Karonudib: a novel treatment for myeloma

The goal of this project is to validate Karonudib as a treatment for myeloma, using patient cells to confirm data in cell lines and animal models.

Learn more about this project

Supervisors

Dr Alanna Green (a.c.green@sheffield.ac.uk)
Dr Helen Bryant (h.bryant@sheffield.ac.uk)

Objectives

Determine whether Karonudib kills myeloma patient cells
Identify if a dormant cell population can be detected in patient samples, and if so whether Karonudib kills these dormant cells
Validate the mechanism of Karonudib in patient cells

Research Methodology

The student will isolate CD138+ myeloma cells from patient bone marrow (or plasma cells from healthy donors) using magnetic bead separation. Patient cells will be cultured with Karonudib (or vehicle) and full spectrum flow cytometry will be used to measure apoptosis, cell cycle phases, reactive oxygen species (ROS), DNA damage, MTH1 and AXL (dormancy marker) simultaneously in each sample.
Samples will also be taken for qPCR, to correlate Karonudib sensitivity with gene expression, to help validate biomarkers of sensitivity and resistance (which are currently being identified through a Karonudib genome-wide CRIPR screen) to guide a precision medicine approach.

Expected Outcome

We expect that patient cells will respond to Karonudib similarly to cell lines, whereby induction of ROS causes apoptosis. Our data have led to a phase I trial in myeloma patients, and our goal is to progress to phase II. The data generated in this project will help facilitate translation to a phase II trial.
If we can identify a dormant cell population in patient cells, and Karonudib can kill these cells, this may also guide treatment strategies. For instance, whether Karonudib should be given as a maintenance therapy to eradicate minimal residual disease, which persists after chemotherapy.

Type of Project

Lab/Bench Project - primarily working in a lab environment

Additional Training

Lab techniques: cell culture, 2D/3D multicellular models, magnetic bead purification, large-panel full spectrum flow cytometry, apoptosis assays, cell cycle assays, ROS assays, measuring DNA damage markers.
Analysis of flow cytometry data in FlowJo and statistical analysis is GraphPad Prism.

Rare disease phenotyping and genotype-phenotype correlation for HNRNP-related disorders

Heterogeneous nuclear ribonucleoproteins (HNRNPs) have been linked to various diseases, including cancer; neurodevelopmental disorders such as spinal muscular atrophy, amyotrophic lateral sclerosis, congenital myasthenic syndrome, multiple sclerosis, Alzheimer’s disease, and fronto-temporal lobe dementia (Low et al., 2021). Their key roles in regulating transcriptional and post-transcriptional gene expression and their links to numerous diseases mean that it is important to research these conditions with potential wider utility.

Learn more about this project

Supervisors

Dr Meena Balasubramanian (m.balasubramanian@sheffield.ac.uk)

Stuart Wilson (stuart.wilson@sheffield.ac.uk)

Objectives

In this project, the student will recruit patients with HNRNP-related disorders to an ongoing natural history study for which the primary supervisor is the PI. The project will focus on collating clinical information, undertaking literature review, generating methylation episignature and publishing deep dive datasets in this group of disorders.

Methodology

Clinical phenotyping
Data collation from clinical records
Developmental assessment and co-ordination
DNA samples for methylation episignature
Patient consent
Writing up case series of patients with rare genetic disorders

Expected outcome

Clinical series in a peer-reviewed journal
Methylation episignature for HNRNP-related disorders
Conference abstracts

Type of project

Clinical project - based in the clinical environment with patients/including service evaluation

Additional training

Variant interpretation
Clinical phenotyping
Lab work (if interested)

Regenerative strategies for the treatment of human osteoarthritis

This project aims to provide Proof of Concept data supporting the use of a novel injectable hydrogel for repair and restoration of damaged cartilage.

Learn more about this project

Supervisors

Professor Christine Le Maitre (c.lemaitre@sheffield.ac.uk)
Professor Claire Brockett (c.brockett@sheffield.ac.uk)
Professor Mark Wilkinson
Professor Endre Kiss-Toth

Objectives

To determine whether the biomaterial integrates with local cartilage tissue following application
To determine whether articular chondrocytes migrate into the biomaterials within an ex vivo culture system
To carry out biomechanical assessment of biomaterial-induced repair

Methodology

The student will investigate the application of a novel biomaterial on models of osteoarthritis using a combination of waste animal tissues and human tissue from surgery. They will perform ex vivo culture of living osteochondral explants treated with biomaterials. Culture samples will be investigated with a variety of downstream analysis including micro-CT, histology and immunohistochemistry to understand the ability of the biomaterial to induce repair and potential regeneration. In addition, biomaterials will be biomechanically characterised including testing following application to whole joints.

Expected outcome

This project will establish important proof of concept data, as to whether our injectable biomaterial system supports tissue repair, cellular migration and biomechanical restoration of osteoarthritic tissues as a pre requisite for future development for clinical application.

Type of project

Lab/Bench Project - primarily working in a lab environment

Additional training

Issolation of tissues from surgical samples
Ex vivo culture within physiologically relevant conditions
biomaterial handling
biomechanical testing
histology
immunohistochemistry
QPath automated analysis software
Graph Pad Prism
Statistical analysis

Investigating barriers and drivers using Quality Improvement methodology to support implementation of the NHS Green Plan

The student will work with the Quality Improvement Team, the Trust Sustainability Lead and corporate and clinical staff working with the team, including Deputy Medical DirectorDr Helen Crimlisk.

