Impact Stories (HTML) 

Highlighting impactful work across our themes. 

You are viewing the accessible HTML format of this page. Click here to return to the main impact page. 

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? 

• In 2% of MND patients, an inherited mutation in the SOD1 gene makes the SOD1 protein toxic, causing the disease. 

• Human genetic therapy trial (reference 3): an antisense oligonucleotide (ASO) binds to the mRNA and prevents SOD1 protein from being produced.  Monthly doses of the ASO were administered by lumbar puncture in the NIHR Sheffield Clinical Research Facility and CSF collected for biomarker analysis. The ASO binds to the mRNA preventing the SOD1 protein being made.

• At the highest dose, the ASO lowered the amount of SOD1 protein by 37% and the neurofilament light biomarker detected in blood and cerebrospinal fluid (CSF). 

• Identification of key biomarkers of therapeutic efficacy will have a major impact on future clinical trials. Exploratory clinical measure of motor function also showed a beneficial effect. 

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.

References: 

1. Ralph GS, Radcliffe PA, Day DM, et al, Azzouz M. Silencing mutant SOD1 using RNAi protects against neurodegeneration and extends survival in an ALS model. Nature Medicine. 2005 Apr;11(4):429-33

2. Iannitti T, Scarrott JM, Likhite S, et al, Shaw PJ, Azzouz M. Translating SOD1 gene silencing toward the clinic: a highly efficacious, off-target-free, and biomarker-supported strategy for fALS. Molecular Therapy-Nucleic Acids. 2018 Sep 7;12:75-88

3. Miller T, Cudkowicz M, Shaw PJ, et al, Furguson T. Phase 1-2 trial of antisense oligonucleotide tofersen for SOD1 ALS. New England Journal of Medicine.E 2020 Jul 9;383(2):109-19.

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). 

Process:

1. Stem cells are extracted from bone marrow

2. Chemotherapy wipes out the immune system 

3. Stem cells are treated and stored 

4. Stem cells are reintroduced to the patient

5. Disease progression halts and symptoms improve in most relapsing-remitting MS patients (reference 2) and in 80% of cases there is no evidence of disease activity 5 years later.

StarMS

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. 

• NIHR Sheffield BRC patient representative and member of the Sheffield MS Research Advisory Group sits on the StarMS steering committee. 

• The primary outcome measure was of 'no evidence of disease activity' at 2 years. 

• This received a £2.3m EME grant.

• Sheffield leads 19 UK hospital sites.

The MIST Trail (reference 3)

• Sheffield is 1 of 4 international centres, the only one in the UK. 

• MIST is the only phase 3 trail to assess the efficacy of AHSCT vs standard care in patients with inflammatory MS failing on existing DMTs.

• Results published in JAMA showed significant improvement in patients receiving AHSCT (reference 1). 

• Results showed an unprecedented reduction in disability levels compared to the worsening levels of disability in the control group.

References 

1. Burt RK, Balabanov R, Burman J, Sharrack B, Snowden JA, Oliveira MC, Fagius J, Rose J, Nelon F, Barreira AA, Carlson K. Effect of nonmyeloablative hematopoietic stem cell transplantation vs continued disease-modifying therapy on disease progression in patients with relapsing-remitting multiple sclerosis: a randomised clinical trial. JAMA. 2019 Jan 15;321(2): 165-74.

2. Sharrack B, Saccardi R, Alexander T, Badoglio M, Burman J, Farge D, Greco R, Jessop H, Kazmi M, Kirgizov K, Labopin M. Autologous haematopoietic stem cell transplantation and other cellular therapy in multiple sclerosis and immune-mediated neurologic disease: updated guidelines and recommendations from the EBMT Autoimmune Disease Working Party (ADWP) and the Joint Accreditation Committee of EBMT ad ISCT (JACIE). Bone Marrow Transplantation. 2020 Feb; 55(2): 283-306.

