Impact Case Studies (HTML) 

Translational Neuroscience

Case Study 1: Developing the most promising treatment approach to date for patients with motor neuron disease (MND)

MND (sometimes referred to as ALS) is a fatal, rapidly progressing, paralysing disease. Connections from the brain to the spinal cord (upper motor neurons) and from the spinal cord to the muscles (lower motor neurons) may die, resulting in loss of muscle control. There is no treatment to slow disease progression. Patients die on average within 2-3 years of symptom onset. 

Researchers in Sheffield, supported by the Sheffield Motor Neuron Disease Research Advisory Group, pioneered a genetic therapy approach to lower the production of the mutated SOD1 protein in pre-clinical models of MND. This pre-clinical translational work achieved the best improvement to date, improving motor function and survival and giving confidence that this approach might work in human patients (references 1 and 2). 

How did it work? 

Study Sponsor: Biogen

"These advances signal a new beginning for ALS therapeutics" Editorial: New England Journal of Medicine. 

The NIHR Sheffield BRC was the only UK site; enrolling 7 of the 50 total patients worldwide. 

The pivotal phase 3 evaluation was fast-tracked for regulatory approval.


Case Study 2: Increasing access to Autologous Haematopoietic Stem Cell Transplantation (AHSCT) for patients with relapsing remitting MS

Multiple Sclerosis (MS) is the leading cause of disability in young adults.  More than 120,000 people are affected in the UK. Currently available disease-modifying therapies (DMTs) reduce relapse rate and slow disability to varying degrees, but do not halt progression.  The annual cost per patient of current DMTs, excluding the costs of clinical care, is £15,000-£35,000

Is there a solution?

AHSCT is a novel therapeutic strategy based on deleting autoreactive lymphocytes with the use of various 'conditioning regimens' and restarting a new immune system, using the person's own stem cells in a non-inflammatory environment without co-stimulatory signals (as featured on BBC's Panorama in 2016). 



Professor Sharrack, in partnership with Haematology Professor John Snowden, developed a UK-led, randomised controlled trial of AHSCT versus Alemtuzumab or Ocrelizumab (Star MS) in relapsing-remitting MS. They worked collaboratively with the NIHR EME board, the MS Society, MS patients, NIHR Imperial BRC, Sheffield Clinical trails Research Unit, and NIHR Sheffield CRF. 

The MIST Trail (reference 3)


Case Study 3: The CognoSpeak solution: An improved, faster way to assess people with memory problems

There has been an almost 7-times rise in referrals to specialised memory clinics over recent years. creating an urgent need to ensure quicker access to specialist assessment. 

Proven clinical need:

The solution?

Working closely with our Equality, Diversity and Inclusion team members, we have developed CognoSpeak, a tool that uses the automatic analysis of conversations that patients have with an on-screen digital doctor (reference 2). Patients' speech is examined for signs of cognitive decline using automatic speech recognition, diagnostic feature identification and classification involving machine learning (reference 3). 

CognoSpeak distinguished between those in the Alzheimer's Disease or Mild Cognitive Impairment groups and those in the Functional Cognitive Disorder or healthy control groups with a sensitivity of 86.7% (reference 1). These levels of accuracy are comparable to the manually administered assessments currently available. 

CognoSpeak has an £86m potential NHS cost saving of 52.6%. The NHS pathway cost (via GP and memory clinics) over 5 years is £164m. The proposed CognoSpeak pathway would cost just £78m.

Patient Engagement and Co-Design


Cardiovascular Disease

Case Study 1: Reducing blood clot risk in patients with cardiovascular disease and diabetes

Cardiovascular disease (CVD) is the leading cause of death in type 2 diabetes. 

High blood sugar due to diabetes causes:

Insulin therapy for diabetes can cause hypoglycaemia (when blood sugar levels drop too low). This side-effect of treatment increases adrenaline levels and causes inflammation, an increased clotting tendency and increased risk of serious heart rhythm disturbances.

