NIHRDataInsights/HRCSData huggingface dataset:
Title: Bilateral organisation in the spinal cord.
Funder: Medical Research Council

Abstract: Multiple structures contribute to the bilateral control of arm movements. The spinal cord has substantial bilateral connectivity, both in terms of descending corticospinal and reticulospinal projections, but also in terms of intrinsic commissural interneurones within the spinal cord itself. The impact of this connectivity, particularly during bilateral movements is not clear. In macaque monkeys I will record the responses of muscles bilaterally to stimulation of corticospinal and reticulospinal systems during a bilateral "reach to grasp and pull" task. Movements will be with either or both hands together and for bilateral trials the two levers will be linked together. The responses in proximal and distal muscles from the stimulation of corticospinal and reticular formation will be used to assess how these two descending tracts can affect spinal excitability bilaterally and if this effect depends if one or both hands are used. Similar protocols will be applied to stimulation of sensory afferents (through implanted nerve cuffs) on one arm to assess effects in the other arm during movement, and how these vary with the bilateral movement context. Recordings of spinal interneuronal (and pre-motoneuronal) activity in the same monkeys will be made to asses cell activity during this task, and how they respond to bilateral descending and sensory stimulation. This will show how bilateral descending and afferent inputs co-localise on the same spinal neural populations and how the inputs a cell receives can determine its response pattern. Human experiments will also be performed to assess 1) crossed effects in distal hand muscles but also 2) if distal sensory information can affect more proximal muscles (forearm and elbow) in the opposite hand.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MUSCULOSKELETAL;NEUROLOGICAL
Title: Supporting Activity Engagement in People with Huntington’s Disease: A Phase II Evaluation” (Acronym ENGAGE-HD)
Funder: Division for Social Care and Health Research (Wales)

Abstract: This study aimed to evaluate muscle weakness due to a range of central and peripheral mechanisms in a range of neurological disorders and the related functional impact thereof. Specific focus was on evaluating methods to assess community mobility and factors that were influential on participation. This was one of the first studies to highlight the importance of evaluating the impact of interventions in neurological disorders using direct community based measures rather than instantaneous hospital based assessments. Outputs included 6 publications in peer reviewed journals and numerous published abstracts from conference proceedings. The measurement of mobility and investigation of community activity levels has continued to be an important methodology in my post-doctoral work. It was also at this time that my attention became focussed on the importance of physical activity and exercise, and how specifically limited people with neurological conditions are in their daily physical activity. Furthermore, I became interested in the barriers to participation in physical activity and the ways in which changing physical activity behaviours could be achieved.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL;NEUROLOGICAL
Title: Post-operative pain in children with cerebral palsy following major hip surgery: a double blind randomised placebo controlled trial of pre-operative Botulinum toxin type A.
Funder: Department of Health (England)

Abstract: Background Botulinum toxin injected intramuscularly is beneficial in the management of spasticity and as a treatment for chronic hip pain in children with cerebral palsy. Botulinum injections also seem to be useful in reducing spasticity in the acute post operative period; the benefits of botulinum toxin have been described in one study for post-operative pain following minor hip surgery. After major (bony) hip surgery these children experience significantly more pain, which also seems to be exacerbated by spasticity. Botulinum toxin may therefore reduce pain following major hip surgery. Research is required to assess its value in this setting. This cannot be studied in adults as they rarely undergo such surgery. Aims To assess the benefit to children with cerebral palsy of having botulinum toxin injections prior to major hip surgery, in order to reduce their post-operative pain.To describe the pain experience of children with cerebral palsy undergoing major hip surgery. Plan of Investigation Recruitment will begin as soon as funding is available and all staff are in post. We expect at least 2 patients per month for 32 months. Database entry will continue throughout. An interim analysis will be carried out after ten patients have been recruited to each group. Recruitment will cease at month 32, the final analysis will require 2 months. Results will be presented and submitted for publication. Potential Impact The impact of improving post-operative pain management in this vulnerable group of children is potentially enormous, and the effects are likely to be much greater than the simple numerical measures of pain employed in the study. If botulinum toxin is effective in reducing post-operative pain in these children it could become a standard treatment prior to bony hip surgery. If it is not effective, children will benefit from a reduction in the ad hoc or impirical use of this treatment, and the NHS will benefit from a reduction in the uneccessary use of this drug for this purpose. The results of this study are likely to benefit approximately 20 patients a year in our institution alone.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL;NEUROLOGICAL
Title: Improving the clinical management of carpal tunnel syndrome
Funder: Department of Health (England)

Abstract: Carpal tunnel syndrome is characterised by pain, tingling, numbness and weakness of the hands which can be treated conservatively and surgically. However, it is not possible at present to predict which patients respond to treatment. This study will identify the factors which best predict a successful outcome from corticosteroid injection and surgery and to estimate the cost of CTS to patients and society.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING;6.7 PHYSICAL
Health categories: MUSCULOSKELETAL;NEUROLOGICAL
Title: Topical lidocaine for neuropathic pain and fibromyalgia
Funder: Department of Health (England)