3. Burt RK, Tappenden P, Han X, Quigley K, Arnautovic I, Sharrack B, Snowden JA, Hartung D. Health economics and patient outcomes of hematopoietic stem cell transaplantation versus disease-modifying therapies for relapsing remitting multiple sclerosis in the United States of America. Multiple Sclerosis and Related Disorders. 2020 Oct 1;45: 102404. 

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:

• Lack of accurate GP stratification. 

• Stretched services. 

• Need for remote assessment. 

• Under-representation of minority groups. 

• National inconsistencies. 

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

• The success of CognoSpeak will be in its accessibility and usability, regardless of language, culture and socio-economic background. 

• Workshops were held for people with mild cognitive impairment, Alzheimer's Disease and their families to explore barriers to technology use. 

• Worked with ISRAAC Somali Community Association to explore barriers experienced when accessing the current diagnostic pathway. 

• Worked closely with NIHR Devices for Dignity MedTech Cooperative to develop grant proposals and facilitate work with local groups. 

• Global Challenge research funding allowed the team to collect in-person data from the Aga Khan Hospital, Kenya. 

References 

1. O'Malley RP, Mirheidari B, Harkness K, Reuber M, Venneri A, Walker T, Christensen H, Blackburn D. Fully automated cognitive screening tool based on assessment of speech and language. Journal of Neurology, Neurosurgery & Psychiatry. 2021 Jan 1;92(1):12-5. 

2. Mirheidari B, Blackburn D, Walker T, Reuber M, Christensen H. Dementia detection using automatic analysis of conversations. Computer Speech & Language. 2019 Jan 1;53:65-79. 

3. Mirheidari B, Pan Y, Blackburn D, O'Malley R, Christensen H. Identifying Cognitive Impairment Using Sentence Representation Vectors. Proc. Interspeech 2021. 2021:2941-5. 

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:

• inflammation

• Increased platelet reactivity

• Impaired fibrinolysis (break down of blood clots), 

• Endothelial dysfunction (blood vessels supplying the heart and other vital organs constrict instead of dilate). 

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.

• Tricagrelor is an antiplatelet medicine which reduces the chances of a blood clot. It was shown to be more effective than the previous standard treatment, clopidogrel. The addition of a novel dose of ticagrelor to low-dose aspirin reduced the risk of cardiovascular death, heart attack, or stroke among patients who had had a heart attack 1 to 3 years earlier (reference 2). Particular benefit was seen in those with diabetes. 

• Feedback from our Cardiovascular Patient Panel was integral to the interpretation of the results of this study. 

• Using large clinical trial databases and biobanks we can identify targets and strategies for improving residual risk (reference 3). 

References 

1. Chow E, Iqbal A, Walkinshaw E, Phoenix F, Macdonald IA, Storey RF, Ajjan R, Heller SR. Prolonged prothrombotic effects of antecedent hypoglycemia in individuals with type 2 diabetes. Diabetes Care. 2018 Dec1;41(12):2625-33. 

2. Bonaca MP, Bhatt DL, Cohen M, Steg PG, Storey RF, Jensen EC, Magnani G, Bansilal S, Fish MP, Im K, Bengtsson O. Long-term use of ticagrelor in patients with prior myocardial infarction. New England Journal of Medicine. 2015 May 7;372(19):1791-800. 

3. Sumaya W, Wallentin L, James SK, Siegbahn A, Gabrysch K, Bertilsson M, Himmelmann A, Ajjan RA, Storey RF. Fibrin clot properties independently predict adverse clinical outcome following acute coronary syndrome: a PLATO substudy. European Heart Journal. 2018 Apr 1;39(13):1078-85. 

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

• changes in the smaller branches of the pulmonary arteries (which supply the lungs) 

• artery walls become thick and stiff, narrowing the space for blood to pass through and increasing blood pressure. 

The outcome of PAH

• right heart failure

• symptoms of breathlessness, lethargy and fainting

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). 

• Early diagnosis of PAH in 'at risk' populations.

• Molecular and imaging stratification using AI approaches to aid treatment selection (reference 1).