Learn more about this project

Supervisors

Dr Helen Crimlisk (helen.crimlisk@shsc.nhs.uk)
Ms Parya Rostami (Parya.Rostami@shsc.nhs.uk)
Sarah Ellison
Jo Hardwick
Dr Jaimee Wylam
Dr Dasal Abayaratne

Objectives

The student will identify barriers and drivers in clinical and corporate teams using a quality improvement approach outlined in the SusQI Framework.

They will go on to test some of their ideas in conjunction with the QI team measuring outcomes and impact using data collection methods as appropriate to the project.

Research Methodology

This will be a mixed methods approach. The student will use quantitative and qualitative methods including focus groups, literature exploration and data collection through routine quality improvement processes to demonstrate outcome of interventions chosen. It is anticipated that the range of options will include improvements based around individual behaviour, service models and delivery and corporate procurement themes.

Expected Outcome

The student will gain experience at an organisational level in the speciality of mental health of the challenge of implementing transformation to meet challenging targets and the methodologies needed to enable this within an organisation which include a focus on quality and experience of individuals and looking at drivers and barriers and addressing some of these through systems orientated change and leadership.

There will also be the opportunity to understand and participate in specific Quality Improvement projects identified and learn about the system leadership and partnership approach which is necessary to drive change. There is organisational (and indeed NHS) commitment on this strategic aim which will support the project

Type of Project

Qualitative Project/non-lab based - primarily using qualitative methods

Additional Training

Training will be offered in SusQI methodology through and also via the Sheffield Microsystems Academy or other appropriate QI Academy.

There is also the opportunity to link with the RCPsych who offer networking and CPD on Sustainability.

The student will have the opportunity to link with this group through the support of one of the previous College Sustainability Fellows, Dr Dasal Abayaratne, and understand the links to Public and Population Health through the support of Dr Jaimee Wylam, Public Health Registrar, and Jo Hardwick, Head of Population Health. The student will also be supported by SHSC Sustainability Lead Sarah Ellison.

Equitable bereavement care for all

This study aims to understand the needs and experiences of bereavement support services for people from ethnically diverse (ED) communities and begin to identify solutions to better meet current needs. The BSc would represent an individual study within a larger, NIHR-funded research project which is currently being conducted.

Learn more about this project

Supervisors

Dr Catriona Mayland (c.r.mayland@sheffield.ac.uk)
Ms Emily Fisher (e.fisher1@sheffield.ac.uk)

Objectives

The original project objectives were:

To explore awareness, accessibility, and experiences of bereavement support services for people representing specific ED communities.
To investigate barriers and facilitators to improving accessibility, acceptability, and appropriateness of bereavement support services from the perspective of bereaved people

For this project, the individual will conduct a secondary analysis of an established database of qualitative data. This is composed of individual interviews and focus group transcripts of those who have been bereaved and self-identify as being part of an ethnically diverse community. Additionally, the individual will work with specific community organisations helping share findings and considering ways to improve community support.

The specific topic of interest can be discussed between the individual and supervisor but may relate to an overarching concept such as racism or the costs of caring or a specific aspect of formal or informal bereavement support.

Methodology

Concurrent focus group and individual interviews targeting bereaved individuals from a specific community. We will aim to achieve representation of different ages and genders to address intersectionality. The student will potentially work with community researchers, multi-lingual researchers, and interpreters where needed.

Design

Expected outcomes

Description of the facilitators and barriers for awareness, acceptability, accessibility, and ‘appropriateness’ of bereavement support services within a specific ethnically diverse community.
Data regarding contexts and mechanisms of action to improve bereavement support services
Outputs will include an abstract and publication. In addition, the student will assist in the production of a short film of participant narratives, that will form one of the outputs within the larger study.

Type of project

Qualitative Project/non-lab based - primarily using qualitative methods

Additional training

Introduction to qualitative research methods
Training in NVIVO (specific qualitative research package) and qualitative analysis

How can clinical learning in addressing health inequities through holistic care be supported by co-created community placements?

To better understand the impact of community based placements on undergraduates clinical learning in relation to health inequities and holistic care.

Learn more about this project

Supervisors

Dr Joanne Thompson (j.thompson1@sheffield.ac.uk)
Dr Ben Jackson (Ben.jackson@sheffield.ac.uk)
Dr Andy Douglas

Objectives

o explore the co-created element of community based placements through questionnaires and interviews. Students can seek to target recruitment of community partners to particular areas of clinical interest.

Methodology

Students will undertake qualitative research through focus groups and/or semi-structured interviews with medical students who have completed a community based placement during their studies and community providers. A short questionnaire may be used to help inform the qualitative work.

Students will lead the research project and develop skills in creating a research proposal and research ethics application, as well as developing skills in collating, analysing and presenting qualitative data

Expected outcome

Students will complete a research project that develops new knowledge in the emerging medical education field of co-creation and student knowledge exchange. We anticipate that this project will generate sufficient new knowledge for publication in a peer-reviewed journal.

Type of project

Qualitative Project/non-lab based - primarily using qualitative methods

Additional training

Students will receive training in qualitative research methods. They will also be invited to our departmental medical education scholarship forum as well as any relevant GP and/or health inequity events that will support their work.

If more than one student opts for the project, a peer learning group will be supported.

How does cartilage respond to mechanical loading?

The student will lead the project and will be supported by the supervisory team and the lab PhD students and post-docs.