This leaves the patient in a pro-thrombic, pro-atherosclerotic state (reference 1), increasing the risk of thrombosis (blood clots in blood vessels) and a thickening or hardening of the arteries (caused by a build-up of plaque in the inner lining of the artery). Atherothrombosis causes the majority of heart attacks and strokes through blood clots blocking blood vessels supplying the heart and brain. Patients who have had a heart attack or stroke remain at heightened risk of further CVD events over the long term. 

Creating a solution?

Characterisation of novel anti-clotting drug targets (molecules in the body linked to a particular disease process) and development of novel anti-clotting drug regiments (prescribe courses of drugs). 

Optimised antiplatelet therapy.


Case Study 2: Precision medicine for Pulmonary Arterial Hypertension

With around 6000 annual UK cases, Pulmonary Arterial Hypertension (PAH) is a rare, but fatal, disease.

The cause of PAH

The outcome of PAH

The problem

Current therapies target the tightened blood vessels in the lung  and only ease symptoms. There are no drug to cure PAH, and lung transplantation is rarely undertaken. Treatment strategies are based on experience of disease severity. Patients often receive multiple (expensive) drugs, with unwanted side effects; medications used to dilate the blood vessels have a varied response. 

Current trails focus on the time to clinical worsening, requiring large patient numbers and a long study duration. Therefore, new surrogate end-points are needed.

The solution

There are several root causes of PAH; working with our Imaging and Engineering for Health theme, we can look at patients individual traits and identify those most likely to benefit from specific treatment (personalised medicine). 

Working closely with the Pulmonary Hypertension Association UK, we listen to patients needs, prioritising studies with the most important outcomes to them. 


Case Study 3: Non-invasive vagal nerve stimulation (VNS) for post stroke arm recovery

A stroke occurs when the supply of blood to the brain is either interrupted or reduced. When this happens, the brain does not get enough oxygen or nutrients, and the brain cells start to die. There are 1.3 million UK stroke survivors and 50-60% of stroke patients will experience arm weakness, affecting their ability to perform even simple tasks. 

In a major breakthrough, we showed that stimulation of the vagus nerve at the same time as physiotherapy improves arm function after stroke (reference 1). However, this required an operation under general anaesthesia, and needs an additional person to activate the stimulator during physiotherapy. 

Our team in Sheffield have developed a non-invasive solution. Our approach involves stimulating the vagus nerve non-invasively at the ear so no operation is needed (references 1 and 2). We created a new system, with an industrial collaborator in Germany that allows us to activate the stimulator via a wrist band. The patient can then self deliver therapy at home, unaided. 

The Sheffield Stroke and Aphasia Patient and Public Involvement Group are at the heart of this development, helping establish optimal settings of the device and how it will fit in with daily life. The group are also assisting in the production of an animated explainer video, which will have a voiceover in a number of languages; aiding regional patient recruitment and representation. 


Infection & Immunity

Case Study 1: Identification and characterisation of a new primary immune deficiency and evaluation of novel treatment options.

Activated PI3-kinase delta syndrome (APDS) was first described in 2014 in a landmark 'Science' paper co-led by Dr Alison Condliffe, The University of Sheffield (reference 1). Dr Condliffe co-founded, and co-leads, the Europe-wide APDS registry, which tracks the clinical features and response to treatment of ~200 APDS patients in 12 countries.  

APDS is a severe immunodeficiency syndrome affecting 100s of patients worldwide. It is associated with frequent severe infections, autoimmunity and lymphoma. It is one of the most common causes of antibody deficiency caused by a single gene. 