• Discovery of new translational treatments and repurposing of existing drugs (reference 1 and 2).

• Development of new surrogate end-points: imaging and remote monitoring to assess treatment response in real-time.

• Incorporation of imaging and remote monitoring into 'smart' clinical trials will lead to improved categorisation for existing and novel therapies (reference 2 and 3).

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

References 

1. Kariotis S, Jammeh E, Swietlik EM, Pickworth JA, Rhodes CJ, Morrell NW, Wilkins MR, Lawrie A, Wang D. Biological heterogeneity in idiopathic pulmonary arterial hypertension identified through unsupervised transcriptomic profiling of whole blood. Nature Communications. 2021 in Press. 

2. Arnold ND, Pickworth JA, West LE, Dawson S, Carvalho JA, Casbolt H, Braithwaite AT, Iremonger J, Renshall L, Gernaschewski C, McCourt M. A theraputic antibody targeting osteoprotegerin attenuate sever experimental pulmonary arterial hypertension. Nature Communications. 2019 Nov 15;10(1):1-8.

3. Rothman AMK, Arnold ND, Pickworth JA, Iremonger J, Ciuclan L, Allen RMH, Guth-Gundel S, Southwood M, Morrell NW, Thomas M, Francis SE, Rowlands DJ, Lawrie A. MicroRNA-140-5p and SMURF1 regulate pulmonary arterial hypertension. J Clin Invest. 2016;126:2495-2508. 

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. 

• The small device (about the size of a mobile phone) connects to a discreet earpiece. 

• The earpiece stimulates a branch of the vagal nerve that runs through the outer ear by passing electrical impulses through it. 

• These electrical impulses then travel along nerve fibres to the brain stem where they activate higher centres in the brain. 

• This non-surgical treatment works on the same areas of the brain that invasive vagal nerve surgery stimulates but without the risks associated with major surgery. 

References 

1. Dawson J, Liu CY, Francisco GE et al. Vagus nerve stimulation paired with rehabilitation for upper limb motor function after ischaemic stroke (VNS-REHAB): a randomised, blinded, pivotal, device trail. Lancet. doi:10.1016/S0140-6736(21)00475-X

2. Baig SS, Falidas K, Laud PJ, Snowdon N, Farooq MU,  Ali A, Majid A, Redgrave JN. Transcutaneous Auricular Vagus Nerve Stimulation with Upper Limb Repetitive Task Practice May Improve Sensory Recovery in Chronic Stroke. Journal of Stroke and Cerebrovascular Diseases. DOI: 10.1016/j.jstrokecerebrovasdis.2019.104348

3. Redgrave JN, Moore L, Oyekunle T, Ebrahim M, Falidas K, Snowdon N, Ali A, Magid A. Transcutaneous Auricular Vagus Nerve Stimulation with Concurrent Upper Limb Repetitive Task Practice for Poststroke Motor Recovery: A Pilot Study. Journal of Stroke and Cerebrovascular Diseases. DOI: 10.1016/j.jstrokecerebrovasdis.2018.02.056

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. 

References 

1. Angulo I, Vadas O, Garcon F, Banham-Hall E, Plagnol V, Leahy TR, Baxendale H, Coulter T, Curtis J, Wu C, Blake-Palmer K, Condliffe A. Phosphoinositide 3-kinase delta gene mutation predisposes to respiratory infection and airway damage. Science. 2013 Nov 15;342(6160):866-71.

2. Coulter TI, Chandra A, Bacon CM, Babar J, Curtis J, Screaton N, Goodlad JR, Farmer G, Steele CL, Leahy TR, Doffinger R, Condliffe A.  Clinical spectrum and features of activated phosphoinositide3-kinase delta syndrome: a large patient cohort study. Journal of Allergy and Clinical Immunology. 2017 Feb 1;139(2):597-606. 