Learn more about this project

Supervisors

Professor Mark Wilkinson (j.m.wilkinson@sheffield.ac.uk)
Professor Endre Kiss-Toth (e.kiss-toth@sheffield.ac.uk)

Objectives

To determine how the human chondrocyte transcriptome responds to mechanical loading
To determine whether disease and normal chindrocytes differ in their responses

Methodology

The student will attend theatre to collect the tissue from the patients, will prepare the tissue for culture and loading using our dedicated mechanical testing jig. They will also take the lead role in the downstream processing of the tissues, including tissue and RNA extraction and in analysing the experimental outputs

Expected outcomes

Enthusiasm and confidence in laboratory skills, understanding scientific writing, and a passion for musculoskeletal research
Oral and poster presentations at relevant local, national and international musculoskeletal meetings
Prominent authorship positions on manuscript outputs that will be submitted to leading journals in the field
A successful research dissertation

Previous intercalating students in our group have won local, national and international awards for meeting presentations and had their work published in leading journals including Lancet Rheumatology and Journal of Bone and Joint Surgery.

Type of project

Lab/Bench Project - primarily working in a lab environment

Additional training

This project will expose the student to many clinical and laboratory skills:

Ethics and consent around biobanking of human tissue samples (including patient interaction)
Tissue culturing
Mechanical loading of cells and tissues
Extracting cells from cartilage
Extracting RNA from the cells
Assessing RNA quality
Running PCRs for various genes
Research methodology
Cartilage and osteoarthritis biology

Role of NBAS in human disease beyond bone fragility

This project builds upon our work focusing on the zebrafish model to unravel the molecular causes of this disease and to develop a platform for high-throughput drug screens to identify drugs that may one day be used in the clinic. During your training year, you will use cutting-edge techniques such as lightsheet and AIRY scan microscopy, CRISPR/Cas9 gene editing and robot-based drug library screening.

The overarching hypothesis is that NBAS causes a multi-system disorder affecting skeletal development and liver and immune abnormalities in zebrafish: unravelling disease mechanism.

Learn more about this project

Supervisors

Dr Meena Balasubramanian (m.balasubramanian@sheffield.ac.uk)
Professor Steve Renshaw

Objectives

Analyse in-depth the skeletal, liver and immune abnormalities of homozygous mutant NBAS fish
Recapitulate human phenotype, by generating disease-specific mutant zebrafish using CRISPR-Cas9
Drug screening assay to identify potential therapeutics

Methodology

Whole genome sequencing studies have led to a vast amount of new candidate genes for human diseases. One such gene is the Neuroblastoma Amplified Sequence gene (NBAS) which, when mutated, results in acute liver failure and skeletal abnormalities such as SOPH syndrome, short stature or optic atrophy (Maksimova et al., 2010).

Patients with NBAS mutations are subjected to a lifetime of recurrent fractures, repeated episodes of acute liver failure needing recurrent hospital admissions and immune deficiency (Balasubramanian et al., 2017). We have recently developed a zebrafish model which carries mutations in NBAS and displays skeletal malformations that are reminiscent of the human condition. Analysis done in my lab as well as others suggests that NBAS may play a role in the secretion of collagen.

Expected outcomes

Analyse skeletal and liver abnormalities in NBAS mutant zebrafish
Compare with manifestations in Crispr fish
Drug screening to identify potential therapeutic hits for further work-up

Type of project

Lab/Bench Project - primarily working in a lab environment

Additional training

Genotype-phenotype correlation
Zebrafish genotyping
Skeletal analysis in zebrafish
Immune response in zebrafish model
Literature review of NBAS phenotypes

Investigating novel tissue-resident macrophage populations in vivo

The white blood cells known as macrophages play an essential role in development, homeostasis, immunity and repair. The macrophage lineage is highly heterogeneous owing to the existence of tissue-resident populations alongside the ability to become activated to a range of states (termed macrophage polarisation).

Our lab used the genetically-tractable model organism Drosophila melanogaster (fruit flies) to understand the regulation of macrophage function in vivo. We have recently discovered, for the first time, the existence of developmentally-regulated macrophage subpopulations in this organism. Fruit flies have been extensively utilised to understand immunity, not least in its role in the discovery of the immunoregulatory role of Toll receptors, for which Hoffmann received the Nobel Prize for Medicine.

This project aims to understand the function of these subpopulation macrophages and their relationship to vertebrate macrophages in more detail.

Learn more about this project

Supervisors

Dr Iwan Evans (i.r.evans@sheffield.ac.uk)
Dr Martin Zeidler (m.zeidler@sheffield.ac.uk)

Objectives

In order to understand the importance of these subpopulations the student will use genetic strategies to ablate subpopulation macrophages at various stages of the fly life cycle and examine the consequences for development, survival and immunity. In particular, the student will examine the ability of the organism to fight off infections and repair damage when the macrophage subpopulations are removed. We will also address the effects of expanding these subpopulations.

Genes that are differentially expressed between subpopulations will also be investigated to understand the contributions that they make to immune responses in vivo.

Methodology

This project involves genetics, molecular biology, in vivo imaging, microscopy, image processing and analysis and statistical analysis. The student will take charge of their own Drosophila stocks and conduct genetic crosses to generate progeny in which subpopulation macrophages have been manipulated or candidate genes removed/overexpressed. The resulting fly embryos, larvae and adults will be analysed in a range of assays to understand the role of these subpopulation macrophages. Live imaging will then be analysed using software including Fiji and quantitative data obtained from these images. Other non-microscopic data will also be collected (eg survival of flies following infection or injury).

Expected Outcome

This project will enable us to understand the role of Drosophila macrophage subpopulations in response to infection, during development and during aging.

We will assess the role of candidate genes differentially expressed between subpopulations in these responses.

Type of Project

Lab/Bench Project - primarily working in a lab environment

Additional Training

Full training in all techniques will be provided by my lab. This will include fly genetics, fly husbandry, dissection techniques, in vivo imaging, microscopy, image processing and analysis, statistical analysis in Prism.

We have weekly lab meetings and also take part in bimonthly fly meetings with groups in BMS. We have an annual lab retreat with other immunity-focused groups in IICD/BMS and are part of the Bateson Centre.