Pyramid of Discovery 

Base: PI3-kinase biology and respiratory immunology.
Layer 2: Link to APDS hyperactive PI3k signalling (reference 1) and characterisation of large patient cohorts (reference 2).
Layer 3: Clinical trails, observational and longitudinal studies.
Layer 4: Diagnostic pathways and genetic screening tests. Disease response to difference treatments: APDS-associated mutations are now included in a range of gene panels used to screen patients suspected of having immunodeficiency. 
Top: Optimised personalised treatment strategies for APDS patients. 


Case Study 2: Innovative therapies for the treatment of atopic dermatitis and related diseases. 

Atopic dermatitis (AD) is the most common type of eczema. In severe AD, inflammation becomes systemic, leading to multiple comorbidities, including depression, autism, ADHD, IHD, dementia, allergies and suicide. 

Sheffield is the lead UK site for dermatology biomarker trials. Work alongside our Imaging and Engineering for Health theme allowed us to produce what is essentially a virtual skin biopsy. Until recently, the only way to visualise subclinical inflammation was to take skin biopsies, but these cannot be used at multiple time points and sites. Using Optical Coherence Tomography (OCT) to image the skin, we have identified several non-invasive biomarkers of skin inflammation. 

We have subsequently shown that using angiographic OCT, combined with structural OCT provides a more robust measurement of the epidermal thickness, even in severe AD cases with extensive hyperplasia (increase in the number of tissue cells) and lichenification (skin thickening) (reference 2). 

Pilot data led to funding for a Sheffield-led Dupilumab experimental medicine clinical trial, using non-invasive and traditional biomarkers to track inflammation and changes in skin barrier function from treatment onset. Disease modification is proven if AD is eradicated with no recurrence after discontinuing Dupilumab. 

Example of Success with Dupilumab

Sarah (pre-Dupilumab): " I lost my job, home, relationships, independence and totally lost control over my body and mind, inevitably I eventually lost the will to live. I sought euthanasia, as I feel my life has no purpose, I spend every day trying to relieve the symptoms and side effects of medication. I just exist, I do not live."

Sarah (post-Dupilumab): Unable to obtain a place in an early Dupilumab trial after meeting exclusion criteria, Sarah obtained the first adult compassionate use of Dupilumab internationally, and within a month her life was completely transformed, with complete resolution of her AD and depression. Sarah is now a member of our SDR Patient Partnership Team, has published her story and lectures about her life with AD. 

Supported by the NIHR Sheffield Clinical Research Facility, Sheffield Dermatology Research is an internationally leading research group which has developed a unique combination of imaging and clinical biomarkers that are incorporated into experimental medicine trials of drugs such as Dupilumab (reference 3). Phase 3 trials involving patients with AD showed that Dupilumab improved its signs and symptoms as compared with a placebo (reference 1). 


Case Study 3: Sequencing pathogens to improve NHS patient care.

The national COVID-19 Genomics UK (COG-UK) Consortium is pioneering the use of large-scale, rapid whole-genome sequencing of SARS-CoV-2, the virus causing the COVID-19 pandemic, working to understand viral transmission and evolution and inform public health responses and vaccine development. 

Since the start of the pandemic in the UK, Dr Thushan de Silva from our Infection and Immunity Theme  has spearheaded research into SARS-CoV-2; leading the Sheffield Covid-19 Genomics group formed as part of COG-UK along with multiple research projects. In June 2021, Dr de Silva was recognised in the Queen's Birthday Honours and appointed an MBE for his teams work. He is also involved in international SARS-CoV-2 research; helping build capacity for viral sequencing in Ghana and Sri Lanka, and securing funding to establish community surveillance for SARS-CoV-2 in The Gambia. 

NIHR Sheffield Clinical Research Facility (CRF)

13,000 sequences have been generated using samples throughout Yorkshire using the Oxford Nanopore Technology platform in one the fastest turnaround times from sample acquisition to date release. The COG-HOCI trial investigates how rapid turnaround sequencing may impact infection prevention and control. 

Characterised transmission chains among >2000 staff and patients allowed insight into the source of in-hospital infections (reference 1). 