Abstract: Topical analgesics such as lidocaine are designed to provide local analgesic effects with minimal systemic drug concentrations and minimal consequent adverse events. This differs from transdermal drug delivery where the aim is to produce drug concentrations in blood similar to those achieved by systemic or oral delivery over a long time period. The prospect of good analgesia with minimal adverse events is particularly important in an ageing population with multiple comorbidities because oral drugs (NSAIDs for example) are often contra-indicated. NICE guidance on osteoarthritis now makes topical NSAIDs a first-line treatment suggestion.Chronic painful conditions (moderate or severe pain for six months or more) affect 1 adult in 5. Healthcare use is increased almost three-fold with chronic pain and functioning and work are impaired. Effective therapy reduces healthcare use and restores function and work. We propose to complete this review to inform an overview of Cochrane reviews on topical analgesia (=100 RCTs =14500 patients) providing a convenient single source of good evidence of efficacy and harm of topical analgesics in acute and chronic pain to inform guidelines and improve decision-making. Since topical analgesics are available without prescription there is also a consumer interest here.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL;NEUROLOGICAL
Title: King's College London Medical Engineering Centre.
Funder: Wellcome Trust

Abstract: The King's College London Medical Engineering Centre aims to deliver word-class excellence in Engineering, Physics, Mathematics, Computer Science and Chemistry by breaking down the barriers between these and Biology and Medicine. It will also facilitate closer partnership between the University and industry. Focusing on the important area of medical imaging the aim is also to do clinical trials to show the benefit of the new discoveries and technology that the centre will produce in helping patients. The proposal has a number of key general initiatives including, a Masters programme with related degrees for all the different basic science specialties outlined above, co-funding initial studies between researchers and industry and collaboration with research groups around the world. The main part of the proposal is six specific scientific programmes that bring together strong basic science with medical researchers working in the same area in a hospital setting. The programs are: 1- Key-hole robotic surgery to treat heart rhythm problems without using X-rays; 2- Computer simulation to help improve MRI of the heart in patients with suspected angina; 3- Building specialist combined MRI and PET scanner and the special dyes needed to accurately predict heart attack and stroke; 4- Using special imaging agents to better diagnose and treat cancer; 5- Rebuilding faces after cancer surgery with artificial tissuesand 6- New imaging tools for improved diagnosis and better treatment of psychiatric illness.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: MUSCULOSKELETAL;NEUROLOGICAL;CANCER AND NEOPLASMS;CARDIOVASCULAR
Title: Pressure and Touch-Evoked Pain in Arthritis
Funder: Arthritis Research UK

Abstract: Pain associated with rheumatoid arthritis (RA) and osteoarthritis (OA) remains a major problem despite current treatments. It is characteristically evoked by mechanical pressure. We will focus on the mechanosensitive sensory neurons that elicit such pain. Our programme will address the following questions;_x000D_ _x000D_ 1) Which mechanosensitive ion channels are involved in pain in animal models of arthritis?_x000D_ _x000D_ 2) Can we provide evidence that the same mechanisms occur in humans?_x000D_ _x000D_ 3) How are the properties of these channels regulated to alter sensitivity to mechanical activation?_x000D_ _x000D_ 4) Can we manipulate the expression or the properties of these channels to block mechanically-evoked pain in animal models of arthritis?_x000D_ _x000D_ 5) Can we devise in vitro screens that may be useful for developing specific analgesic agents that are useful for treating the pain associated with arthritis?_x000D_ _x000D_ We suggest that focussing on the primary transduction mechanisms that are involved in mechanosensation may provide a specific approach to treating arthritis–associated pain distinct from, and potentially synergising with, present anti-inflammatory and analgesic approaches. The field of mechanotransduction has been transformed over the past 2 years by the discovery of new classes of mechanotransducers, enabling us to exploit these advances to explore new approaches to treating pain in arthritis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL;NEUROLOGICAL;INFLAMMATORY AND IMMUNE SYSTEM
Title: A CELL ATLAS OF THE DEVELOPING HUMAN SENSORY NERVOUS SYSTEM: INVESTIGATING DEVELOPMENT TO UNDERSTAND DISEASE
Funder: Medical Research Council