Remote haemodynamic monitoring for personalised and experimental medicine in patients with pulmonary arterial hypertension

We have developed a cohort of patients with Pulmonary arterial hypertension (PAH)in whom implanted sensors provide remote assessment of pulmonary artery pressure, cardiac output, heart rate and rhythm, and physical activity daily. Patients from this cohort will be enrolled in an MRC-funded experimental medicine study that aims to determine if devices provide an early indication of clinical efficacy in patients with pulmonary arterial hypertension.

Learn more about this project

Supervisors

Dr Alex Rothman (a.rothman@sheffield.ac.uk)
Dr Jennifer Middleton (j.middleton@sheffield.ac.uk)

Aims

To evaluate the acceptability of the implantable technology in this patient group
To determine the capacity for determination of therapeutic efficacy compared to established clinical study endpoints

Objectives

Enrol patients from the cohort in an MRC-funded experimental medicine study
To evaluate the usability of technology within this patient group
Evaluate the capacity of technology to detect change with the addition of therapy

Methodology

NIHR good clinical practice training for research – online course.
Data analysis study using remote monitoring and clinical data already available from patients recruited into FIT-PH and implanted with remote monitors.
Patient data relayed to an online portal – data will be exported and added to an existing database of clinical parameters, drugs and investigation results.
Statistical analysis undertaken to related changes in therapy to changes in remote monitoring parameters.

Expected outcome

From early participants in the study, it is expected that technology is usable and accurately detects change following the addition of therapy. The study will contribute to an ongoing, funded study which aims to repurpose imatinib for the treatment of PAH

Type of project

Clinical project - based in the clinical environment with patients/including service evaluation

Additional training

Good clinical practice
Remote monitoring
Data extraction and curation
Statistical analysis

The Health of Sheffield in Context: 1893-1973

This project would suit someone interested in the history of medicine and social change but who also wishes to gain experience of data handling and scientific methods. Western Bank Library contains in its archives a large series of yearly Medical Officer's reports on the 'Health of Sheffield' from 1893 to 1973. These include detailed mortality statistics, developments in the city's provision of health services and other important observations. The period in question was clearly a time of great medical, social and political change.

Learn more about this project

Supervisors

Dr William Parker (w.parker@sheffield.ac.uk)
Dr Victoria Parker (v.parker@sheffield.ac.uk)

Objectives

Extract data on health outcomes from an extensive and important historical series of reports on our city's health from 1893 to 1973.
Analyse and plot the data to establish key trends in health outcomes in Sheffield over the period, backed up by robust statistical analysis.
Compare Sheffield's data to available national data from the period and with data from our own time.
Contextualise and rationalise the findings considering local and national medical, social and political factors, identifying case studies and delving into personal stories to illustrate these.
Draw conclusions regarding the relationship between past and current healthcare needs and provision.

Methodology

You will initially digitise mortality data from these reports then use this to study changes in health outcomes over time, including using detailed statistical analysis. You will then reflect on your findings by placing these in the context of medical, social and political change, conducting additional research into this as needed, including using local and national archives where appropriate. Detailed research into several key 'case studies' will involve finding and analysing primary sources that illustrate themes through personal testimony.

Expected outcome

The student will obtain definitive data on local mortality trends relating to a significant historical period that saw many changes including the boom and bust of the industrial age, war, key developments in medical treatments and the establishment of the National Health Service.

They will perform a robust analysis of this data to draw firm conclusions on how health outcomes changed in our city over the period. They will explore these further through historical research with significant flexibility to delve into areas of the findings that particularly interest the student.

The student will have the tools to produce a dissertation that is unique, vibrant and thoughtful, yet contains rigorous scientific analysis of data.

Type of project

Medical Humanities

Additional training

Electronic data handling
Searching and using archive material
Critical appraisal and integration of sources
Statistical analysis and graphical presentation of data
Writing, reflection and oral presentation.
Medical and social history

Therapeutic targeting of hypoxia signalling in TB

Mycobacterium tuberculosis, the causative bacteria of TB, has specialised to survive and proliferate within our immune cells (leukocytes), disarming bacterial killing mechanisms. One such mechanism is hypoxia signalling (mediated by the Hif-alpha transcription factor), a pro-inflammatory signal that is initially activated upon infection but is then dampened by TB. We have shown that stabilising the Hif-alpha signal is beneficial to fight infection, but can have the negative impact of prolonging inflammation.

Learn more about this project

Supervisors

Dr Philip Elks (p.elks@sheffield.ac.uk)
Dr Simon Johnston (s.a.johnston@sheffield.ac.uk)

Objectives

The aim of this project is to determine whether Hif-alpha can be modulated in a beneficial way during infection without causing negative effects on inflammation outcomes.

Methodology

In the lab, we use the zebrafish embryo as an in vivo model to understand host-pathogen interactions. Zebrafish embryos are transparent allowing in vivo time-lapse microscopy of host-pathogen interactions. We have previously developed genetic and pharmaceutical tools to manipulate and follow hypoxia signalling within the zebrafish embryo. These will be used in a Mycobacterium marinum (Mm) model of TB infection and a tailfin inflammation model.

Infection and inflammatory outputs will be assessed using fluorescent microscopy techniques.The project will give the student broad training in a variety of key techniques including zebrafish husbandry, microinjection, molecular biology, microbiology and fluorescent microscopy.

Expected outcomes

Hypoxia signalling will be modulated during infection and inflammation. Understanding the cellular mechanisms involved will help develop hypoxia signalling as an exciting target for therapeutic intervention against TB, without having negative consequences for inflammation.

