BSSH Research Grant/Fellowship

Project title: Using big data and cell biology to understand carpal tunnel syndrome.

Grant Holder: Alexandra Wood

Position: MB DPhil Student

Date of award

06/06/23

Start date for research

02/10/23

Date of report

07/12/24

Grant Awarded (i.e. £10,000)

£48,000

Is this an interim, or final, report

Interim

Lay Summary of the project (100 words)

New Therapies for Carpal Tunnel Syndrome 

Carpal tunnel syndrome (CTS) is a condition where compression of a nerve in the wrist leads to hand pain, numbness, and weakness. CTS affects one in ten people. We don’t have a medication for CTS - it is treated with surgery, but up to one in four patients have incomplete recovery after surgery. This research will use big data and laboratory experiments to understand why this nerve compression occurs, and to identify drugs that can be effective in the treatment of CTS.

Summary of project/progress /findings (approx 300 words)

My DPhil has three components, using both big data techniques and cell biology to unpick the biological mechanisms of carpal tunnel syndrome (CTS) and which medications might be repurposed to treat the condition. The first is a genetic study, using Mendelian randomisation to identify causal relationships between risk factors that have been observationally linked to CTS and the condition itself. The second is a pharmaco-epidemiology study aiming to identify whether metformin may be repurposed to treat CTS by examining whether metformin reduces the risk of CTS in a cohort of diabetic patients. The third will use cell biology techniques to examine the effects of metformin and IGF-1 inhibition on fibroblasts cultured from CTS patient tenosynovium samples. This fellowship is primarily in support of the second two components.

Progress to date on each of the studies is as follows:

Mendelian Randomisation

• I have completed two sample MR analyses on the exposures of interest as identified in my previous literature review: BMI, waist-hip ratio, type 1 and type 2 diabetes, fasting plasma glucose, plasma insulin, HbA1c, triglycerides, HDL and LDL cholesterol and ApoB
• I have completed multivariable MR analyses on exposures of interest which may interact.
• I have written a manuscript for this work and it is in preparation to submit for publication.
• I presented the results of this work at the BSSH Autumn meeting in Belfast.

Pharmaco-epidemiology

• I have developed preliminary cohort definitions and run initial feasibility counts in CPRD, confirming that we will have sufficient power to run this study
• I have presented the protocol draft to expert pharmaco-epidemiology researchers in Oxford and made adjustments to my plan based on the comments and advice on the best approaches to take
• I have submitted the study protocol eRAP for review and received reviewer comments for minor edits
• I attended the London School of Hygeine and Tropical Medicine in July and a University of Oxford course in Real World Epidemiology in June to learn the epidemiology and data handling techniques I have planned to use in my protocol.
• I have received access to the latest version of CPRD and started generating final code lists and study cohort definitions based on clinical definitions of carpal tunnel syndrome and type 2 diabetes.

Cell biology

• I have identified members of the team of hand surgeons in Oxford who are willing to perform tenosynovial sample collections for research.
• This chapter is planned to follow on from the findings of the first few chapters, so no further progress has taken place thus far.

I have also completed and passed my transfer of status examination viva for my DPhil with no reservations.

What is the relevance/value of this research to hand surgery:

Carpal tunnel syndrome (CTS) is a condition affecting one in ten people, where compression of the median nerve in the wrist leads to hand pain, numbness, and weakness. This is commonly treated with surgery to decompress the median nerve, but up to one in four patients have incomplete recovery after surgery. In the UK over 54,000 decompression operations were carried out in 2014, at a cost of around £50 million to the NHS, and surgery rates are predicted to increase by 2030. However, up to 25% of patients either do not improve or have a recurrence of symptoms following surgery.

This research uses both big data and laboratory experiments to understand why this nerve compression occurs, aiming to provide a better insight into the biological processes that lead to CTS, and to identify drugs for repurposing that might be effective in the treatment of CTS. This will hopefully improve patient outcomes, and in addition reduce the need for surgical decompression, potentially enabling the NHS to direct resources to other operative treatments in hand surgery.

If final report, please provide bullet point list of conclusions/important findings

Please list presentations based on work performed in this study

Free Paper Presentation, BSSH Autumn meeting, Belfast - Using genetics to investigate causality in metabolic associations of carpal tunnel syndrome - a Mendelian randomisation study; Miss A Wood, Miss C Lovegrove , Professor D Furniss , Mr A Wiberg (Senior); Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, UK

Please list publications based on work performed in this study

In preparation - Metabolic drivers of carpal tunnel syndrome: a Mendelian randomisation

Study; A. Wood, C. Lovegrove, A. Wiberg, D. Furniss

Please state what additional research this study has/is leading to

Please list any further funding or grant applications (with outcome), which have resulted from the award of this grant

How has this grant awards helped your career development?

Being awarded my BSSH Research Fellowship at the earliest stage of my clinical studies has enabled me to take the opportunity to intercalate during my medical degree and begin my MB DPhil. As a result, I will graduate as a doctor with the ability to produce high quality research from the beginning of my clinical practice, enabling me to pursue a strong career as a surgeon scientist. 

Within my DPhil proposal, BSSH support has allowed me to fund access to the CPRD database in order to conduct a pharmaco-epidemiology study which will hopefully lead us to understand the viability of future clinical trials for carpal tunnel syndrome, as well as enabling me to perform the cell biology work to support this.

In addition, working with our research team has allowed me to collaborate with many surgeon-scientists who are clinically senior to me. The mentorship and advice I’ve been fortunate enough to receive so far from the Furniss Group has been invaluable in supporting my aspirations of becoming an academic hand surgeon, and working on this project will continue to enable me to meet and collaborate with further hand surgeons through both tenosynovial sample collections in Oxford, and future presentations of my work at relevant conferences and meetings.

Grant Holder: Max Stewart

Position: DPhil Candidate, University of Oxford

Date of award

05/4/22

Start date for research

10/10/22

Date of report

6/3/23

Grant Awarded (i.e. £10,000)

£33,966

Is this an interim, or final, report

Interim

Lay Summary

Carpal tunnel syndrome (CTS) is a condition in which nerve compression at the wrist leads to pain, tingling and weakness in the hand. CTS affect one in ten people. The usual treatment is surgery to decompress the nerve, but some people still get symptoms and incomplete recovery after the operation. We know that electricity can help nerves heal after surgery, but currently this requires implanting electrodes in the wrist. Our research is about developing ways to electrically stimulate nerves through the skin instead, to help people recover better after CTS or other nerve surgery

Summary of project/progress /finding

The overall aim of my project is to explore the mechanistic underpinning and first-in-human application of non-invasive, pre-operative electrical nerve stimulation to enhance regeneration of peripheral nerves, using carpal tunnel syndrome as a human model system. In total the project forms a four-year DPhil at the University of Oxford.

My project consists of two stages. First is 12 months of computational modelling to optimise non-invasive stimulation of the median nerve at the wrist. These 12 months are supported by BSSH. Second is the PROSpeCT study (Pre-Operative electrical Stimulation to improve Outcomes after Carpal Tunnel decompression). PROSpeCT is a small mechanistic trial of pre-operative electrical nerve stimulation as a neo-adjunct for patients undergoing carpal tunnel decompression surgery. PROSpeCT is patient and surgeon blind, single centre, randomised, and placebo controlled. The primary outcome is improvement in sensory recovery (cold detection threshold, a measure of small sensory fibre function) at 6 months. Secondary outcomes assess other clinical and biological measures of nerve recovery, including PROMS, motor function, quantitative sensory testing, nerve conduction studies, re-innervation of median nerve innervated skin and structural changes on magnetic resonance neurography. Our recruitment target is 60 patients.

In terms of progress to date on the project:

• Design of a simplified geometric computational model of the wrist
• Design of a detailed anatomical wrist model, based on human MRI data
• Ethics approved and drafted SOP for healthy volunteer testing studies in the University of Oxford to confirm model predictions
• Completion of V1.0 of the PROSpeCT protocol and supporting documents, about to be submitted to sponsor for approval, aiming to open recruitment in January 2024

In terms of training, I have completed the Bristol Oxford Aberdeen Surgical Intervention Trials Course and the University of Oxford’s Department for Continuing Education Clinical Trials Management Course.