Abstract: I aim to test the hypothesis that the process of neo-innervation of the adult osteoarthritic joint by pain-associated nerve afferents recapitulates transcriptional profiles that are active in the developing human fetal sensory nervous system, with a view to obtain mechanistic insight, and identify potential therapeutic targets for pain. First, I will create the first human cell atlas (HCA) of the developing sensory nervous system. Secondly, I will identify the transcriptional profiles of adult osteoarthritic joint cartilage that is innervated by pathogenic nociceptive afferents (absent in the osteochondral junction in health). Finally, I will compare the transcriptional profiles in these states to test our hypothesis, and additionally prioritise potential treatment targets. Single-cell RNA sequencing(scRNAseq) will be applied to human dorsal root ganglia samples between the fetal ages of 6 to 20 weeks, with 1-2 sample(s) each gestational week. To create a spatial atlas, single-nuclei RNAseq and Visium RNAseq (10X genomics) will be applied to sequential slices of the same tissue sample at ages of 6-7 weeks and 18 weeks. In adult osteoarthritis tissue, multiplex in situ hybridization will be used to identify regions of interest by neuronal markers followed by the use of Nanostring GeoMx for targeted sequencing. Finally, computational integration will be applied to reveal reciprocal matches in cell states between development and disease. Potential treatment targets will be tested in further projects through in vitro and in vivo experiments. The study will create the first HCA of the developing nervous system and transcriptional profiles of disease, the findings will provide new insights into normal human development as well as disease, with therapeutic implications. The developmental dataset can also be studied to understand nerve regeneration in adulthood, with implications in regenerative medicine, and in generating in vitro models of sensory nerves.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: MUSCULOSKELETAL;NEUROLOGICAL;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Osteoporosis in coeliac disease associated with novel autoantibodies
Funder: CORE

Abstract: Osteoporosis, or thinning of the bones, is a common complication of coeliac disease, though it is often difficult to predict which patients will develop the condition. We looked after a patient with coeliac disease who developed very severe osteoporosis due to a protein in the blood that caused rapid bone breakdown. This patient did not respond to changing diet and calcium supplements but needed a powerful inhibitor of bone turnover. We have developed a test for this protein and found levels to be raised in some patients attending routine coeliac clinics. We aim to recruit over 600 patients with coeliac disease in whom we will gather detailed information about risk factors for osteoporosis. We wish to establish whether elevated levels of this protein can help identify coeliac patients with an increased risk of severe osteoporosis. If this research is successful it could form the basis of a simple blood test to identify those patients with coeliac disease who require additional investigation and/or more active treatment for osteoporosis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL;ORAL AND GASTROINTESTINAL
Title: Molecular signatures of endocannabinoid induced pain relief in humans: lifestyle interventions, systemic and localised changes.
Funder: Medical Research Council

Abstract: Modulation of endocannabinoids (ECB) in animal models has strong antinociceptive properties and use of cannabis appears effective in reducing neuropathic pain symptoms in humans. However, the pleiotropic effects of ECB receptors and the various feedback loops in the system make the prediction of undesirable central and peripheral effects of such compounds challenging, hindering the deployment of ECB targeting compounds to market. Endocannabinoid tone can also be modulated non-pharmacologically. Both physical exercise and alteration of the gut microbiome via dietary supplementation modify the endocannabinoid tone. Strong clinical evidence that exercise interventions are effective in achieving clinically meaningful musculoskeletal pain relief. Observational and interventional evidence suggest that the gut microbiome is involved in pain intensity, progression and sensitivity for various types of pain. We hypothesize (based on solid preliminary data) that the mechanisms by which these non-pharmacological interventions relieve pain are mostly mediated by modulation of the endocannabinoid system resulting in meaningful anti-inflammatory and antinociceptive effects Using a factorial design of exercise and microbiome modulation of short chain fatty acids. We will perform extensive molecular phenotyping and characterisation of pain responses to these interventions and apply artificial intelligence/machine learning algorithms as we have done for other complex molecular traits. This will allow us to identify the key molecular mediators involved in effective responses to lifestyle interventions. We will validate the pathways involved using independent cohorts such as TwinsUK, StepUp OA, IBEAT-OA with existing data on pain sensitivity and molecular markers. Finally we will assess the direct relevance of ECs in the joint by assessing levels of ECs in synovial fluid from severe knee OA patients and their change with exercise/ gut microbiome modulating interventions


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL;ORAL AND GASTROINTESTINAL
Title: Unlocking cortisol activation in muscle as a treatable cause of muscle wasting in kidney failure
Funder: Medical Research Council