This work is part of a broader aim of the lab to understand the mechanisms of hypoxia signalling in TB infection and it is likely that data from this project will contribute to publication outputs of the lab. Students will be located in a busy and social lab, and will be well-supervised, learning cutting-edge techniques.

Type of project

Lab/Bench Project - primarily working in a lab environment

Additional training

Students will be well-trained in lab techniques including molecular biology, zebrafish husbandry and quantitative imaging. The imaging will be both fluorescent widefield and confocal imaging and will involve the use of image analysis software including Leica LASX and ImageJ. Quantitation and graphical representation of results to obtain statistics will be performed in Graphpad Prism.

In addition to lab techniques the students will have access to scientific training via departmental seminars, journal club and regular lab meetings with the group. If successful then there may be opportunities to present their work at local and national meetings.

Improving detection of pulmonary arterial hypertension in systemic sclerosis patients using hyperpolarised gas magnetic resonance imaging

Learn more about this project

Supervisors

Dr Roger Thompson (R.Thompson@sheffield.ac.uk)
Professor Jim Wild (j.m.wild@sheffield.ac.uk)

Objectives

Establish Xenon-based MRI (Xe-MRI) indices that differentiate between SSc patients who have PAH (SSc-PAH) and those who do not (SSc-noPH).
Assess whether Xenon-based metrics improve the positive predictive value of existing tools.
Determine the utility of Xe-MRI metrics for detecting changes in response to treatment in newly diagnosed PAH-SSc patients.

Methodology

Students will complete GCP, consent and study-specific training. Working alongside a clinical fellow and/or research nurse, students will identify and recruit study participants, carry out study visit assessments (.g clinical assessments, blood samples/processing, lung function testing, imaging scans) and collect and analyse data.

Expected outcomes

Data collected will contribute to publications and the student will be a co-author of these outputs. The student will gain opportunities to present data at national and international conferences. Experience in advanced imaging would prove particularly useful for future careers in radiology, respiratory medicine or cardiology.

Type of project

Clinical project - based in the clinical environment with patients/including service evaluation

Additional training

Students will gain experience of clinical research with an emphasis on imaging techniques. Students will have the opportunity to attend the pulmonary hypertension and imaging MDT meetings, clinics (to help with recruitment) and weekly clinical and scientific educational meetings.

Computational modelling of coronary artery blood flow in acute coronary syndromes

To determine the impact of modelling coronary blood flow in patients with coronary artery disease (CAD)

Learn more about this project

Supervisors

Professor Julian Gunn (j.gunn@sheffield.ac.uk)
Dr Paul Morris (paul.morris@sheffield.ac.uk)

Objectives

Read about the current management of CAD.
Learn about coronary angiography and fractional flow reserve (FFR).
Learn about our computer model systems of flow, based upon the angiogram.
Screen the angiograms.
Run the systems and work out the virtual FFRs.
Determine how virtual FFR can change treatment decisions.

Methodology

Reconstruct the study vessels
Run the 3 software packages
Determine the vFFR values (FFR > or < 0.80)
Compare the performance of the 3 systems
Compare actual angiographic-based management (stent or not) with vFFR-based management

Expected outcomes

We have supervised 28 BMedSci/BSc students over the years and the vast majority have got a first. You will obtain a publication in a Cardiology journal and a presentation at a conference

Type of project

Lab/Bench Project - primarily working in a lab environment (mostly virtual)

Additional training

The data will be ready for you.
The software licences will be available.
We can train you in interpreting angiograms.
We will train you to use the software.
All ethical approvals are in place.
You will be supervised to analyse the data and write a report.
The lab work mentioned above can be remote, on a laptop, in your own time.

Production and characterisation of viral proteins for medical biotech applications

Aims: Optimise production of recombinant viral proteins; characterise viral proteins; determine molecular structure and interactions of viral proteins.

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Supervisors

Professor Jon Sayers (j.r.sayers@sheffield.ac.uk)

Dr Pat Baker (p.baker@sheffield.ac.uk)

Dr Martin Nicklin

Objectives

This project could address many questions, including:

For a project on SARS-CoV-2 Nucleocapsid protein (NCAP, which condenses viral RNA and packages it into the capsid) we can ask how variations in viral protein sequence impact nucleic acid binding. Do these proteins behave differently in diagnostic tests such as ELISA or rapid antigen tests?
Production of SARS-CoV-2 Spike protein (the active immunogen in most currently used vaccines) is limited by the relatively poor yield of Spike protein. We have engineered recombinant Spike protein that we believe can be made in much larger amounts than any currently produced. We can ask whether these altered Spike proteins are still recognised by commercial antibodies to "natural" Spike proteins. Do these proteins behave differently in diagnostic tests such as ELISA or rapid antigen tests?
Recombinant viral nucleases are used in point-of-care diagnostic devices in FDA-approved tests for gonorrhoea with other target pathogens under development. The price of the nuclease represents a large proportion of the overall cost per test. Can we use protein engineering to make more efficient enzymes and hence reduce the cost per test facilitating better monitoring of infection and targeted use of antimicrobial agents?

For examples 1 and 2, we would make use of sera collected under the COVID-19 Humoral ImmunE RespOnses in front-line health care workers (COVID HERO) study in collaboration with Dr Thushan de Silva. Example 3 would not require such samples.

Methodology

We have been making SARS-CoV-2 (causative agent of COVID-19) antigens for DoHSC, NIBSC and UKNEQAS for use as standards and have supplied a UK consortium with this protein to develop new diagnostic technologies that do not rely on PCR. You will use our established recombinant DNA technology to optimise the production of newly arising variant viral Nucleocapsid proteins and other nucleic-acid binding proteins.