In terms of further funding, the BSSH has provided a platform for me to successfully apply for funding totalling just under £500,000 in total value (though a portion of this total is now held in Honorary Fellowships, see below).

What is the relevance/value of this research to hand surgery?

Peripheral injuries affect all aspects of hand surgical practice. Indeed, hand surgeons perhaps carry greatest responsibility for management of these injuries amongst all medical and surgical specialties. In trauma, around 3% of upper limb injuries are complicated by a nerve injury. In the elective context, hand surgeons are uniquely responsible for managing the most prevalent nerve injuries worldwide: compression neuropathies like carpal tunnel and cubital tunnel syndromes. Despite advances in surgical technique, clinical outcomes following PNI have not improved in several decades. This reality is of obvious concern both to surgeons and to our patients. The BSSH’s recent priority setting partnership with the James Lind Alliance identified improving interventions for peripheral nerve injury as a ‘top 10’ research priority in hand and wrist surgery, highlighting the need for work in the area.

My project focuses on electrical nerve stimulation, the only intervention to have improved nerve regeneration and clinical outcomes in multiple human RCTs. At present, our group and our collaborators in Oxford Functional Neurosurgery and the Nuffield Department of Clinical Neurosciences are the only UK team working in this field. I hope that over the next ten years, the support given by the BSSH will enable us to introduce this low risk, low cost, potentially transformative therapy to patients suffering from carpal tunnel syndrome, cubital tunnel syndrome. and distal nerve transections (e.g. digital nerve). In the longer term, I hope the translate the technology into devastating proximal injuries of the brachial plexus, which currently lack any effect treatment.

Please list presentations based on work performed in this study: None at present

Please list publications based on work performed in this study: None at present

Please list any further funding or grant applications (with outcome), which have resulted from the award of this grant:

University of Oxford John Fell Fund (£35,000): outcome awaited

MRC Clinical Research Training Fellowship (£328,585): successful

RCS England One Year Research Fellowship (£50,000): successful, now held as an Honorary Fellowship

University of Oxford St John’s College Clarendon Scholarship (£54,186): successful, now held as Honorary Scholarship

University of Oxford Medical Sciences Division / EPSRC Studentship (£27,452): successful, now held as Honorary

How has this grant awards helped your career development?

The BSSH Research Fellowship has been instrumental to starting my career as a surgeon scientist. The Fellowship has allowed me to begin my DPhil on a potentially transformative therapy, during a narrow window of opportunity. In the short term, BSSH support has enabled me to secure competitive funding for the remainder of my DPhil. In the longer term, the training and development made possible by the Society’s financial support will allow me to develop into a national leader in this field, and hopefully bring electrical nerve stimulation to patients across the UK. I envisage myself eventually running mechanistic and efficacy trials of regenerative therapies in patients with a broad range of nerve injuries, which currently lack effective treatments. In particular, the BSSH’s support of a collaborative project means I am already developing close working relationships with neurosurgeons, basic neuroscientists and clinical trialists, which will allow me to drive large collaborative funding applications in future. The interdisciplinary nature of my supervision prepares me well to explore questions of both mechanistic underpinning and clinical efficacy of new therapies, which will be crucial to maximising patient benefit.

Grant Holder: Miss Mira Pecheva

Position: Specialty Registrar, Trauma and Orthopaedic Surgery, East of England Deanery;

Clinical Research Fellow, University of East Anglia

Date of award

01/11/2021

Start date for research

01/11/2021

Date of report

31/10/22

Grant Awarded (i.e. £10,000)

£46,813

Is this an interim, or final, report

Final Report

Lay Summary 

Dupuytren’s disease (DD) is characterised by thickening of a structure present in all hands (the palmar fascia), affecting hand use, with psychological, family and employment effects. 2 million people have DD in the UK. Treatment is through surgery, but the disease can return. The enzyme MMP-14 is associated with DD severity and recurrence. This project will outline the role of MMP-14 in DD. In the near-term, patients can donate tissue excised as part of their treatment, playing an active role in research. The translation of this research into therapy will provide long-term non-surgical treatment

Summary of project/progress /findings

Based on previous studies, our hypothesis is that the enzyme Matrix Metalloproteinase 14 (MMP-14) has a key and complex role in Dupuytren’s Disease (DD) incidence and progression. The aim of the first year of this three-year PhD project is to ascertain the phenotypic effect of the single nucleotide polymorphism (SNP) in the MMP14 gene, a DD-associated genetic variant.¹

Sample collection of excised Dupuytren’s tissue from patients undergoing surgery as part of their treatment is still ongoing (n = 74). Notably, this is the first study which integrates clinical patient data, including medical comorbidities, social factors, disease activity and examination findings such as fixed flexion deformity, and laboratory data for Dupuytren’s disease-associated genetic variants.

Patient samples have been processed in tissue culture, with myofibroblast derivation and cryopreservation for further characterisation (see below). Optimisation of DNA extraction for genotyping has been successful and a protocol for extraction of genomic DNA with high purity has been developed. A genotyping protocol, to determine the presence of the SNP through end-point PCR, has also been optimised.

A number of protocols have been explored to characterise the tissue phenotype through haematoxylin and eosin staining. This includes sectioning and staining of paraffin-embedded and fresh frozen tissue. Tissue embedding in optimal cutting temperature (OCT) medium and sectioning with a cryostat microtome at -25°C has been successful, producing high quality sections for histological analysis.

Immunocytochemistry and immunohistochemistry techniques were developed to further characterise the SNP phenotype, specifically with antibodies to MMP-14, to determine if there is variability of expression between the wildtype and variant genotypes, and antibodies to alpha-Smooth muscle actin (α-SMA), which is characteristically expressed in the myofibroblasts of DD nodules. Determination of the optimal antibody concentrations was completed on immortalised cell lines – HT1080 cells expressing MMP-14 and HeLa cells expressing α-SMA. These protocols will be used to analyse MMP-14 and α-SMA protein expression in myofibroblasts derived from DD nodules. The protocol for MMP-14 staining in DD tissue is currently underway and will be extended to α-SMA, type I collagen (COL1A1), type III collagen (COL3A1).

1. Ng, M., et al., A genome-wide association study of Dupuytren disease reveals 17 additional variants implicated in fibrosis, The American Journal of Human Genetics 101, no. 3 (2017): 417-427.

What is the relevance/value of this research to hand surgery:

Dupuytren’s disease is the most common localised fibrosis and has a significant burden to patients, their families, employers and the NHS. There is no pharmaceutical therapy available. Treatment is through surgery, but recurrence is frequent and further intervention is less successful. Surgery does not affect the underlying disease activity, confirmed by the high recurrence rates. The direct costs of DD to the NHS are estimated at £61 million per year.¹ This project will outline important molecular mechanisms involved in this disease and identify future therapeutic targets to prevent its progression and recurrence. It is also an opportunity for patients to contribute to the development of our understanding of the disease, through tissue donation.

1. Dias, J, The epidemiology of surgical intervention for Dupuytren contracture in England, Dupuytren disease and related diseases-the cutting edge: Springer, (2017), p. 11–5.

If final report, please provide bullet point list of conclusions/important findings:

Final report findings:

• This grant has funded the first year of a three-year project and work is ongoing. However, I have established a comprehensive collection of DD tissue samples and corresponding database of clinical data for genotyping correlation analyses.
• Preliminary analyses have examined the SNP frequency in the DD patient population (n= 74) number of operations, flexion deformity measures, age at onset of disease and age at initial surgery.
• Data will be published following completion of collection and analyses.

The next stages of the project will be to:

• Establish an explant model of DD - the ex-vivo ‘clinical trial,’² to monitor gene expression by qRT-PCR and protein by immunofluorescence.
• Zymography will be used to measure proMMP-2 activation (an outcome of MMP-14 activity). This will establish a baseline of information for MMP-14 function.
• MMP-14 function will then be blocked using inhibitory antibodies and validated small interfering RNA (siRNA).
• The downstream effects of MMP-14 inhibition will be monitored to understand the mechanism by which MMP-14 acts in DD.
• Long-term post-operative data will be collected to assess clinical outcomes in the context of the SNP genotype. 