By working with our themes and the Sheffield Bioinformatics Core, we have been able to use our sequencing data in the following ways: 


Imaging & Engineering for Health

Case Study 1: POLARIS - Xenon MRI engineering for clinical lung and brain imaging

Hyperpolarised xenon-129 is a contrast agent used in diagnostic magnetic resonance imaging (MRI) - 129Xe MRI. 

When inhaled, the gas is distributed by ventilation throughout the lungs. Xenon also gets taken up by blood in the capillaries and can give unique information on lung function in lung and pulmonary vascular disease. 

POLARIS: Polarised lung and respiratory imaging Sheffield - POLARised Imaging Systems. 

Sheffield investigators were first in the world to:

This work lead to:


Case Study 2: Connecting digital mobility assessment to clinical outcomes

As the world population ages, it becomes clear that the key problem is loss of mobility due to age or disease. This leads to: 

The Solution

Step 1: develop an innovative assessment approach
Step 2: validate against 'gold standard' methods
Step 3: test with ~ 2400 patients. 


The theory behind Mobilise-D is that the loss of mobility (e.g. slower walking, fewer steps per day, or more time sitting) predicts adverse medical outcomes regardless of the underlying disease. 

Until recently, we could see when someone has trouble moving about, but we could not easily measure this loss. Thanks to new technologies, we can measure mobility accurately in people's homes. Wearable digital sensors have revolutionised the ability to find out if someone is losing their ability to walk and to what degree. Sheffield pioneered this approach in patients with multiple sclerosis (references 1 and 2). 

In collaboration with the NIHR Newcastle Clinical Aging Research Unit and BRC, NIHR Sheffield BRC led the technical development and validation in multiple diseases, and continues to lead the clinical validation of digital mobility assessments in patients with multiple sclerosis, chronic obstructive pulmonary disease (COPD) and heart disease and supports the regulatory approval process (reference 3). 

Addressing the needs and wishes of people with mobility problems is fundamental. Mobilise-D has a well-established patient and public advisory group who have been integral since project initiation. Co-designed YouTube videos introduce viewers to clinical trials, and explore the lives of those affected by mobility problems, and regular newsletters share progress with all participants involved. The goal is to understand, develop and engage. 

Impact will be established by creating valid tools to better detect and prevent mobility loss for patient benefit. We also aim to increase usability and acceptability of devices and data collection methods from both patient and researcher perspectives. 

Key Facts


Case Study 3: An image guided approach to non-invasive cardiovascular pressure measurement

Sheffield researchers are world-leading in the development of non- and minimally-invasive tools to ensure timely and appropriate management and risk stratification for heart failure and coronary heart disease. 

Coronary Heart Disease is:

Heart Failure facts: 

Improving the diagnosis and monitoring of cardiovascular disease 

Cordella Heart Failure System
Acute and chronic models of increased pulmonary artery pressure and heart failure were developed to demonstrate the safety and accuracy of the pressure monitor and to develop implantation techniques (reference 2). This lead to $150m investment, an established award-winning clinical service and it integration into experimental medicine studies. 

Image based models in pulmonary hypertension (PH)
Statistical and computational modelling was used to improve diagnosis and risk prediction in pulmonary hypertension (PH). Artificial Intelligence was used to automate PH diagnosis, and predict therapy response with MRI (reference 3). 

Virtual Fractional Flow Reserve (reference 1).
Fractional flow reserve (FFR) is a procedure used to measure blood pressure and flow through a specific part of a coronary artery. FFR is ideal to guide treatment of coronary artery disease, but few receive it because it needs a pressure wire (which is invasive).
Virtual (computed) FFR (vFFR) works with a good quality angiogram and our software. No pressure wire is required (and it is, therefore, non-invasive).
vFFR successfully allows the cardiologist to judge whether the vessels need treatment or not, and could be used in any cardiac catheter laboratory. 

These lead to:


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