You will use biophysical and structural biology techniques to determine the biological activity and 3D structure of the proteins using a range of state-of-the-art technologies available locally. Full training in all laboratory techniques will be given.

Expected outcomes

The student will be trained in laboratory and computer-based 3D structure-determination methods underpinning modern structure-based drug discovery. You will produce useful reagents that we will disseminate to the wider scientific and commercial sectors as they are potentially useful for the development of diagnostic and molecular biological reagents.

You will produce quantitative data showing the strength of interactions between viral proteins and their interaction partners.

Type of project

Lab/Bench Project - primarily working in a lab environment

Additional training

I run an advanced module in analysis of protein interactions and in silico structural biology. The student could participate in these during semester ( 7 days hands-on workshops) and classes in recombinant protein production and purification.

Discovering new drugs for neglected tropical diseases

We work on flap endonucleases which are essential enzymes that process the branched DNA that accumulates during cell division. We have developed inhibitors of bacterial FEN enzymes that can kill bacteria but are relatively non-toxic to human cells.

This project aims to African trypanosomiasis, Chagas disease and leishmaniasis. FEN activity is crucial for the survival of all organisms tested, from mammals to bacteria, making them viable targets for antimicrobials.

The project is based on experience from pilot projects and a spin-out company focusing on the design of bacterial FEN inhibitors and is overseen by Professor Jon Sayers, who has 30 years of experience with nucleases.

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Supervisors

Professor Jon Sayers (j.r.sayers@sheffield.ac.uk)
Dr Martin Nicklin (m.nicklin@sheffield.ac.uk)

Objectives

You will receive training in structure-based drug design and use that training to answer the following research questions:

Can inhibitors with selectivity for parasites over human flap endonuclease enzymes be identified by a combination of fragment library and in silico screening?
Do these inhibitors interact with the protein, the DNA or both?
Do these inhibitors kill parasites?

Methodology

The student will be trained in laboratory and in silico methods underpinning modern structure-based drug discovery. This multidisciplinary structure-based inhibitor design project involves in vitro and/or in silico screening, hit identification using FRET-based enzyme assays, and protein crystallisation, on top of standard molecular biology techniques, like recombinant protein production and characterisation.

If appropriate, further techniques are available, including biophysical characterisation of protein-inhibitor interactions using our new state-of-the-art Bio-Layer Interferometry equipment, or structural biology employing X-ray crystallography

Expected outcomes

You will produce recombinant protein, check quality and activity and carry out enzyme inhibitor assays on parasite and human FEN enzymes to screen a library of so-called "drug fragments". You will compare the results for the human and parasite enzymes to identify molecules which show some level of selectivity (ie inhibit the parasite but not the human enzyme). You will also generate a computer-based model and attempt to refine it according to the data you acquire. You will then use these data to carry out a "hit expansion" to identify more potent but selective inhibitors.

Type of project

Lab/Bench Project - primarily working in a lab environment

Additional training

I run an advanced module in the analysis of protein interactions and in silico structural biology. The student could participate in these during the semester (seven days of hands-on workshops).

Investigating novel tissue-resident macrophage populations in vivo

The white blood cells known as macrophages play an essential role in development, homeostasis, immunity and repair. The macrophage lineage is highly heterogeneous owing to the existence of tissue-resident populations alongside the ability to become activated to a range of states (termed macrophage polarisation).

Our lab used the genetically-tractable model organism Drosophila melanogaster (fruit flies) to understand regulation of macrophage function in vivo. We have recently discovered, for the first time, the existence of developmentally-regulated macrophage subpopulations in this organism. Fruit flies have been extensively utilised to understand immunity, not least in its role in the discovery of the immunoregulatory role of Toll receptors, for which Hoffmann received the Nobel Prize for Medicine.

This project aims to understand the function of these subpopulation macrophages and their relationship to vertebrate macrophages in more detail.

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Supervisors

Dr Iwan Evans (i.r.evans@sheffield.ac.uk)
Dr Martin Zeidler (m.zeidler@sheffield.ac.uk)

Objectives

To understand the importance of these subpopulations the student will use genetic strategies to ablate subpopulation macrophages at various stages of the fly life cycle and examine the consequences for development, survival and immunity. In particular, the student will examine the ability of the organism to fight off infections and repair damage when the macrophage subpopulations are removed. We will also address the effects of expanding these subpopulations.

Genes that are differentially expressed between subpopulations will also be investigated to understand the contributions that they make to immune responses in vivo.

Methodology

Expected outcomes

This project will enable us to understand the role of Drosophila macrophage subpopulations in response to infection, during development and ageing.

We will assess the role of candidate genes differentially expressed between subpopulations in these responses.

Type of project

Lab/Bench Project - primarily working in a lab environment

Additional training

Full training in all techniques will be provided by my lab. This will include fly genetics, fly husbandry, dissection techniques, in vivo imaging, microscopy, image processing and analysis, and statistical analysis in Prism.

We have weekly lab meetings and also take part in bimonthly fly meetings with groups in BMS. We have an annual lab retreat with other immunity-focused groups in IICD/BMS and are part of the Bateson Centre.

Involvement of the brain in painful diabetic peripheral neuropathy

What is the progression of structure and functional changes within the brain in painful diabetic peripheral neuropathy?

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Supervisors

Dr Gordon Sloan (gordon.sloan@sheffield.ac.uk)
Dr Dinesh Selvarajah (d.selvarajah@sheffield.ac.uk)

Objectives

Determine the changes in brain structure in key regions associated with somatosensory function (S1 cortex and thalamus) and nociception (insular cortex and anterior cingulate cortex) from baseline in patients with Painful-DPN compared to patients with Painless- and No-DPN.