2. Karkampouna, et al., Human Dupuytren's ex vivo culture for the study of myofibroblasts and extracellular matrix interactions, JoVE (Journal of Visualized Experiments) 98 (2015): e52534.

Please list presentations based on work performed in this study:

An abstract will be submitted to the European Federation of National Associations of Orthopaedics and Traumatology (EFORT) Conference, 2023.

Further work will be submitted to the International Dupuytren’s Symposium, International Federation of Societies for Surgery of the Hand (IFSSH), the Tissue Repair and Regeneration Gordon Research Conference and the British Society for Matrix Biology (BSMB).

Please list publications based on work performed in this study:

• The research conducted in this study has not been published yet.

Please state what additional research this study has/is leading to:

• I am working with the Research Park Biorepository to develop a larger study to understand the role of SNPs in the aetiology of DD. This will look at the prevalence of other SNPs in the general population and patients with DD.
• The project has attracted an undergraduate Biomedicine research student project (The characterisation of MMP14 in Dupuytren’s disease and the bioactive sulforaphane as a potential therapy.)

Please list any further funding or grant applications (with outcome), which have resulted from the award of this grant:

• Action Arthritis Charitable Trust – Full funding for Year 2 of the PhD project confirmed
• Gwendoline Fish Charitable Trust – Funding for Year 3 of the PhD project confirmed
• Orthopaedics Research UK – Funding for Year 3 of the PhD project confirmed

How has this grant awards helped your career development?

This grant has been immensely helpful as it has set the foundation for the project by supporting the first year. It has been instrumental in securing the rest of the funding for the project. This degree offers the opportunity to develop extensive laboratory-based skills and numerous other transferable skills which are invaluable in an academic surgical career.

Grant Holder: Dr Manal Irshad Patel

Position: Final Year Medical Student, University of Cambridge

Date of award

20/04/2021

Start date for research

21/4/2021

Date of report

29/5/2021

Grant Awarded (i.e. £10,000)

£520

Lay summary

Upper limb trauma represents approximately 30% of A&E attendances. Flexor tendons are commonly injured resulting in loss of finger flexion. Frequently used repair techniques include tendon lengthening, grafting or tendon transfers. A less commonly described technique is tendon turnover (see figure) which avoids the complications associated with other repair techniques and precludes the need for a secondary wound from graft tendon retrieval. The aim of this study is to analyse the mechanical properties of tendon turndown. This would help demonstrate that it is biomechanically secure and therefore may be convenient and safe for tendon reconstruction in the upper limb.

Summary of project/progress /findings

Since receiving the award from BSSH, we have been able to undertake the full-scale experiment, preparing and testing 48 animal-derived tendon reconstructions with an Instron tensile testing machine at the University of Cambridge Department of Engineering, measuring ultimate tensile strength and stiffness of the tendon turndown reconstruction versus more conventional tendon repair techniques. I am currently undertaking data analysis and preparing an abstract for presentation. 

What is the relevance/value of this research to hand surgery:

Upper limb trauma represents approximately 30% of A&E attendances. Flexor tendons are commonly injured resulting in loss of finger flexion. Frequently used repair techniques include tendon lengthening, grafting or tendon transfers. A less commonly described technique is tendon turndown which avoids the complications associated with other repair techniques and precludes the need for a secondary wound from graft tendon retrieval. The aim of this study is to analyse the biomechanical properties of tendon turndown repair and to evidence its utility for tendon reconstruction in the upper limb.

How has this grant awards helped your career development?

The ‘tendon turndown’ project has been in invaluable step in equipping me with skills to take a hypothesis to a proof-of-concept pilot which has led us to plan the upcoming full-scale project. I believe this is crucial in my development as I work to become a future clinician scientist.

With the support of my supervisors, I have written a basic science study protocol, coordinating between clinicians, medical suppliers and technicians at the Department of Engineering which has allowed us to run a pilot study, demonstrating feasibility and ultimately successfully running the full-scale experiment. Having analysed the pilot data, I am becoming adept in biomechanical data analysis – applying first principles in order to understand the mechanical properties of the repairs.

I am looking forward to the next steps as there is a great deal of scope to expand upon the work which could have a greater impact on patient care and outcomes.

Grant Holder: Justin Wormald

Position: NIHR Academic Clinical Lecturer and ST7 Plastic Surgery

Date of award

October 2020

Start date for research

October 2020

Date of report

September 2024

Grant Awarded (i.e. £10,000)

£50,000

Is this an interim, or final, report

Final

Lay Summary of the project 

Hand and wrist injuries, or hand trauma, are really common in the UK and many require surgery. Surgical site infections (SSIs) can worsen outcomes after surgery, sometimes resulting in longer hospital stays or even amputations. My research investigated the risk of SSIs in hand trauma surgery and explored using antimicrobial stitches to reduce this risk. Through various studies, I found a risk of SSI of at least 5%, with some studies showing risks of over 10%. I also showed that we can test treatments to reduce this risk in hand trauma. Further work is now needed to improve patient outcomes.

Summary of project/progress /findings

Background

The hand and wrist are important for occupational and recreational activities. Hand and wrist injuries account for 1-in-5 ED attendances, an incidence of 5 million injuries/year and 250,000 operations/year in the United Kingdom (UK). Hand trauma, which includes fractures of the hand and wrist bones, nerve injuries, tendon injuries and traumatic amputations, can cause significant short and long-term morbidity. Emergency surgery to repair the damage is key in maximising the chances of restoring function, allowing people to return to work and independence. SSI in hand trauma surgery can result in additional significant morbidity, further emergency surgery, prolonged hospital stay and even amputation. The risk of SSI following hand trauma surgery is unknown but may be as high as 20% based on the literature. Antimicrobial sutures might prevent SSI according to studies in other surgical fields. This cannot be extrapolated to hand trauma surgery, as the patients and clinical pathway are very different from existing study populations. Further investigation of antimicrobial sutures is warranted.

Aim

To increase our understanding of the risk of SSI in hand trauma surgery through high quality research, and to establish the feasibility of running interventional trials to moderate it.

Objectives

1. To estimate the risk of SSI following hand trauma surgery
2. To assess the feasibility and acceptability of conducting an RCT of antimicrobial sutures versus standard sutures in patients undergoing hand trauma surgery.

Methods

A systematic review and meta-analysis of hand trauma surgery research to determine the pooled risk of SSI and treatments in the published literature. This is followed by an analysis of routinely collected primary (CPRD) and secondary care (HES) data to better define the risk of SSI following hand trauma surgery. Having established SSI risk in this population, a multi-centre, randomised feasibility study of antimicrobial sutures in hand trauma surgery is designed and executed. This study includes 116 participants across three hand trauma units in England.

Results

Systematic review and meta-analysis of 201 studies synthesising 315,618 patients demonstrated that the risk of SSI following hand trauma surgery is approximately 5% and may be as high as 10%. Analysis of 3,088 primary care records of hand trauma patients revealed that 6.2% required treatment for infection in the community with SSI-appropriate antibiotics (superficial SSI) by 30 days following surgery, rising further to 14.4% at 90 days. Analysis of HES data found that admission for treatment of post-operative infection was the commonest adverse occurrence following surgery for hand trauma. Across all 280,747 admissions, the risk of serious post-operative infection requiring re-admission (deep, organ/space SSI) was 1.4% by 30 days and 2% by 90 days. In terms of feasibility for testing antimicrobial interventions in hand trauma, 116 participants were recruited across three sites in seven months. All participants were randomised and over 99% received the allocated treatment. Follow-up was challenging and is a target for future definitive trials. SSI incidence within the trial was comparable to figures obtained in this thesis.

Conclusions

SSI following hand trauma surgery is more common than is routinely quoted, is the most common reason for re-admission following surgery and results in significant antibiotic prescription in the community. There is a clear rationale for evidence-based prevention of SSI in hand trauma surgery, informed by clinical trials of antimicrobial interventions. Such trials can recruit efficiently but require innovative follow-up strategies to maximise retention.