3. Maccari ME, Abolhassani H, Aghamohammadi A, Aiuti A, Aleinkova O, Bangs C, Baris S, Barzaghi F, Baxendale H, Buckland M, Burns SO. Disease evolution and response to rapamycin in activated phosphoinositide 3-kinase delta syndrome: the European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase delta syndrome: the European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase Delta Syndrome Registry. Frontiers in Immunology. 2018 Mar 16;9:543.

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). 

References 

1. Simpson EL, Bieber T, Guttman-Yassky E, Beck LA, Blauvelt A, Cork MJ, Silverberg JI, Deleuran M, Kataoka Y, Lacour JP, Kingo K. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. New England Journal of Medicine. 2016 Dec 15;375(24):2335-48.

2. Byers RA, Maiti R, Danby SG, Pang EJ, Mitchell B, Carre MJ, Lewis R, Cork MJ, Matcher SJ. Sub-clinical assessment of atopic dermatitis severity using angiogenic optical coherence tomography. Biomedical optics express. 2018 Apr 1;9(4):2001-17.

3. Cork MJ, Thaci D, Eichenfield LF, Arkwright PD, Sun X, Chen Z, Akinlade B, Boklage S, Guillemin I, Kosloski MP, Kamal MD. Dupilumab provides favourable long-term safety and efficacy in children aged 6 to 12 years with uncontrolled severe atopic dermatitis: results from an open-label phase IIa study and subsequent phase III open-label extension study. British Journal of Dermatology. 2021 May; 184(5):857-70. 

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 COVID-10 research visits facilitated.

• >4,000 patients recruited to COVID-19 studies.

• 45+ COVID-19 studies.

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: 

• Further exploration of hospital transmission, and methods to inform infection prevention and control practice (reference 1). 

• By tracking changes in the SARS-CoV-2 spike region we provided evidence that the D614G mutation increases infectivity (reference 2). 

• We have discovered that the D61G spike mutation is not expected to be an obstacle for vaccine development (reference 3). 

• A tool named 'Periscope' was developed as a new way to identify variants. This rapid assessment allowed us to identify changes in the B.1.1.7 lineage (alpha-variant) which could explain its increased transmissibility. 

References 

1. Lindsey BB, Villabona-Arenas CJ, Campbell F, Keeley AJ, Parker MD, Shah DR, Parsons H, Zhang P, Kakkar N, Gallis M, Foulkes BH. Characterising within-hospital SARS-CoV-2 transmission events: a retrospective analysis integrating epidemiological and viral genomic data from a UK tertiary care setting across two pandemic waves. medRxiv. 2021 Jan 1. 

2. Korber B, Fischer WM, Gnanakaran S, Yoon H, Theiler J, Abfalterer W, Hengartner N, Giorgi EE, Bhattacharya T, Foley B, Hastie KM. Tracking changes in SARS-CoV-2 spike: evidence that D614G increases infectivity of the COVID-19 virus. Cell. 2020 Aug 20;182(4): 812-27. 

3. Weissman D, Alameh MG, de Silva T, Collini P, Hornsby H, Brown R, LaBranche CC, Edwards RJ, Sutherland L, Santra S, Mansouri K. D614G spike mutation increases SARS CoV-2 susceptibilty to neuralization. Cell Host & Microbe. 2021 Jan 12;29(1):23-31. 

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. 

• The POLARIS xenon polariser (reference 1) is the world's highest performing 129Xe polariser. It is now installed in 6 locations worldwide. 

• Sheffield is world leading in hyperpolarised gas MRI research.

• Four other NIHR BRCs (Oxford (reference 3), UCL, Manchester, Nottingham)installed POLARIS 129Xe polarisers and MRI sequences as a platform for post-COVID lung disease . 

• Premier European MR engineering collaborator of GE Healthcare. Other collaborators include: AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Novartis.

Sheffield investigators were first in the world to:

• Take xenon lung MRI to clinical practice with MHRA regulatory approval for NHS diagnostic scanning. Now taking referrals from NHS clinics Nationwide.