Methodology

The student will both be involved in the assessment of participants within the study, which involves detailed clinical and neurophysiological tests. The students will be trained to perform some of these study visits independently. Moreover, the study will involve analysis of the data, including brain imaging data.

Expected outcomes

In addition to the report, it is expected that this study will lead to publications in peer-reviewed journals, for which the student will be included in the authorship. Moreover, the student may be able to present the work at national and international professional conferences.

Type of project

Clinical project - based in the clinical environment with patients/including service evaluation

Additional training

In addition to the report, it is expected that this study will lead to publications in peer-reviewed journals, for which the student will be included within the authorship. Moreover, the student may be able to present the work at national and international professional conferences.

Quantification of trans-mural perfusion gradients to improve the diagnostic accuracy of stress-perfusion cardiac magnetic resonance imaging

Quantitative assessment of trans-mural perfusion gradients on stress-perfusion cardiac magnetic resonance imaging is feasible and can improve the diagnostic accuracy compared to standard visual assessment.

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Supervisors

Dr Rebecca Gosling (r.gosling@sheffield.ac.uk)
Dr Paul Morris (paul.morbis@sheffield.ac.uk)

Objectives

Develop a technique for quantifying the TPMG on stress-perfusion cardiac magnetic resonance imaging.
Apply the refined technique to retrospective cases to demonstrate feasibility and compare results with standard visual assessment.
Identify a threshold of TPMG that best correlates with the presence of significant disease at coronary angiography.
Determine the ability of TPMG to identify patients with significant coronary artery disease at angiography by assessing the diagnostic accuracy, sensitivity, specificity, positive predictive value and negative predictive value.
Compare the diagnostic accuracy of TPMG with standard visual assessment.

Methodology

The student will be instructed in how to use MASS imaging analysis software which will be used to analyse the CMR scans. They will then be given access to retrospective cases. The student will work with the supervisor to test several proposed techniques to quantify the TPMG on a small subset (n=~10).

They will determine the best strategy by comparing the results with coronary angiography results. They will then employ the optimum technique in a larger cohort (N=~40) and assess the diagnostic accuracy in terms of the ability to predict the presence of significant disease at coronary angiography. They will compare this with standard visual assessment to test the hypothesis that this novel technique can improve the accuracy.

Expected outcomes

At the end of the project the student will have identified the optimal technique for quantifying the TMPG and will have tested it on a cohort of patients who have also undergone invasive coronary angiography; the gold standard. They will then determine the diagnostic accuracy of this novel technique and compare it with visual assessment (the current standard method used in clinical practice).

We aim to show that this technique can improve the diagnostic accuracy of stress perfusion CMR.

Type of project

Lab/Bench Project - primarily working in a lab environment

Additional training

The student will be trained in CMR image analysis using the MASS software that will be used for this project. This will be via face-to-face sessions with the supervisor as well as access to online tutorials and pre-recorded videos.

The student will also have the opportunity to visit the cardiac catheter laboratory at the Northern General Hospital to witness some invasive coronary angiography and PCI procedures as well as the university CMR scanner to witness some CMR scans. This will help them gain insight into the clinical problem being addressed and the patient cohort they are studying.

The student will gain hands-on experience of SPSS that will support the taught element of the course.

Zebrafish tales to human intervention for inflammatory disease

Inflammatory diseases such as COPD, asthma, heart disease, arthritis, and more recently COVID-19, contribute to significant death rates worldwide. We have little understanding of how the severe inflammation associated with something like pneumonia can completely resolve, while other sorts of inflammation persist with associated tissue damage.

We know little of the processes that cause the resolution of inflammation in any setting. The primary inflammatory leukocyte, the neutrophil, is key to mounting an inflammatory response. However, the regulation of these cells is critical for a successful inflammatory response. When the functions of this cell become dysregulated, tissue damage and disease occur. In our lab, we are interested in mechanisms that regulate neutrophil function and removal from inflammatory sites.

Because it is not very easy to genetically manipulate human neutrophils, we have developed a zebrafish model where genes can easily be mutated or pharmacologically inhibited, and neutrophils can easily be seen throughout the inflammatory process. We are currently investigating RNA binding proteins (RBPs) as a method of controlling neutrophil function for therapeutic intervention.

Hypothesis: Neutrophil-specific expression of the RNA-binding protein ELAVL1, determines RNA stability and regulates neutrophil function in the inflammatory response.

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Supervisors

Mrs Catherine Loynes (c.loynes@sheffield.ac.uk)
Professor Stephen Renshaw (s.a.renshaw@sheffield.ac.uk)

Objectives

Generate neutrophil-specific elavl1a/b mutants in zebrafish using CRISPR/Cas9.
Characterise the neutrophil phenotype in these mutants using in vivo neutrophil function assays including apoptosis, reverse migration, ROS production.
Assess RNA transcript levels using qPCR in these mutants.
Use ELAVL1 inhibitors to pharmacologically block ELAVL1 function and assess neutrophil function assays.

Methodology

You will use molecular cloning to generate DNA constructs that will allow mutation of elavl1a/b genes in zebrafish embryos. You will then perform single-cell injections of these into the freshly fertilised embryos to cause genetic mutations in Elavl1 genes. You will assess neutrophil function following tailfin transection using recruitment and resolution assays, cell counts, cell death (apoptosis) and reverse migration and RNA transcript level by qPCR.

Zebrafish will be treated with chemical inhibitors to block Elavl1 function and perform neutrophil assays. Training will be given in fluorescent and confocal microscopy. Zebrafish handling will be trained and performed routinely.