What is the relevance/value of this research to hand surgery:

I have provided highly accurate estimates for the risk of infection following hand trauma surgery. This data can be used to inform patients pre-operatively, improving our shared decision making process.

This data can also be used to inform power calculations for future clinical trials of antimicrobials, including antibiotics, in hand trauma surgery.

Lastly, the feasibility data attained from the HAWAII demonstrates that RCTs in hand trauma surgery and infection are eminently achievable in thy UK. This has already been used to secure further funding for a clinical trial in hand fracture surgery.

If final report, please provide bullet point list of conclusions/important findings

• The risk of SSI following hand trauma surgery may be as high as 10%
• The risk of severe SSI requiring admission and/or further surgery is 2%
• The risk of non-severe SSI requiring antibiotic prescription may be as high as 14%
• In the HAWAII trial, the risk of SSI in both groups (antimicrobial sutures and standard sutures) was 20%, with no evidence of effect of antimicrobial sutures
• Further trials of antimicrobial interventions in hand trauma surgery are feasible

Please list presentations based on work performed in this study

1. Establishing Clinical Trials in Plastic & Reconstructive Surgery. Invited Speaker. JCR Wormald. Royal College of Surgeons of Ireland Charter Week, 9^th February 2024, Dublin, Ireland
2. How to get into research: tips from a PhD student. Invited Speaker. JCR Wormald. IFSSH, IFSHT & FESSH Combined Congress 2022, 6-10 June 2022 | ExCeL, London, UK
3. The burden of hand trauma surgery on primary care in the UK: a nation-wide analysis of antibiotic and opioid prescriptions. JCR Wormald, M Catala-Sabate, A Demelstri , J Rodrigues, J Cook, M Costa, D Prieto-Alhambra. BSSH Spring Scientific Meeting, 25^th-26^th April 2024, Leeds, UK
4. Surgical site infection after hand trauma surgery in low- and middle-income countries: a systematic review and meta-analysis. AV Shaw, G Chaplin, S Graham, D Beard, K Agarwal-Harding, JCR Wormald. BSSH Autumn Scientific Meeting, 23^rd-24^th November 2023, Glasgow, UK
5. Operating outside of main theatre and the risk of SSI in hand trauma: a systematic review and meta-analysis. S Shafi, W Audei, AV Shaw , S Fullilove, JN Rodrigues, JCR Wormald. BSSH Autumn Scientific Meeting, 23^rd-24^th November 2023, Glasgow, UK
6. Systematic review of the management of pyogenic flexor tenosynovitis. M Hennessy, B Forder, B Turner, JCR Wormald. BSSH Autumn Scientific Meeting, 23^rd-24^th November 2023, Glasgow, UK
7. Antibiotics in hand surgery. JCR Wormald, J Totty. BSSH Autumn Scientific Meeting, 12-14^th October 2022, Winchester, UK
8. PEMCAT Trauma: further refinements of the PEM for a hand trauma population. JCR Wormald, R Kamran, J Rodrigues, N Gape, T Dobbs, R Trickett, C Harrison. BSSH Autumn Scientific Meeting, 12-14^th October 2022, Winchester, UK
9. Surgical site infection following surgery for hand trauma: a systematic review and meta-analysis. JCR Wormald, A Shaw, A Baldwin, H Nadama, J Rodrigues, J Cook, D Prieto-Alhambra, M Costa. Stoke Mandeville Symposium – Ganga Prize Competition, 14^th December 2021 (Virtual)
10. Epidemiology of acute flexor tendon injury and an analysis of severe adverse outcomes – a study of 101,559 patients in England and Wales. JCR Wormald, J Lane, M Ng, J Mawhinney, D Furniss. BSSH Autumn Scientific Meeting, 9-10^th September 2021, Oxford, UK
11. Surgical site infection following surgery for hand trauma: a systematic review and meta-analysis. JCR Wormald, A Shaw, A Baldwin, H Nadama, J Rodrigues, J Cook, D Prieto-Alhambra, M Costa. BSSH Autumn Scientific Meeting, 9-10^th September 2021, Oxford, UK

Please list publications based on work performed in this study

1. Zhang C, Yusuf SM, Farag S, Wade RG, Wormald JC. Protocol for a systematic review and network meta-analysis of the use of prophylactic antibiotics in hand trauma surgery. Systematic Reviews. 2024 Jun 14;13(1):157.
2. Shafi SQ, Yoshimura R, Harrison CJ, Wade RG, Shaw AV, Totty JP, Rodrigues JN, Gardiner MD, Wormald JCR. Hand and Wrist trauma: Antimicrobials and Infection Audit of Clinical Practice (HAWAII ACP) protocol. Bone Jt Open. 2024 Apr 24;5(4):361-366.
3. Wormald JCR, Rodrigues J, Bheekharry R, Riley N, Tucker S, Furniss D, Dunlop R, Jones R, Applebe D, Herbert K, Prieto-Alhambra D, Cook J, Costa ML. The Hand and Wrist: AntImicrobials and Infection (HAWAII) trial. Br J Surg. 2023 Nov 9;110(12):1774-1784.
4. Wormald JC, Baldwin AJ, Nadama H, Shaw A, Wade RG, Prieto-Alhambra D, Cook JA, Rodrigues JN, Costa ML. Surgical site infection following surgery for hand trauma: a systematic review and meta-analysis. J Hand Surg Eur Vol. 2023 Nov;48(10):998-1005.
5. Wormald JCR, Rodrigues JN, Cook JA, Prieto-Alhambra D, Costa ML, HAWAII Collaborative. Hand and Wrist Trauma: Antimicrobials and Infection (HAWAII) a protocol for a multicentre, feasibility study of antimicrobial sutures in hand and wrist trauma surgery. Bone & Joint Open. 2022 Jul 1;3(7):529-35
6. Wormald JCR, Claireaux HA, Baldwin AJ, Chan JK-K, Rodrigues JN, Cook JA, Prieto-Alhambra D, Clarke MJ, Costa ML. Antimicrobial sutures for the prevention of surgical site infection. Cochrane Database of Systematic Reviews 2022, Issue 6. Art. No.: CD014719. DOI: 10.1002/14651858.CD014719. Accessed 07 July 2022.
7. Baldwin AJ, Jackowski A, Jamal A, Vaz J, Rodrigues JN, Tyler M, Murray A, Wormald JCR. Risk of surgical site infection in hand trauma, and the impact of the SARS-CoV-2 pandemic: A cohort study. J Plast Reconstr Aesthet Surg. 2021 Nov;74(11):3080-3086.

Please state what additional research this study has/is leading to

• This research has lead to a successful grant application (NIHR RfPB) to run a multi-centre RCT of buried vs exposed K-wires in hand and distal radius fractures, opening November 2025
• Three meta-analyses/network meta-analyses follow on from this work, evaluating antimicrobial interventions for SSI risk reduction

Please list any further funding or grant applications (with outcome), which have resulted from the award of this grant

• NIHR RfPB 2024

How has this grant awards helped your career development?

• This grant was essential in allowing me to undertake my DPhil. It has resulted in further personal and project grants that have secured my career as a future clinical academic hand and plastic surgeon.

Grant Holder: Karishma Shah

Position: DPhil Candidate, NDORMS, University of Oxford

Date of award

21/12/2017

Start date for research

1/8/2018

Date of report

9/11/24

Grant Awarded (i.e. £10,000)

£50,000

Is this an interim, or final, report

Final

Lay Summary of the project 

Hand osteoarthritis is a complex disease, most commonly affecting women. This PhD project aimed to identify risk factors for hand (particularly finger) osteoarthritis developing and worsening.

In the development of finger osteoarthritis, older age in women, female sex, family history, and injury were considered to be important risk factors. The development of the disease could be predicted by older age, manual occupation, and thumb osteoarthritis.

Whilst for the progression of disease, older age and family history were considered to be important risk factors, with disease progression found to be predicted by female sex.

Injury is also often considered to be a risk factor for osteoarthritis in larger joints. To assess this risk in the hands, almost 10,000 cricketers with hand injuries were studied. Results showed that hand injury was associated with osteoarthritis.