• Produce high resolution xenon images of the brain in stroke patients as an injection-free contrast agent of cerebral perfusion.

• Use 129Xe and 1H MRI in children with Cystic Fibrosis (CF). As a result, MRI has replaced CT in the annual assessment of CF patients, saving children from a dose of radiation of around 3mGy each year (reference 2). 

This work lead to:

• The first ever NIHR Research Professorship awarded to a non-clinician . 

• Technology development with Engineering and Physical Sciences Research Council.

• A £7.5M award from the Medical Research Council. 

References 

1. Norquay G, Collier GJ, Rao M, Stewart NJ, Wild JM. Xe 129-Spin-Exchange Optical Pumping with High Photon Efficiency. Physical Review Letters. 2018 Oct 8;121(15):153201.

2. Smith LJ, Horsley A, Bray J, Hughes PJ, Biancardi A, Norquay G, Wildman M, West N, Marhsall H, Wild JM. The assessment of short- and long-term changes in lung fucntion in cystic fibrosis using 129Xe MRI. European Respiratory Journal. 2020 Dec 1-56(6).

3. Grist JT, Chen M, Collier GJ, Raman B, AbuEid G, McIntyre A, Matthews V, Fraser E, Ho LP, Wild JM, Gleeson F. Hyperpolarized 129Xe MRI abnormalities in dyspneic participants 3 months after covid-19 pneumonia: preliminary results. Radiology. 2021 May 25:210033. 

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: 

• Loss of independence 

• Increased risk of falls 

• Hospitalisation

• Death

The Solution

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

Mobilise-D 

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

• £25.4m Innovative Medicine Initiative funding 

• 10 pharmaceutical partners

• 20 public institutions 

• High-quality patient engagement 

• 2 SMEs and 2 technology partners

• Multidisciplinary expertise

References 

1. Angelini L, Buckley E, Bonci T, Radford A, Sharrack B, Paling D, Nair KP, Mazza C. A multifactorial model of multiple sclerosis gait and its changes across difference disability levels. IEEE Transactions on Biomedical Engineering. 2021 Feb 24. 

2. Angelini L, Hodgkinson W, Smith C, Dodd JM, Sharrack B, Mazza C, Paling D. Wearable sensors can reliably quantify gait alterations associated with disability in people with progressive multiple sclerosis in a clinical setting. Journal of Neurology. 2020 Oct;267:2897-909.

3. Viceconti M, Hernandez Penna S, Dartee W, Mazza C, Caulfield B, Becker C, Maetzler W, Garcia-Aymerich J, Davico G, Rochester L. Toward a regulatory qualification of real-world mobility performance biomarkers in Parkinson's patients using digital mobility outcomes. Sensors. 2020 Jan;20(20):5920. 

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:

• One of the UK's leading causes of death 

• The most common cause of premature death 

Heart Failure facts: 

• 26 million people affected worldwide

• 1 million in-patient bed days per year (2% of the NHS total)

• 5% of emergency admissions, costing the NHS ~£2billion. 

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:

• less invasive interventions

• faster and improved diagnosis

• reduced costs due to timely management

References 

1. Gosling RC, Morris PD, Silva Soto DA, Lawford PV, Hose DR, Gunn JP. Virtual coronary intervention: a treatment planning tool based upon the angiogram. JACC: Cardiovascular Image. 2019 May;12(5):865-72.

2. Mullens W, Sharif F, Dupont M, Rothman AM, Wijins W. Digital health care solution for proactive failure management with the Cordella Heart Failure System: results of the SIRONA first-in-human study. European Journal of Heart Failure. 2020 Oct;22(10):1912-9. 

3. Swift AJ, Lu H, Uthoff J, Garg P, Cogliano M, Taylor J, Metherall P, Zhou S, Johns CS, Alabed S, Condliffe RA. A machine learning cardiac magnetic resonance approach to extract disease features and automate pulmonary arterial hypertension diagnosis. European Heart Journal-Cardiovascular Imaging. 2021 Feb;22(2):236-45.