Expected outcomes

Generate DNA constructs containing guide RNA sequence for elavl1a/b
Generate data on key neutrophil functions by performing tail fin transections on larvae.
Assess RNA transcript levels to ascertain the role of elavl1 and elavl1b in controlling these functions through gene expression.
Try and complement the data from genetic manipulation of Elavl1 through pharmacological inhibition of Elavl1 using tanshinones.
Be competent at data analysis, interpretation and presentation.
Learn scientific writing styles at journal clubs and through thesis write-up.
Be aware of the legalities of animal research and be competent at handling zebrafish.

Type of project

Lab/Bench Project - primarily working in a lab environment

Additional training

All wet lab work will be trained by C Loynes. You will have a specific aquarium induction and learn how to handle fish, sort embryos and perform tailfin transection on larvae.

You will also be trained in the Light Microscope Facility to access a variety of microscopes.

You will learn how to use Snapgene, Ensembl, and statistical analysis packages.

Determinants of the thrombotic response in women with or at risk of hypertensive disorders of pregnancy

What is the fingerprint of the thromboinflammatory response in women with hypertensive disorders of pregnancy such as pre-eclampsia?

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Supervisors

Dr William Parker (w.parker@sheffield.ac.uk)
Professor Robert Storey (r.f.storey@sheffield.ac.uk)

Objectives

Gain an understanding from the literature of current knowledge around dysfunction of the thromboinflammatory response in hypertensive disorders of pregnancy.
Recruit participants to obtain blood and urine +/- placental samples from women with and without hypertensive disorders of pregnancy.
Analyse these samples to gain a new understanding of the dysfunction of the thromboinflammatory system in hypertensive disorders of pregnancy.

Methodology

The student will recruit participants with hypertensive disorders of pregnancy (e.g. pre-eclampsia) and women with healthy pregnancies from the Jessop Wing. They will obtain blood and urine samples and then process and analyse these in the laboratories at The Jessop Wing and in the Cardiovascular Research Unit at the Northern General.

Expected outcomes

You will obtain comprehensive data on thrombotic and inflammatory parameters in women with and without hypertensive disorders of pregnancy. This can be combined with existing data we have obtained to.

You will gain experience of both clinical and laboratory research and the chance to study both women's health and cardiovascular elements.

Type of project

Clinical project - based in the clinical environment with patients/including service evaluation

Additional training

Good Clinical Practice certification to undertake clinical research.
Recruiting and communicating with participants.
Venepuncture.
Laboratory techniques of platelet function testing, measuring proteins, flow cytometry, molecular biology

Artificial intelligence assessment of imaging investigations can detect pulmonary hypertension more effectively than humans

Can an automatic classification network detect and distinguish effectively between pulmonary hypertension and non pulmonary hypertension cases using multi scanning modalities?

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Supervisors

Professor Andy Swift (a.j.swift@sheffield.ac.uk)
Dr Samer Alabed (s.alabed@sheffield.ac.uk)

Objectives

Collect different modalities of cardiac imaging data (MRI, X-ray, CT, echo)
Create a data structure linking different diseases and scanning modalities
Apply different AI classifier techniques to detect different cardiac pathology
Combine the different AI classifiers and extract a main framework for cardiac disease detection.

Methodology

The student will be involved in collecting and curating imaging data from various modalities (MRI, X-ray, CT, and echocardiography). They will assist in developing and optimizing AI classifiers to identify pulmonary hypertension. The student will gain hands-on experience in AI model development, medical imaging analysis, and multi-modality integration.

Specific AI techniques (such as CNNs or ensemble learning) will be taught, and the student will have the opportunity to work closely with experts in both radiology and machine learning.

Expected outcomes

The expected outcome of the project is the development of an AI-based framework capable of detecting pulmonary hypertension from multimodal imaging data. The study will assess the accuracy and effectiveness of this AI model compared to human interpretation.

The AI system is anticipated to provide faster and more accurate diagnosis, ultimately improving patient outcomes in clinical settings.

Type of project

Clinical project - based in the clinical environment with patients/including service evaluation

Additional training

The student will receive training in machine learning techniques specific to medical imaging, including image pre-processing and AI model optimization. Additionally, they will be introduced to statistical analysis methods used to evaluate AI performance and will learn how to use Python-based AI libraries.

Training will also include ethical considerations in AI and data handling, as well as guidance on publishing research findings.

Characterising the nature and outcome of coronary artery ectasia

Coronary artery ectasia (CAE) is a rare phenomenon where the coronary arteries become markedly dilated and dysfunctional, often resulting in clots forming that cause recurrent heart attacks. We have little idea of the risk factors for CAE and even less of an idea how to treat it.

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Supervisors

Dr William Parker (w.parker@sheffield.ac.uk)
Professor Julian Gunn (j.gunn@sheffield.ac.uk)

Objectives

The aims of this project will be to

perform a comprehensive literature review to establish current knowledge
build a database of cases from the Sheffield cardiac cath lab records to study the characteristics, risk factors, imaging findings and treatment of CAE cases
perform computer modelling using imaging of several cases to gain insights into the physiological disturbances associated with CAE

Methodology

Literature review
Clinical database work
Statistical analysis
Computer modelling

There will also be the opportunity to work on other projects and to gain clinical experience in cardiology if desired.

Expected outcomes

This project will build a large database of CAE cases using records from our busy interventional cardiology centre (3rd busiest in the UK) that will likely be the biggest for this condition developed to date. They will build up an unrivalled expertise in the condition and gain further insights by computer modelling. The student will therefore generate original, impactful data, and develop a range of skills such as data analysis and computational modelling.

Type of project

Clinical project - based in the clinical environment with patients/including service evaluation

Additional training

Training in coronary artery physiology, pathology and treatment. Data analysis and presentation, computer modelling.