Summary of project/progress /findings

Background

Radiographic osteoarthritis most commonly affects joints in the hands, with osteoarthritis at the finger interphalangeal joints (IPJs) thought to be a different subset to that at the first carpometacarpal joint (CMCJ). The thesis aimed to identify risk factors for hand (particularly IPJ) osteoarthritis.

Methods

Systematic reviews and Delphi studies were performed to identify risk and prognostic factors for incident and progressive IPJ osteoarthritis.

A risk prediction model for incident radiographic IPJ osteoarthritis (Kellgren Lawrence (KL) ≥2 in ≥1 IPJ), and a prognostic model for the progression of IPJ osteoarthritis (increase of KL ≥1 in ≥1 IPJ), in the Chingford 1000 Women Study were developed. As the prognostic model performance was poor, the model was revised in the Johnston County Osteoarthritis (JoCo) Project.

The burden of hand injury requiring hospital admission, and the association between hand injury and osteoarthritis was investigated in cricketers.

Results

From the systematic review and Delphi study for incident IPJ osteoarthritis, older age in women, female sex, family history, and injury were important risk factors. Whilst for the progression of IPJ osteoarthritis, older age and family history were important prognostic factors.

The prediction model included 459 participants (257 with osteoarthritis at 10 years). Older age, manual occupation, and first CMCJ osteoarthritis were important predictors.

The prognostic model included 195 participants (181 progressing at 10 years), with no prognostic factors found to be important. Following revision, female sex was found to be an important factor.

Over ten years, 9,188 cricketers presented with hand injuries, most commonly in young adults, with thumb and little finger injuries, particularly fractures and dislocations. Hand injury was associated with osteoarthritis.

What is the relevance/value of this research to hand surgery:

This research aimed to develop a better understand of risk factors for development of, and prognostic factors for progression of, hand IPJ osteoarthritis.

The results from this research suggests that overall women are both more likely to develop radiographic interphalangeal joint (IPJ) osteoarthritis, and more likely to have progressive disease, compared to men. As the research suggests that female sex is an important risk factor for radiographic IPJ osteoarthritis progression, it would be important to consider targeting women in the first instance for preventative strategies.

This research also investigated hand injury patterns and its role in osteoarthritis development. The results indicate that clinicians can expect that cricketers who require hospital treatment are most likely to be young adults with fractures. These injuries are likely to necessitate admission for further management, though these inpatient stays are likely to be for <2 days, suggesting they can be appropriately managed in day-case or ambulatory settings. The prevalence of chronic pain in former cricketers was higher than that observed in the general UK population, highlighting hand osteoarthritis may be causing this high prevalence of pain which is reported in other research studies.

If final report, please provide bullet point list of conclusions/important findings

• Hand osteoarthritis is more likely to develop in women than men
• In people with hand osteoarthritis, the disease is more likely to progress in women than men
• People with 1^st CMCJ osteoarthritis are at higher risk of progressive IPJ osteoarthritis
• Manual occupation is also a risk factor for the development of IPJ osteoarthritis, though the mechanisms are still unclear
• Hand fractures from sports such as cricket are likely to require short hospital admissions for acute management
• Hand fractures from sports such as cricket result in higher levels of chronic pain than in the general population

Please list presentations based on work performed in this study

ORAL PRESENTATIONS

Shah K, Arden NK, Silman AJ, Furniss D, Collins GS. Development and Validation of a Prediction Model for Incident Radiographic Finger Interphalangeal Joint Osteoarthritis. Osteoarthritis Research Society International (OARSI) Virtual World Congress. 2021; Denver, Colorado (virtual).

Shah K, Arden NK, Silman AJ, Collins GS, Furniss D. Development of Risk Calculators for Hand Osteoarthritis and Invasive Treatment. Surgical Research Society Virtual Meeting. 2021; Dublin, Ireland (virtual).

Shah K, Yang X, Cai H, Lane JCE, van Santen J, Collins GS, Filbay SR, Arden NK, Furniss D. Risk factors for the Development and the Progression of Finger Interphalangeal Joint Osteoarthritis: Systematic Reviews and Delphi Studies. British Society for Surgery of the Hand (BSSH) Autumn 2019 Scientific Meeting. 2019; Dublin, Ireland.

Shah K, Furniss D, Collins GS, Peirce N, Arden NK, Filbay SR. The odds of Hand Pain and Osteoarthritis in individuals with cricket-related hand injury. Osteoarthritis Research Society International (OARSI) World Congress. 2019; Toronto, Canada.

POSTER PRESENTATIONS

Shah K, Bullock GS, Silman AJ, Furniss D, Arden NK, Collins GS. Calculating Risk of Hand Osteoarthritis Progression at Ten years through a Prediction Model. Annual European Congress of Rheumatology European Alliance of Associations for Rheumatology (EULAR). 2021; Paris, France (virtual).

Shah K, Furniss D, Perera NK. Epidemiology of hospital treated cricket-related hand injuries over a 5-year period in Victoria, Australia. International Olympic Committee (IOC) World Conference on Prevention of Injury and Illness in Sport. 2021; Monte Carlo, Monaco (postponed).

Shah K, Cai H, Lane JCE, Collins GS, Arden NK, Furniss D, Filbay SR. Risk factors for the incidence of hand interphalangeal joint osteoarthritis- A systematic review. Osteoarthritis Research Society International (OARSI) World Congress. 2020; Vienna, Austria (cancelled).

Shah K, Yang X, Lane JCE, Collins GS, Arden NK, Furniss D, Filbay SR. A systematic review of risk factors and diagnostic methods for hand interphalangeal joint osteoarthritis progression. Osteoarthritis Research Society International (OARSI) World Congress. 2020; Vienna, Austria (cancelled).

Shah K, Furniss D, Peirce N, Arden NK, Filbay SR. Is hand dominance and a history of hand injury associated with a higher prevalence of hand pain and osteoarthritis in cricketers? 14^th International Federation on Societies for Surgery of the Hand (IFSSH) Triennial Congress. 2019; Berlin, Germany.

Please list publications based on work performed in this study

Shah K, Cai H, Lane JCE, Collins GS, Arden NK, Furniss D, Filbay SR. Prognostic factors for finger interphalangeal joint osteoarthritis: A systematic review. Rheumatology (Oxford). 2021;60(3):1080-1090.

Shah K, Furniss D, Collins GS, Peirce N, Arden NK, Filbay SR. Cricket related hand injury is associated with increased odds of hand pain and osteoarthritis. Sci Rep. 2020;10(1).

Shah K, Yang X, Lane JCE, Collins GS, Arden NK, Furniss, D, Filbay SR. Risk factors for the progression of finger interphalangeal joint osteoarthritis: A systematic review. Rheumatol Int. 2020;40(11):1781-1792.

Shah K, van Santen J, Furniss D. Delphi consensus of risk factors for development and progression of finger interphalangeal joint osteoarthritis. J Hand Surg Eur Vol. 2019;44(10):1089-1090.

Please state what additional research this study has/is leading to

• The epidemiological research technique used in this study were important in multi-discplinary research. In particular, I was a co-author on a book chapter on ‘longitudinal study designs’ in Interventional Radiology: Shah K, Qamhawi Z, Makris G.C. Longitudinal study designs. In: Translational Interventional Radiology. Elsevier Inc. 2023. https://www.sciencedirect.com/book/9780128230268/translational-interventional-radiology

• This study also led to further research in Hand Osteoarthritis assessing hand pain symptoms: Perera RS, Gulati M, Shah K, Hart DJ, Spector TD, Arden NK, Radojcic M. No evidence of leptin mediating the effect of body mass index on hand pain and its duration in the Chingford 1000 Women Study. Arthritis Rheumatol. 2022 Aug. 74 (8). https://pubmed.ncbi.nlm.nih.gov/35347876/ 

Please list any further funding or grant applications (with outcome), which have resulted from the award of this grant

Successful grant applications:

• Medical Science Divisional Scholarship at the University of Oxford and the Oxford Biomedical Research Centre
• Warr-Goodman Scholarship from Lady Margaret Hall, University of Oxford

Successful honorary research fellowship applications:

• Honorary Research Fellowship at the Royal College of Surgeons of England

How has this grant awards helped your career development?