Abstract: Patients with renal failure suffer reduced functional status, low quality of life and higher morbidity due to muscle wasting. Uraemia and acidosis disturb metabolism in skeletal muscle, leading to insulin resistance and protein loss. This process requires glucocorticoids (GC) as a critical co-factor. My new data show that GC signals are amplified within skeletal muscle by the 11bHSD1 enzyme in uraemic conditions. I aim to clarify how intramuscular GC activation by 11bHSD1 contributes to insulin resistance and muscle atrophy in renal failure, and test 11bHSD1 inhibition as a novel therapy in pre-clinical models. I will use primary healthy human muscle cell cultures stimulated with uraemic serum or acidosis to model renal failure in vitro. In this system, I will determine the role of 11bHSD1 activity for insulin resistance and protein degradation using biomolecular and functional metabolic assays. I will correlate findings from the in vitro model with experiments on muscle biopsies from patients with kidney failure. Using uraemic human muscle ex vivo and derived primary cultures, I will test the capacity to reverse metabolic defects through 11bHSD1 inhibition. To test therapeutic viability of 11bHSD1 inhibition in vivo, I will study mice with uraemia and 11bHSD1 deletion systemically or in muscle. Metabolic and muscular phenotype will be assessed by in vivo muscle strength, muscle weight, histology, GC metabolism analysis and biomolecular assays. Opportunities are: - Unravel mechanisms whereby GC contribute to muscle dysfunction, leading to transferrable insights for other diseases and new prevention strategies - Pioneer primary muscle culture to study uraemic muscle complications - Unlock 11bHSD1 inhibition as a potential treatment for muscle wasting in CKD and other chronic illnesses, helping patients to remain independent and healthier - Refine commercial value and medical application of 11bHSD1 inhibiting pharmaceuticals in development


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL;RENAL AND UROGENITAL
Title: Evaluating Acupuncture and Standard care for pregnant women with Back pain (EASE Back): a feasibility study and pilot randomised trial
Funder: Department of Health (England)

Abstract: Background: Back pain affects more than two-thirds of women during pregnancy interfering with their everyday activities work and sleep. Current treatment of this condition is limited and variable. Acupuncture is a promising intervention for pregnancy-related back pain. It has been recommended within recent UK national guidelines for persistent non-specific low back pain but only limited although promising evidence currently exists that’s supports its usefulness for pregnancy-related back pain. A large high quality trial is now needed to test the clinical and cost-effectiveness of acupuncture for pregnancy-related back pain. Aims: This is a feasibility and pilot study that aims to ensure that the trial recruitment processes interventions and outcomes are acceptable to pregnant women with back pain and to key health care professionals and to inform the sample size for a future main trial. Methods: This is a mixed methods study over 24 months involving two phases. Phase 1 comprises a national survey of physiotherapists to explore their current management of pregnant women with back pain and focus group and one-to-one interviews with pregnant women midwives and physiotherapists to explore their views about the proposed pilot trial design and treatments the information that patients will need about the pilot trial and outcome measures. Phase 2 is a pilot trial with 180 pregnant women with back pain identified from community and antenatal clinics in North Staffordshire. Participants will be randomly allocated to receive usual care or usual care plus one of two different types of acupuncture.Results: Outcomes will be assessed at baseline and approximately 12 weeks after randomisation (to be finalised following the interviews). Clinical outcome measures including pain disability and work loss will be sought in addition to process outcomes including recruitment and retention rates attendance at treatment sessions and whether treatment was provided per protocol.


Research activity codes: 6.8 COMPLEMENTARY
Health categories: MUSCULOSKELETAL;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Developmental and endocrine regulation of mitochondrial function in fetal skeletal muscle.
Funder: Wellcome Trust

Abstract: Little is known about the normal developmental and endocrine regulation of mitochondria in skeletal muscle before term despite their essential role in meeting the increased postnatal energy requirements. Skeletal muscle is a major site of glucose uptake and skeletal muscle mitochondrial dysfunction arising before birth may increase risk of metabolic abnormalities in adulthoodas altered muscle structure and mitochondrial function have been observed in diabetic patients, as well as in adults growth-restricted in utero. This project aims to determine the developmental changes in mitochondrial function that occur in ovine fetal skeletal muscle during late gestation and the extentto which they depend on the normal maturational increases in cortisol and triiodothyronine (T3) concentrations. Mitochondrial respiratory activity and oxidative stress will be assessed in skeletal muscles of sheep fetuses during late gestation after cortisol infusion and fetal thyroidectomy and compared toappropriate controls. Our hypothesis is that mitochondrial function will change in a hormone-dependent manner towards term. An increased understanding


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MUSCULOSKELETAL;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: The feasibility and predictive value of monitoring exercise capacity in patients recovering from critical illness in Intensive Care.
Funder: Department of Health (England)

Abstract: Is it possible to identify critically ill patients who would gain long-term benefit from an exercise program whilst in ICU?Studies:1) Ensuring a new measuring tool is usable with ICU patients.2) Identifying methods to measure patients’ exercise capacity, which are accurate and acceptable to patients.3) Verifying measured exercise capacity can predict long-term prognosis.4) Pilot study testing whether exercise regimes in ICU have long-term benefits for patients.This should finally enable identification of patients who would benefit from exercise. A springboard to prove exercise in ICU reduces long-term incapacity and impact on family, healthcare and society.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;6.7 PHYSICAL
Health categories: MUSCULOSKELETAL;RESPIRATORY