• I was able to complete my DPhil at the University of Oxford. This grant was fundamental in allowing me to undertake the DPhil and to complete it.
• This grant also funded my attendance at the ‘Introductory course in Epidemiology and Medical statistics’ at the London School of Hygiene and Tropical Medicine. This course allowed me to gain a deeper understanding of the fundamental methodology used to complete the studies in a robust manner.
• This grant also enabled me to better understand the landscape of clinical hand surgery and develop my network in the field. I went on to complete Core Surgical Training, following completion of my DPhil.

Project title: Single cell analysis of the fibrotic landscape in Dupuytren’s disease

Grant Holder: Thomas B Layton

Position: Academic Clinical Fellow, NIHR, Otolaryngology, Nottingham.

Date of award

01/06/2018

Start date for research

01/06/2018

Date of report

4/12/2024

Grant Awarded (i.e. £10,000)

£21,500

Is this an interim, or final, report

Final

Lay Summary of the project 

Dupuytren’s disease is a fibrotic or scarring condition, caused by the development of scar tissue in the palm. For this project, we obtained Dupuytren’s disease tissue and applied an advanced gene profiling technology called single cell sequencing.  cell atlas of the condition. Applying this technique to Dupuytren’s disease we were able to describe

two new cell types, never reported in this condition. Moving forward, our project will benefit patients by opening several strong avenues for future research.

Summary of project/progress /findings 

Dupuytren’s disease is a fibrotic or scarring condition, caused by the development of scar tissue in the palm. Over time, this scar tissue often contracts and can lead to severe deformities of the fingers. Dupuytren’s disease remains a common condition, effecting up to 10% of the population in the UK, but despite this no treatment is available to halt disease progression. A major barrier to identification of novel targets and successful clinical translation is a poor understanding of microenvironment in this condition. Given this, the major goal of this project was to improve our understanding of the cells that make up Dupuytren’s disease.

For this project, we obtained Dupuytren’s disease tissue and applied an advanced gene profiling technology called single cell sequencing. This method allows us to isolate single cells from the diseased tissue, obtain a readout of the entire set of genes expressed in each cell, and build a single cell atlas of the condition. Applying this technique to Dupuytren’s disease we were able to describe two new cell types, never reported in this condition. Subsequently, we have validated our findings based on gene profiling with several experiments and demonstrated that these new cell types were functionally distinct.

Our single cell atlas of Dupuytren’s disease provides important insights into the cells contained within this condition. Moving forward, our project will benefit patients by opening several strong avenues for future research. The two cell types we have discovered are defined by several key molecules and these represent exciting potential therapeutic targets. In future, targeting these molecules may help identify a medical treatment to reduce the need for surgery, which at present many Dupuytren’s disease patients still require.

What is the relevance/value of this research to hand surgery:

Define new disease biomarkers and novel therapeutic targets in Dupuytren’s disease.

If final report, please provide bullet point list of conclusions/important findings

• Built single cell atlas of Dupuytren’s disease
• Identified cellular source of TNF in DD and mechanism of action
• Elucidated novel cell types in DD
• Demonstrated CD82 marks DD myofibroblasts and acts to regulate cell cycle
• Defined functionally distinct spatial niches in DD.

Please list presentations based on work performed in this study

Keystone Conference Inflammation, Injury and Fibrosis (Utah, USA) 2017: Poster and oral presentation Localised inhibition of histone acetylation may offer a novel therapeutic strategy to down regulate the myofibroblast phenotype in Dupuytren’s disease (Immunology)

Celgene Symposium (Oxford) 2019: Oral Presentation; Identifying novel therapeutic targets in fibrosis using Dupuytren’s disease as a model (Immunology)

Celgene Symposium (Oxford) 2017: Oral Presentation; Identifying novel therapeutic targets in fibrosis using Dupuytren’s disease as a model (Immunology)

Celgene Symposium (Oxford) 2018: Oral Presentation; Identifying novel therapeutic targets in fibrosis using Dupuytren’s disease as a model (Immunology)

BAPRAS Summer Meeting (London) 2018: Oral presentation. Single cell analysis of the fibrotic landscape in Dupuytren’s Disease.

BSSH Winter meeting (London) 2018; Oral Presentation. Single cell analysis of the fibrotic landscape in Dupuytren’s Disease.

Please list publications based on work performed in this study

Layton TB, Williams L, Yang N, Zhang M, Lee C, Feldmann M, Trujillo G, Furniss D, Nanchahal J. A vasculature niche orchestrates stromal cell phenotype through PDGF signaling: Importance in human fibrotic disease. Proc Natl Acad Sci U S A. 2022 Mar 29;119(13).

Layton T, Thomas R, Harris C, Holmes S, Fraser L, Silva P, Winter SC. Functional Outcomes

Following Total Laryngectomy and Pharyngolaryngectomy: A 20-Year Single Center Study. Ann Otol Rhinol Laryngol. 2022 Jan 26.

Layton T, Thomas R, Harris C, Holmes S, Fraser L, Silva P, Winter SC. Functional Outcomes

Following Total Laryngectomy and Pharyngolaryngectomy: A 20-Year Single Center Study. Ann Otol Rhinol Laryngol. 2022 Jan 26.

Layton T, Thomas R, Harris C, Holmes S, Fraser L, Silva P, Winter SC. Clinical outcomes following pharyngolaryngectomy reconstruction: a 20-year single centre study. J Laryngol Otol. 2022 Jan 10:1- 18

Williams L, Layton T, Yang N, Feldmann M, Nanchahal J. Collagen VI as a driver and disease biomarker in human fibrosis. FEBS J. 2021 Jun 9.

Kendal AR, Layton T, Al-Mossawi H, Appleton L, Dakin S, Brown R, Loizou C, Rogers M, Sharp R,

Carr A. Multi-omic single cell analysis resolves novel stromal cell populations in healthy and diseased human tendon. Sci Rep. 2020 Sep 3;10(1):13939.

Williams LM, McCann FE, Cabrita MA, Layton T, Cribbs A, Knezevic B, Fang H, Knight J, Zhang M, Fischer R, Bonham S, Steenbeek LM, Yang N, Sood M, Bainbridge C, Warwick D, Harry L, Davidson D, Xie W, Sundstrӧm M, Feldmann M, Nanchahal J. Identifying collagen VI as a target of fibrotic diseases regulated by CREBBP/EP300. Proc Natl Acad Sci U S A. 2020 Aug 25;117(34):20753- 20763.

Layton, T.B., Williams, L., McCann, F. et al (2020). Cellular census of human fibrosis defines functionally distinct stromal cell types and states. Nat Communications 11, 2768.

Izadi, D* &amp; Layton T*, et al. (2019). Identification of TNFR2 and IL-33 as therapeutic targets in localized fibrosis. Science Advances 5(12): *first authors.

Layton T and O’Leary D (2019) Incorporating art into practice. Clinical teacher.

Layton T and Nanchahal J (2019). Recent advances in the understanding of Dupuytren’s disease. F1000Research. 8(F1000 Faculty Rev):231

Please state what additional research this study has/is leading to

• Role and functional of distinct fibroblast subsets in Dupuytren’s disease.

Please list any further funding or grant applications (with outcome), which have resulted from the award of this grant

• Academic clinical fellowship NIHR ENT
• Oxford-Celgene Fellowship
• RCS One Year fellowship
• Oxford-BMS postdoctoral fellowship
• Hunterian Professorship
• Visiting Professorship

How has this grant awards helped your career development?

• Provide foundation in basic science research during DPhil.
• Helped secure ACF and Hunterian Professorship.

Grant Holder:

1. Kavit Amin

2. Prof Jason Wong

3. Prof James Fidles

Position (at time of award):

EPSRC/MRC PhD student in Regenerative Medicine, University of Manchester

Date of award

1^st January 2017

Date of report

15^th December 2017

Grant Awarded (i.e. £10,000)

£50,000

Is this an interim, or final, report

Final

Lay Summary of the project 

Patients who have an injury, infection or surgery to the hand, experience pain and swelling. Inflammation of the hand progresses to stiffness. This usually resolves with good hand physiotherapy, however in many the stiffness persists. There are gliding layers in the hand, under the skin, that are “sponge-like” and scar after injury. How this occurs is not fully understood. Our study aims to identify the cells and signals that promote scarring of this tissue to find treatments that can be given immediately after injury or before surgery to reduce stiffening of the hand, restoring function and quicker return to work.

Summary of progress /findings

We were able to develop a large animal model limb perfusion model. This required serial experiments using scientific analyses to develop a platform suitable to study the early processes involved in fibrosis. The mechanisms leading to fibrosis are underpinned by the interaction, presence and movement of immune cells and their messengers after inflammation and injury occurs.

Over 50 porcine experiments using cardiopulmonary bypass equipment were performed and the immunological changes observed to characterise the immune cells released into the blood stream after revascularisation. The initial experiments at the time of the grant award could keep limbs viable for less than an hour and at the time of the end of this award we could achieve over 6 hours.

The first study flushed limbs to assess which immune cells are present within the tissues compared with the blood circulation (using flow cytometry) and to identify which cytokines and chemokines are released when wounding occurs. We identified large populations of viable leucocytes in the flush effluent (8.65 × 10⁸ ± 3.10 × 10⁸ cells at 2 h and 1.02 × 10⁹ ± 2.63 × 10⁸ at 6 h). This comprised T cells, B cells, NK cells and monocytes. Post-preservation flush yielded significant concentrations of pro-inflammatory cytokines including IL-6, IL-18, GM-CSF, IL-1β, IL1α and CXCL-8 and mitochondrial DNA. The regulatory cytokine, IL-10 was undetectable.

A follow-on study using a physiological platform looked at the temporal kinetics of these immune mediators. Flow cytometry revealed increasing populations of viable leukocytes over time, reaching 49 billion leukocytes by 6 h. T (3.0 × 10⁹ cells) and B cells (3.1 × 10⁸ cells) lymphocytes, monocytes (2.7 × 10⁹ cells), granulocytes (8.1 × 10⁹ cells), NK (6.3 × 10⁸) and γδ (8.1 × 10⁸) cells were all identified. Regulatory T cells comprised a minor population (1.6 × 10⁷ cells). There was a cumulative increase in pro-inflammatory cytokines suggesting an inflammatory response that could contribute to leucocyte activation and diapedesis and later fibrosis.

What is the relevance/value of this research to hand surgery

Understanding scar tissue formation (adhesions) within the hand is vital to avoid reoperation with adhesiolysis and to develop future strategies and novel therapies at the time of surgery to overcome this problem, that most hand surgeons will have come across in routine practice.

If final report, please provide bullet point list of conclusions/important findings

• Our research supports the finding that there is a significant inflammatory burden after injury and how these changes with time within the circulation over an acute period of time.

• The mediators responsible for during the initial inflammatory period largely include T cells but importantly macrophages and monocytes with mass cytokine release. These macrophages are known to induce fibrosis.

• Importantly, the model that was developed using normothermic machine perfusion has clinical implications for further study into how to mitigate the initial inflammatory response and target immunomodulation.

Please list presentations based on work performed in this study

Oral Presentation

Poster

Please list publications based on work performed in this study

• Amin, KR., Stone, J. Kerr, J. Wong J and Fildes JE  2021. Normothermic ex vivo perfusion of the limb allograft depletes donor leukocytes prior to transplantation. J Plast Reconstr Aesthet Surg. 2021

• Amin KR, Ball AL, Chhina C, Edge RJ, Stone JP, Critchley WR, et al. Ex-vivo flush of the limb allograft reduces inflammatory burden prior to transplantation. J Plast Reconstr Aesthet Surg. 2017.

Please state what additional research this study has/is leading to:

• With this award, we were able to contribute to the literature further by now extending our viability using the platform at normothermia for 24 hours.

• This research is now being used to explore bionic interface technologies so that we can understand how to deliver and record biological signals between a peripheral nerve and bionic prostheses after amputation. 

Please list any further funding or grant applications (with outcome), which have resulted from the award of this grant

How has this grant awards helped your career development?

Receiving the BSSH research grant was pivotal for my career given it was the first grant I had ever been awarded. This grant provided the resources to delve into fibrosis, a key issue that affects hand function after injury or surgery. It gave me the chance to contribute to the development of models that could improve treatment outcomes for patients with hand-related conditions​ and explore other avenues relevant to cutting edge hand surgery, including transplantation and the emerging role of bionic technologies.

The BSSH grant also allowed me to present my findings at various scientific meetings, raising my profile in the field. One of the highlights was being awarded the FESSH Research Award in 2019 for my research on limb perfusion protocols for composite tissue transplantation, which was a continuation of the work I started with BSSH's support​.

Ultimately, the BSSH grant was more than just financial support; it was a gateway to recognition and opportunities in the field of plastic and reconstructive surgery.

Grant Holder: Prof Abhilash Jain

Position: Associate Professor Plastic and Hand Surgery

Date of award

2013

Start date for research

2014

Date of report

2024

Grant Awarded (i.e. £10,000)

£27,207

Is this an interim, or final, report

Final

Lay Summary of the project

Nail bed injuries are the commonest hand injury in children. During surgery, the nail is removed and the cut stitched up. The nail can either be put back on or thrown away. Some doctors think that the replaced nail prevents infection; others think that it may cause them. We undertook a randomised controlled trial and compared the two treatments on cosmetic appearance, occurrence of  infection, pain, and healthcare use. We recruited 451 patients from 20 NHS hospitals.

The number of infections and cosmetic appearance were similar in both groups. However, replacing the nail increased costs and was unlikely to be cost-effective.

Summary of project/progress /findings

Objective - to assess the clinical and cost effectiveness of paediatric nail bed repair with fingernail replacement compared to repair without fingernail replacement.

Design - 2-arm parallel group open multicentre superiority randomised controlled trial.

Setting - 20 secondary care hospitals in the United Kingdom.

Participants - 451 children aged below 18 years presenting with a suspected nail bed injury between July 2018 to July 2019, 224 patients allocated to the nail discarded arm, and 227 to the nail replaced arm.

Interventions – participants randomized to either nail bed repair and replacement of fingernail or nail bed repair and fingernail discarded.

Main outcome measures - the co-primary outcomes were surgical site infection at around 7 days following surgery and cosmetic appearance summary score at a minimum of 4 months.

Results – no difference in surgical site infection at around 7 days or cosmetic appearance. The mean total healthcare cost over the four months following surgery was £75 lower for the nail discarded arm than the nail replaced arm (95% confidence interval £30, £124; p<0.001).

Conclusions – Following nail bed repair, discarding the fingernail does not change infection rates or cosmesis, but is less costly

What is the relevance/value of this research to hand surgery:

Provides evidence to stop the practice of replacing the nail following nail bed surgery

If final report, please provide bullet point list of conclusions/important findings

• No difference in infection or cosmetic appearance with either replacing the nail or not following nail bed repair.
• Less costly to discard the nail following repair of nail bed

Please list presentations based on work performed in this study

• C Cooper, J Cook, A Grieg, M Gardiner, R Pinder, A.Jain, D Beard. Patient and public involvement into the design of a Paediatric surgical trial: The NINJA study. 38th Annual Meeting of the Society for Clinical Trials / 4^th International Clinical Trials Methodology Conference. May 7 - 10, 2017 Liverpool, United Kingdom.

Please list publications based on work performed in this study

Abhilash Jain^1 2, Aina V H Greig ³, Amy Jones ¹, Cushla Cooper ¹, Loretta Davies ¹, Akiko Greshon ¹, Heidi Fletcher ¹, Adam Sierakowski ⁴, Melina Dritsaki ¹, Thi Thu An Nguyen ¹, May Ee Png ¹, Jamie R Stokes ⁵, Helen Dakin ⁶, Jonathan A Cook ¹, David J Beard ¹, Matthew D Gardiner ^1 7; NINJA Collaborative .Effectiveness of nail bed repair in children with or without replacing the fingernail: NINJA multicentre randomized clinical trial. Br J Surg. 2023 Mar 30;110(4):432-438. (impact factor 8.6)

A Jain, J Stokes, MD Gardiner, A Jones, J Cook, D Beard, C Cooper, A Sierakowski, B Shirkey, S Dupré , RZ Adami, B Baker, M Fleet, D Miles, R Nicholas, A Nicola, A Plonczak, A Sleiwah, G Williams, AVH Greig. The Oxford Finger Nail Appearance Score - a new scoring system for finger nail deformity. JPRAS 2021 Jan;74(1):94-100.

J Stokes, M E Png, A Jain, A V H Greig, B A Shirkey, M Dritsaki, J A Cook. Nail bed INJury Analysis (NINJA): statistical and health economic analysis plan for a randomised controlled trial investigating if the nail plate should be replaced or discarded after nail bed repair in children. Trials. 2020 Oct 7;21(1):833.

A Jain, A Jones, MD Gardiner, C Cooper, A Sierakowski, M Dritsaki, ME Png, J Stokes, B Shirkey, J Cook, D Beard, A Greig. The NINJA Trial - should the nail plate be replaced or discarded after nail bed repair in children? Protocol for a multi-centre randomised control trial. BMJ Open 2019 Dec 4;9(12):e031552.

Greig, M.D. Gardiner, A. Sierakowski, C. Zweifel, R. Pinder, D. Furniss, J.A. Cook, D. Beard, N. Farrar, C.D. Cooper, A. Jain. Feasibility study to inform a randomized clinical trial of replacing or discarding the nail plate after nail bed repair in children. Br J Surg. 2017 Nov;104(12):1634-1639 (impact factor 5.899)

Please state what additional research this study has/is leading to

NINJA represents a definitive RCT that has provided evidence to support discarding the nail following nail bed repair in children. This trial has demonstrated that large scale trials in paediatric hand trauma are feasible and acceptable to NHS surgeons and patients. Demographic data we have collected during this trial have confirmed that this surgery is common and represents a significant burden on NHS resource and theatre time with the majority of operations performed under general anaesthetic (90%). The range of trauma suggests that the commonest injuries to the nail bed are simple (62%) or stellate (8%) lacerations with overall low infection rates and excellent cosmetic outcomes. There is data to suggest that children may not require formal surgery to explore and repair the nail bed and in our study 2% of children were found not to have had a nail bed injury at the time of surgery suggesting that they underwent an unnecessary operation. Further work should investigate whether surgery is indeed beneficial and results in better outcome than simple dressings. A large scale RCT funded by the NIHR HTA program would be reasonable to answer this question. The benefit to patients and healthcare system are significant in terms of outcome and cost.

Please list any further funding or grant applications (with outcome), which have resulted from the award of this grant

NIHR Research for Patient Benefit (RfPB) Programme: PB-PG-1215-20041

Nail bed Injury Analysis Trial. Chief Investigator

(November 2016)                                                                                £348,637

How has this grant awards helped your career development?

• YES

A feasibility randomised controlled trial of open carpal tunnel release versus steroid injection for moderate carpal tunnel syndrome

Grant Holder: Will Mason

Position: Consultant Orthopaedic Surgeon, Gloucestershire Royal Hospitals NHS Foundation Trust

Date of award

2012

Start date for research

16^th November 2015

Date of report

5^th September 2024

Grant Awarded (i.e. £10,000)

£50,000

Is this an interim, or final, report

Final

Lay Summary of the project

We designed a large trial to investigate the best way to treat patients with carpal tunnel syndrome (a common problem of a trapped nerve at the wrist). We planned to compare two treatments – surgical release of the nerve or anti-inflammatory injection of steroid.

This smaller study of 40 patients aimed to investigate whether it was possible to recruit patients for the larger study. We tried recruiting from different places – GP practices and departments of surgery and neurology. Unfortunately, we found that it was too difficult to recruit participants to effectively conduct the larger study.

Summary of project/progress /findings

The Chief Investigator (WM) developed the research project in collaboration with the Oxford Clinical Trials Research Unit. Prior to a full trial, it was agreed to perform a feasibility trial of 40 patients to assess the ability to recruit participants. Gloucestershire Hospital sponsored the trial. Participants were prospectively identified from three UK NHS trusts (two surgical units and one neurophysiology unit) and 15 GP practices. Recruitment took place between November 2015 and August 2016.

Eligible patients had a clinical diagnosis of typical CTS with symptoms for more than 3 months, had troublesome symptoms, had not been treated by steroid injection and had no signs of severe neuropathy.

853 patients were screened for inclusion; 244 met the inclusion criteria. 40 eligible patients (32 from secondary care, 8 from primary) were successfully recruited

and randomized.

40 patients were recruited over a 10-month period from 2 of the sites. 2 sites were aborted, as the CCG would not fund surgery.

The proportion of eligible patients recruited to the trial was 21% (18/85) in the neurophysiology department. In the orthopaedic department it was 54% (14/26) when patients were identified in secondary care and 32% (8/25) when identified in primary care.

The average rate of compliance with follow up questionnaires was 89% at 1month, 89% at 3months, 61% at 6months, and 74% at 12months

This feasibility trial has demonstrated that recruitment of this patient population in current care pathways is difficult and sufficiently problematic as to prohibit the design in a larger RCT at the present time.

What is the relevance/value of this research to hand surgery:

There is no consensus on how moderate CTS should be either defined or treated. The critical question is whether injection should be tried before surgery.

A lack of robust evidence to answer this question has resulted in inconsistent policies by

Clinical Commissioning Groups (CCGs) in the National Health Service and varying clinical practice, leaving patients and their care providers with difficulty in choosing the most appropriate treatment.

If final report, please provide bullet point list of conclusions/important findings

• This feasibility trial demonstrated that recruitment of this patient population in current care pathways was sufficiently problematic to prohibit the design of a larger randomized controlled trial.
• Challenges for recruitment included
  1. a paucity of patients in secondary care who had not previously received a steroid injection
  2. the refusal of some CCGs to fund surgery in the trial for patients with moderate CTS who have tried night splints.
• Recruitment from primary care was possible but required more resources to facilitate it.
• Patient identification and recruitment by specialist carpal tunnel treatment centres in primary care is the most likely alternative method.
• Any future larger trial to answer this important clinical question will require a modified approach.

Please list presentations based on work performed in this study

1. Kerr H, Khan A, Mason W. Audit on the treatment of patients with carpal tunnel syndrome prior to tertiary referral and those eligible for the INDICATE (Injection or Decompression Carpal Tunnel) Trial. Southwest Orthopaedic Club 2015

2. Lim D, Ryan D, Mason W. Management of moderate carpal tunnel syndrome: what is your practice? A preliminary survey. BSSH Spring Scientific Meeting, Bath 2015

3. Ryan D, Shaw A, Graham S, Mason W Variation in CCG policies for the treatment of carpal tunnel syndrome. BSSH Autumn Scientific Meeting, London 2016

4. Jones A, Dorman R, Vadher K, Beard, D, Cook J, Cooper C, Mason W. Feasibility Study of a Randomised Clinical Trial of Injection or Decompression for Carpal Tunnel Syndrome (INDICATE) Jones A, Dorman R, Vadher K, Beard, D, Cook J, Cooper C, Mason W. Mr Will Mason, BSSH Autumn Meeting 2017.

Please list publications based on work performed in this study

1. Mason W, Ryan D, Khan A et al. Injection versus decompression for carpal tunnel syndrome—pilot trial (INDICATE-P)—protocol for a randomised feasibility study. Pilot Feasibility Stud. 2017, 3: 20.
2. Ryan D, Shaw A, Graham S, Mason W. Variation in CCG policies for the treatment of carpal tunnel syndrome. Bulletin Royal College of Surgeons of England. Vol 99 Issue 1, Jan 2017, pp. 28-31 https://doi.org/10.1308/rcsbull.2017.28

Please state what additional research this study has/is leading to

Unfortunately none, as yet

Please list any further funding or grant applications (with outcome), which have resulted from the award of this grant

None

How has this grant awards helped your career development?

It has given me experience in the field of research